Pathophysiology and Pharmacological Treatment of Insulin Resistance* ¨ RING

0163-769X/00/$03.00/0
Endocrine Reviews 21(6): 585– 618
Copyright © 2000 by The Endocrine Society
Printed in U.S.A.
Pathophysiology and Pharmacological Treatment
of Insulin Resistance*
STEPHAN MATTHAEI, MICHAEL STUMVOLL, MONIKA KELLERER,
¨ RING
HANS-ULRICH HA
AND
Department of Internal Medicine IV (Endocrinology, Metabolism, Angiology, Pathobiochemistry and
Clinical Chemistry), University of Tu¨bingen, D-72076 Tu¨bingen, Germany
ABSTRACT
Diabetes mellitus type 2 is a world-wide growing health problem
affecting more than 150 million people at the beginning of the new
millennium. It is believed that this number will double in the next 25
yr. The pathophysiological hallmarks of type 2 diabetes mellitus consist of insulin resistance, pancreatic ␤-cell dysfunction, and increased
endogenous glucose production. To reduce the marked increase of
cardiovascular mortality of type 2 diabetic subjects, optimal treatment aims at normalization of body weight, glycemia, blood pressure,
and lipidemia. This review focuses on the pathophysiology and molecular pathogenesis of insulin resistance and on the capability of
antihyperglycemic pharmacological agents to treat insulin resistance,
i.e., ␣-glucosidase inhibitors, biguanides, thiazolidinediones, sulfonylureas, and insulin. Finally, a rational treatment approach is proposed based on the dynamic pathophysiological abnormalities of this
highly heterogeneous and progressive disease. (Endocrine Reviews
21: 585– 618, 2000)
I. Introduction
II. Pathophysiology and Pathogenesis of Insulin Resistance
A. Introduction
B. Multiple sites of insulin resistance: muscle, liver, and
adipose tissue
C. Pathogenesis of insulin resistance
D. Inactivity-related insulin resistance
E. Molecular events in obesity-related insulin resistance
III. Pharmacological Treatment
A. ␣-Glucosidase Inhibitors
B. Biguanides
C. Thiazolidinediones
D. Insulinotropic agents
E. Insulin
IV. Perspectives
A. Agents to enhance insulin action
B. Agents to increase insulin secretion
C. Agents to inhibit fatty acid oxidation
V. Summary and Conclusion
sulin resistance and decreased pancreatic ␤-cell function
caused by both genetic and acquired abnormalities (1–7).
Currently, type 2 diabetes mellitus is diagnosed when the
underlying metabolic abnormalities consisting of insulin resistance and decreased ␤-cell function cause elevation of
plasma glucose above 126 mg/dl (7 mmol/liter) in the fasting state and/or above 200 mg/dl (11.1 mmol/liter) 120 min
after a 75-g glucose load (8). However, the fact that many
newly diagnosed type 2 diabetic subjects already suffer from
so called “late complications of diabetes” at the time of diagnosis (9) indicates that the diagnosis may have been delayed and, in addition, that the prediabetic condition is harmful to human health and requires increased awareness by
physicians and the general public. Thus, type 2 diabetes
mellitus represents only the “tip of the iceberg” (Fig. 1) of
long existing metabolic disturbances with deleterious effects
on the vascular system, tissues, and organs. Consequently,
urgent efforts are required to avoid the growing number of
patients with this form of a “silently killing” metabolic disease.
Until the importance of screening for, as well as treating,
the early stage of the metabolic syndrome is appreciated by
health insurance companies and physicians, the optimal
treatment of patients with type 2 diabetes mellitus to avoid
diabetic complications and to preserve quality of life is a
major focus in today’s medical world. Although nonpharmacological treatment modalities such as reduced caloric
intake and increased physical activity represent the basis of
the treatment of insulin resistance and their efficacy have
been demonstrated in numerous studies and summarized in
recent reviews (10, 11), the actual number of patients sufficiently treated without pharmacological agents is comparatively low. The United Kingdom Prospective Diabetes Study
(UKPDS) has recently demonstrated that nonpharmacological treatment is sufficient only in 25% of patients with a 3-yr
I. Introduction
D
IABETES mellitus type 2 represents the final stage of a
chronic and progressive syndrome representing a heterogeneous disorder caused by various combinations of inAddress reprint requests to: Hans-Ulrich Ha¨ring, M.D., Department
of Internal Medicine IV, University of Tu¨bingen, Otfried-Mu¨ller-Strasse
10, D-72076 Tu¨bingen, Germany. E-mail: [email protected]
uni-tuebingen.de
* The work of the authors has been supported by the German Research Foundation (DFG), the European Community (Biomed-Program), the intramural fortu¨ne-program of the University of Tu¨bingen,
Aventis (Germany), Bayer Corp. (Germany), NovoNordisk (Denmark),
Merck (Germany), Sankyo Co., Ltd. (Japan), and SmithKline Beecham
(United Kingdom).
585
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MATTHAEI ET AL.
Vol. 21, No. 6
FIG. 1. Diabetes mellitus type 2: the tip of the iceberg. This simplified schematic presentation illustrates the evolution of type 2 diabetes
mellitus. Diabetes mellitus type 2 represents the end stage of long lasting metabolic disturbances caused by insulin resistance associated with
hyperinsulinemia, obesity, dyslipoproteinemia, arterial hypertension, and consequently premature atherosclerosis. Since this detrimental
metabolic milieu is present for many years before plasma glucose levels (as our diagnostic indicator) are elevated, it is not surprising that type
2 diabetic patients have already micro- and/or macrovascular complications at the time of the initial diagnosis. Subjects in stage I have normal
glucose tolerance due to the ability of their ␤-cells to compensate for the insulin-resistant state. At this stage elevated triglyceride levels and
reduced HDL levels as well as an increased waist to hip ratio may indicate insulin resistance and should lead to therapeutic action. In stage
II, glucose tolerance after an oral glucose load (75 g) is impaired due to developing insulin-secretory deficiency. To avoid progression to clinically
overt type 2 diabetes (stage III), these IGT subjects must receive treatment options to reduce insulin resistance, such as dietary advice and
increase of physical activity. The stage model of the pathophysiology of type 2 diabetes has been adapted from Beck-Nielsen and Groop (9).
duration of diabetes (time after diagnosis). With advancing
duration of the disease, which is associated with progressive
deterioration in ␤-cell function (12), this number fell to less
than 10% after 9 yr (13). Thus, these data implicate that
pharmacological treatment is required in the vast majority of
type 2 diabetic patients.
After an introduction into the pathophysiology and molecular pathogenesis of insulin resistance, this review will
focus on the mechanism of insulin action and the capability
of the available antihyperglycemic pharmacological agents
to treat insulin resistance. In the conclusion a rational treatment approach, based on the dynamic pathophysiological
abnormalities of the disease, is proposed. The importance of
optimal treatment of other abnormalities often associated
with type 2 diabetes, i.e., obesity, hypertension, dyslipidemia, disturbances in the fibrinolytic system, becomes evident
when the pathophysiology of the type 2 diabetic syndrome
is examined closely (see Fig. 1). These essential aspects in the
medical care of type 2 diabetic patients have been recently
reviewed (14 –20) and thus will not be covered in this review.
II. Pathophysiology and Pathogenesis of
Insulin Resistance
A. Introduction
Clinically overt type 2 diabetes is characterized by ␤-cell
dysfunction and insulin resistance in all major target tissues,
such as skeletal muscle, liver, kidney, and adipose tissue.
Various studies have been performed in genetically predisposed individuals to elucidate whether insulin resistance or
␤-cell dysfunction represents the primary defect in the pathogenesis of type 2 diabetes (reviewed in Ref. 1). These studies
provided evidence that both insulin resistance and ␤-cell
dysfunction are prevalent in offspring of type 2 diabetic
subjects. Although ␤-cell dysfunction and insulin resistance
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December, 2000
TREATMENT OF INSULIN RESISTANCE
are well accepted as pathogenetic factors of type 2 diabetes,
there is still controversy whether these defects have a primary genetic origin or occur secondarily due to other factors.
This debate has been recently summarized in the reviews by
Gerich (1) and Ferrannini (4). There is also an ongoing discussion on which target tissue is mainly affected by insulin
resistance (reviewed in Refs. 2 and 21). Therefore, the contribution of the different target tissues to insulin resistance
will be discussed in the following section.
B. Multiple sites of insulin resistance: muscle, liver, and
adipose tissue
The term “insulin resistance” in humans is frequently used
synonymously with impaired insulin-stimulated glucose
disposal (3, 22, 23) as measured with the hyperinsulinemiceuglycemic clamp technique (24). Consequently, basic research in the area of insulin resistance as a fundamental
component of the pathogenesis of type 2 diabetes has focused
on tissues responsible for insulin-mediated glucose uptake,
namely muscle and, to a minor degree, adipose tissue (5).
However, it is well known that not only muscle glucose
uptake but also adipose tissue lipolysis and suppression of
glucose production are regulated by insulin.
1. The euglycemic-hyperinsulinemic clamp for the assessment of
insulin resistance in vivo. It is unquestioned that in conditions
commonly associated with the term “insulin resistance,”
such as obesity or type 2 diabetes, peripheral glucose disposal, as measured by a hyperinsulinemic-euglycemic
clamp, is lower for the level of hyperinsulinemia achieved
compared with healthy subjects. However, it is important to
point out that, in people with type 2 diabetes, glucose uptake
by skeletal muscle, both in the fasting state and postprandially, although inefficient for prevailing insulin levels, is not
reduced in an absolute sense (25–27). In an attempt to identify “insulin resistance genes” underlying the disease (9, 28,
29), the hyperinsulinemic-euglycemic clamp has also been
used to determine insulin resistance in healthy subjects with
a first-degree family history of type 2 diabetes, who are of
normal weight and whose glucose tolerance is normal. The
classical hyperinsulinemic-euglycemic clamp, however,
generates insulin levels above those these subjects usually
experience and may therefore fail to reveal potential abnormalities of processes regulated by lower insulin concentrations. The manner in which insulin sensitivity is determined
during the hyperinsulinemic-euglycemic clamp (using MCR,
i.e., glucose infusion rate divided by plasma glucose at steady
state) is based upon the assumption [unless appropriate
tracer techniques are used (30)] that endogenous glucose
production [largely attributable to liver, less so to kidney
(31)] is completely shut off by the insulin infusion. This
implies, however, that suppression of glucose production is
regulated by much lower insulin concentrations than stimulation of glucose uptake. This should make the liver (and
kidney) a target for insulin resistance whose effects on glucose homeostasis would be at least as important as those of
muscle insulin resistance. In fact, excessive basal glucose
production in the presence of fasting hyperinsulinemia is a
key feature of type 2 diabetes (32–35). Moreover, defective
587
suppression of endogenous glucose production by normal or
elevated insulin levels has been observed in type 2 diabetes
(36, 37). Both observations demonstrate that insulin resistance of glucose production is involved in the pathogenesis
of type 2 diabetes.
2. Potential role of adipose tissue for insulin resistance. In addition
to muscle and liver, adipose tissue is the third metabolically
relevant site of insulin action. While insulin-stimulated
glucose disposal in adipose tissue is of little quantitative
importance compared with that in muscle, regulation of lipolysis with subsequent release of glycerol and FFA into the
circulation by insulin has major implications for glucose homeostasis. It is widely accepted that increased availability
and utilization of FFA contribute to the development of skeletal muscle insulin resistance (38 – 40). Moreover, FFA have
been shown to increase endogenous glucose production both
by stimulating key enzymes and by providing energy for
gluconeogenesis (41). Finally, the glycerol released during
triglyceride hydrolysis serves as a gluconeogenic substrate
(42). Consequently, resistance to the antilipolytic action of
insulin in adipose tissue resulting in excessive release of FFA
and glycerol would have deleterious effects on glucose
homeostasis.
3. Glucose uptake vs. glucose production: comparison of EC50s.
Only one study has examined the entire insulin dose response characteristics for stimulation of glucose uptake and
suppression of glucose production in normal and type 2
diabetic subjects (43). This study showed a significant right
shift of the dose-response curve for glucose uptake with an
EC50 for glucose uptake (58 ␮U/ml) more than double that
for glucose production (26 ␮U/ml). In another study also
using the stepwise hyperinsulinemic-euglycemic clamp, a
plateau for glucose uptake was not reached at the highest
insulin concentration. Thus, dose response characteristics
could only be approximated but appeared to range in the
same order (44). These findings clearly demonstrate that with
low physiological increments in plasma insulin, the liver is
the primary determinant of whole body glucose homeostasis.
In patients with type 2 diabetes the dose-response curves for
both glucose uptake and glucose production were markedly
shifted to the right (43, 44). The EC50 values for glucose
uptake (EC50, 118 ␮U/ml) and glucose production (EC50, 66
␮U/ml) in the patients with type 2 diabetes, however, were
increased similarly (⬃2-fold) compared with normal subjects. Similarly, in obesity a parallel right shift of the doseresponse curve for both glucose disposal and production was
found (45). Thus, the relative impairment in the sensitivity of
glucose uptake and suppression of glucose production was
not different, which suggests that both processes are equally
resistant to insulin in type 2 diabetes. At plasma insulin
concentrations below 50 ␮U/ml, however, impaired suppression of glucose production appears to contribute quantitatively more than defective glucose uptake to the abnormal
glucose homeostasis of type 2 diabetes.
4. Lipolysis is most sensitive to insulin. More data on whole
body lipolysis as determined by isotopic measurements of
glycerol appearance in plasma are available from stepwise
hyperinsulinemic-euglycemic clamps. The insulin EC50 val-
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588
MATTHAEI ET AL.
ues for suppression of lipolysis in normal subjects ranged
between 7 and 16 ␮U/ml (44, 46 – 49), placing the doseresponse curve of adipose tissue distinctly left of those for
glucose production and glucose uptake. From these studies
it becomes evident, that lipolysis is the process most sensitive
to the action of insulin with a greater than 90% effect well
within the physiological insulin range. In obese subjects and
patients with type 2 diabetes the EC50 values are increased
2- to 3-fold (44, 47, 49), indicating that adipose tissue lipolysis
is at least as resistant to the action of insulin as muscle and
liver. Since failure to adequately turn off lipolysis directly
affects liver (and kidney) and muscle metabolism while the
reverse does not hold true, it is tempting to speculate that
adipose tissue might even be a primary site for the defect
leading to insulin resistance elsewhere and, ultimately, to
type 2 diabetes.
To summarize, lipolysis is the most insulin-sensitive process followed by glucose production and, far behind, glucose
uptake with EC50 values in the physiological range only for
insulin-induced inhibition of lipolysis and glucose production, but not for insulin-stimulated glucose uptake. In fullblown diabetes mellitus, insulin sensitivity in muscle, liver
(and kidney), and adipose tissue is compromised to a similar
degree. While several studies unanimously showed defective
insulin action on glucose uptake and lipolysis in prediabetic
states [obesity, impaired glucose tolerance (IGT)], data for
suppression of glucose production are somewhat divergent.
During an oral glucose tolerance test, suppression of endogenous glucose production was significantly diminished in
IGT (50), whereas during a hyperinsulinemic-euglycemic
clamp, suppression was comparable between IGT and normal glucose-tolerant (NGT) (51).
C. Pathogenesis of insulin resistance
Insulin resistance, as determined by the euglycemichyperinsulinemic clamp technique, reflects defective insulin
action predominantly in skeletal muscle and liver. The major
causes of skeletal muscle insulin resistance in the prediabetic
state may be grouped into genetic background-related and as
obesity- and physical inactivity-related (Fig. 2). Despite intensive research efforts, there is, so far, no clear understand-
FIG. 2. Pathogenesis of skeletal muscle insulin resistance. Schematic
presentation of factors involved in the pathogenesis of skeletal muscle
insulin resistance in prediabetes and type 2 diabetes.
Vol. 21, No. 6
ing of the factors that define the genetic accessibility of insulin resistance. One approach to analysis of the genetic
background is to define candidate genes based on the present
knowledge of the insulin-signaling chain. We have recently
reviewed the present knowledge of the insulin-signaling
chain (52). Abnormalities in insulin signaling that may induce insulin resistance in type 2 diabetes will be discussed
in the following section.
1. The insulin-signaling chain: alterations found in insulin resistance and type 2 diabetes. Figure 3 shows a simplified draft of
the signaling steps from insulin receptor binding to glucose
transport activation. Insulin signaling at the cellular level is
mediated by binding of insulin to a specific receptor. Insulin
binding to the receptor stimulates autophosphorylation of
the intracellular region of the receptor ␤-subunit (53). A
reduced autoactivation status of the insulin receptor from
skeletal muscle and adipocytes of type 2 diabetic patients has
been described by several but not all investigators (54 – 62).
Some of these studies have shown that obesity was a major
contributory factor for the development of a reduced insulin
receptor activity (56, 63). This could suggest that the defective
insulin receptor kinase activity is secondarily acquired due
to obesity and metabolic changes such as hyperinsulinemia
and hyperglycemia.
a. Insulin receptor substrates. The first substrate of the insulin receptor was described by White et al. in 1985 (64).
Subsequently, this intracellular protein was cloned by Sun et
al. (65) and named insulin receptor substrate-1 (IRS-1). IRS-1
and other recently cloned IRS proteins (IRS-2, -3, -4) are
phosphorylated upon insulin stimulation and have adaptor
function between the insulin receptor and other cellular substrates such as the phosphatidylinositol 3-kinase (PI 3kinase) (65– 68). The contribution of IRS-1 and IRS-2 to insulin resistance and diabetes was recently tested by targeted
disruption of the respective gene in mice. IRS-1 knockout
mice were insulin resistant but not hyperglycemic (69). It has
been shown that the recently cloned IRS-2 was at least partially able to compensate for the lack of IRS-1, which could
explain the mild and nondiabetic phenotype of IRS-1 knockout mice (70). In the meantime, IRS-2 knockout mice have
also been generated. Although IRS-1 and IRS-2 are highly
homologous proteins and share many signaling properties,
the phenotype of IRS-2 knockout mice is markedly different
from that of IRS-1 knockout mice (71). IRS-2-deficient mice
are severely hyperglycemic due to abnormalities of peripheral insulin action and failure of ␤-cell secretion (71). This
phenotype with severe hyperglycemia as a consequence of
peripheral insulin resistance and insufficient insulin secretion due to a significantly reduced ␤-cell mass reveals many
similarities to type 2 diabetes in man and outlines the role of
IRS proteins for the development of cellular insulin resistance and ␤-cell function.
b. PI 3-kinase and protein kinase B (PKB). At the molecular
level, insulin causes activation of the insulin receptor and
phosphorylation of IRS proteins on tyrosine residues. Phosphorylation of IRS proteins creates binding sites for PI 3kinase and enables activation of PI 3-kinase. The activated PI
3-kinase converts PI 4- or PI 4,5-phosphate into PI 3,4- and
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December, 2000
TREATMENT OF INSULIN RESISTANCE
589
FIG. 3. Molecular mechanism of insulin-stimulated transport. The insulin-dependent glucose transporter 4 (GLUT4) is translocated by a
phosphatidylinositol 3-kinase (PI 3K)-dependent pathway including PKB/AKT and PKC stimulation downstream of PI3K [Reproduced with
permission from H. U. Ha¨ring: Exp Clin Endocrinol Diabetes 107[Suppl 2]:S17—S23, 1999 (7).] PI3,4,5P, Phosphatidylinositol 3,4,5-phosphate;
PDK, phosphatidylinositol (3,4,5)-phosphate-dependent kinase; IRS, insulin receptor substrate.
PI 3,4,5-phosphate (PIP3). PIP3 can bind PKB/AKT (for cellular homolog of the transforming oncogene v-akt) and phosphatidylinositol-3,4,5-phosphate-dependent kinase-1 (PDK-1)
by their PH (pleckstrin homologous) domains (72). Colocalization of PKB/AKT and PDK-1 at the plasma membrane
region enables phosphorylation of PKB/AKT on threonine308 by PDK-1. PKB/AKT regulates several protein kinase
cascades involved in insulin signal transduction to glucose
uptake, to glycolysis, to glycogen synthesis as well as to
protein synthesis (73). In addition to phosphorylation of
PKB/AKT, there is evidence that PDK-1 is also able to phosphorylate protein kinase C (PKC) isoforms (74, 75). Insulindependent activation of the atypical PKC␨ isoform has been
demonstrated recently (76). Recent evidence suggests that
PDK-1 mediates insulin-dependent activation of atypical
PKC␨ through phosphorylation on threonine410 in the activation loop (74, 75). In addition, insulin-dependent stimulation of atypical PKC␨ has been shown to mediate insulin
effects on protein synthesis (76). Moreover, there is evidence
that the atypical PKC isoforms ␨ and ␭ are involved in coupling of the insulin signal to the glucose transport system (77,
78). This demonstrates that insulin-stimulated glucose transport can be mediated via different signaling cascades. This
signaling diversity potentially opens compensatory mechanisms if gene mutations were to occur, for example, in PKB/
AKT or atypical PKCs.
Expression level and possible gene mutations of PI 3kinase and PKB in insulin-resistant and diabetic patients
have been investigated by a small number of studies. Decreased activation of PKB in skeletal muscle of type 2 diabetic
patients in spite of normal protein levels has been described
(79). However, these results are controversial since another
recently published study described normal PKB/AKT activation in skeletal muscle of type 2 diabetic patients (80). In
skeletal muscle of lean and obese type 2 diabetic patients,
decreased IRS-1 phosphorylation and PI 3-kinase activity as
well as a 50 – 60% reduction in the protein expression level of
IRS-1 and PI 3-kinase have been shown (81, 82). Thus, decreased expression and phosphorylation level of early insulin signaling elements (i.e., IRS, PI 3-kinase, and PKB) have
been demonstrated in insulin target tissues of type 2 diabetic
patients. This may contribute to insulin resistance in type 2
diabetic patients. However, it does not necessarily mean that
this represents a genetic defect since it is not clear to what
extent metabolic disturbances are able to induce the above
mentioned signaling defects.
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590
MATTHAEI ET AL.
2. Possible genes for insulin resistance and obesity. Substantial
evidence that type 2 diabetes is an inherited disease was
demonstrated by twin studies, familial clustering of type 2
diabetes, and the high prevalence of this disease in some
ethnic groups. Efforts to identify potential type 2 diabetes
and insulin resistance genes have been undertaken by screening of different candidate genes and genome scans.
a. Candidate gene studies for insulin resistance and type 2
diabetes.
1. Insulin receptor. In the candidate gene approach, several
genes have been screened for their potential role in the development of insulin resistance. A wide spectrum of insulin
effects is mediated by the insulin receptor and its substrates
IRS-1 and IRS-2 as well as the PI 3-kinase (reviewed in Ref.
5). Therefore, these genes have been tested for their potential
role in the pathogenesis of insulin resistance. It is now well
established that mutations of both insulin receptor alleles
occur in very rare cases and cause severe syndromes of
insulin resistance (e.g., leprechaunism, and Rabson-Mendenhall syndrome), which, in most patients, result in death during the first year (reviewed in Refs. 83 and 84). Other insulin
receptor mutations affecting only one allele are compatible
with life and cause severe insulin resistance syndromes
(called “type A insulin resistance”) often without developing
hyperglycemia during young adulthood. Since these early
reports have clearly demonstrated that insulin receptor mutations could induce insulin resistance, patients with common type 2 diabetes were also screened for the presence of
insulin receptor gene mutations. Thus far, several insulin
receptor mutations (Lys1068Glu, Arg1152Gln, and Val985
Met) have been identified in about 1–5% of patients with
common type 2 diabetes (85– 87). Only one population-based
study in the Netherlands could demonstrate a Val985 Met
mutation of the insulin receptor at a relatively high rate of
5.6% (87), which was not found in other population groups
(85). Functional characterization of the described insulin receptor mutations in type 2 diabetes revealed only mild degrees of insulin-signaling defects. However, overt diabetes
may develop in combination with other genetic defects. In
summary, insulin receptor mutations were not commonly
found in random type 2 diabetes, and only a small number
of individuals may have mutations that could contribute to
insulin resistance, probably in concert with other genetic
defects which are not yet identified.
2. IRS-1 and -2. Mutations of IRS-1 and IRS-2 have also
been described in humans. However, these mutations were
found with the same frequency in nondiabetic compared
with diabetic individuals (⬃12% for Gly972Arg mutation in
the IRS-1 gene and 33% for Gly1057Asp in the IRS-2 gene) (88,
89). Cell culture studies indicated that the mutation in codon
972 of IRS-1 impairs insulin-stimulated signaling (90).
Whether this mutation is correlated with insulin resistance in
vivo seems contradictory at present (88, 91, 92). It appears,
however, that Gly972Arg is associated with a slightly lower
insulin secretion rate (88, 91, 93), which has recently been
confirmed by in vitro studies (94) and which might also
contribute to the development of type 2 diabetes. In addition
to IRS-1, an amino acid polymorphism of the IRS-2 gene
causing replacement of glycine to aspartate at position 1,057
Vol. 21, No. 6
was found at a high frequency of 33% in an unselected
Scandinavian population. This amino acid exchange, however, was not associated with type 2 diabetes (89). Furthermore, genome screening of the IRS-2 locus has been performed in families with early-onset autosomal dominant
type 2 diabetes (95). The results of this study did not suggest
that the IRS-2 gene represents a major pathogenetic factor in
this highly selected group. In summary, mutations of the
IRS-1 and IRS-2 genes seem to occur at a relatively high rate
of 12–33% in nonobese healthy, as well as type 2 diabetic,
human subjects (88, 89). Although some data suggest impaired insulin action by these mutations, the high prevalence
in healthy subjects does not support a major role in the
development of type 2 diabetes in humans.
3. PI 3-kinase. Gene mutations in the PI 3-kinase gene have
also been studied. Screening for mutations in the PI 3-kinase
gene could be complicated by the existence of several isoforms of the PI 3-kinase regulatory and catalytic subunit
(reviewed in Ref. 96). In human skeletal muscle more than
four different regulatory subunit variants are expressed and
differently regulated by insulin (97). It has been shown that
a splice variant of approximately 50 kDa of the p85␣ regulatory subunit of PI 3-kinase is highly sensitive upon insulin
stimulation in human skeletal muscle (97). Although PI 3kinase activation seems crucial for insulin-dependent glucose uptake, mice lacking the p85␣ subunit of PI 3-kinase are
surprisingly more insulin sensitive and mildly hypoglycemic
(98). This has been explained by a switch from p85␣ to the
p50␣ subunit expression and activation which led to increased generation of phosphatidylinositol 3,4,5-phosphate
(98). These results demonstrate that interpretation of potential mutations in the regulatory subunit of PI 3-kinase is
difficult without the knowledge of total PI 3-kinase activity
and the functional status and expression level of other regulatory isoform subunits. Screening for PI 3-kinase mutations in human subjects has revealed a mutation at codon 326
replacing methionine by isoleucine in the regulatory subunit.
This mutation was found in a Scandinavian insulin-resistant
population at a frequency of approximately 30% in its heterozygous form and 2% in its homozygous form. The homozygous mutation was found to be associated with a significant reduction of insulin sensitivity (99). However, this
could not be found in Japanese type 2 diabetic patients (100).
Moreover, in Pima Indians, this mutation was not associated
with insulin resistance but rather with an increased acute
insulin response after a glucose challenge test (101). It has
been suggested by these investigators that the Met326Iso
mutation might even protect homozygous carriers in the
female Pima population against the development of type 2
diabetes. This may also agree with the data from p85␣ knockout mice, which are characterized by increased insulin sensitivity and hypoglycemia instead of developing diabetes
(98).
4. Other candidate genes. In addition to these early insulinsignaling elements, mutations of the liver glucokinase promoter, of GLUT4, glycogen synthase, and the protein phosphatase-1, among others, have also been identified, but these
mutations were not associated with insulin resistance or type
2 diabetes apart from a very few cases (reviewed in Ref. 102).
Although a large number of genes remain to be screened
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December, 2000
TREATMENT OF INSULIN RESISTANCE
for their potential role in insulin resistance, it can be concluded from present studies that heterozygous mutations in
insulin signaling molecules are often found with a high frequency in human subjects. In most cases these mutations are
not sufficient to cause insulin resistance or type 2 diabetes.
However, if these mutations are in rare cases homozygous or
occur together with mutations of other insulin-signaling proteins or obesity, this combination of different disturbances
might ultimately lead to insulin resistance and type 2 diabetes. This would also be in agreement with the postulated
polygenic pathogenesis of type 2 diabetes.
b. Genome scans for susceptibility genes for insulin resistance
and type 2 diabetes. While the candidate gene approach serves
to identify mutations of known genes, the method of genome
scanning in family cohorts or sib pairs could reveal previously undetected type 2 diabetes genes (103–119). This
method has identified new diabetes loci on different chromosomes, which are listed in Table 1 (103–115). The chromosomal loci are partially located in the vicinity of known
genes such as the hepatic nuclear factor 1␣ (HNF 1␣), the
sulfonylurea receptor, the apolipoprotein A-2, and others. To
date, most of the genome scan studies suggested that there
are different chromosomal linkage regions for type 2 diabetes
confirming the role of diabetes susceptibility genes. However, these gene loci are often restricted to a special trait and
ethnic group, which means that they are probably not a major
gene locus for the large group of common type 2 diabetic
patients. A more general impact for common type 2 diabetes
has recently been discussed for a gene locus on chromosome
20 near the hepatic nuclear factor 1 gene, but more studies are
needed to identify this gene and to evaluate its potential role
for the development of diabetes.
D. Inactivity-related insulin resistance
Obesity and lack of physical exercise are major contributory factors to insulin resistance. It has been demonstrated
that insulin sensitivity could be improved by exercise independently from weight reduction and changes in body composition. Most of these studies refer to the effect of exercise
on skeletal muscle. There is evidence that skeletal muscle
training leads to altered expression of insulin signaling elements, in particular glucose transporters (reviewed in Ref.
120). In insulin-resistant offspring of type 2 diabetic patients,
6 weeks of training caused increased glucose uptake and
591
glycogen synthesis, which led to improved insulin sensitivity
(121). In addition to the effect of physical exercise on glucose
transporter molecules, increased blood flow and availability
of insulin in target tissues may contribute to metabolic improvement during training (122). Another non-insulindependent effect by exercise is release of local bradykinin,
which has been shown to have stimulatory effects on glucose
uptake (123). In addition to the effects on skeletal muscle,
there is evidence that insulin resistance of liver can be improved as well. This has been demonstrated by a significant
reduction of hepatic glucose production after endurance
training (124). Moreover, insulin responsiveness toward glucose uptake can be enhanced in adipocytes after acute exercise (125). Thus, it is generally accepted that muscle, liver,
and fat contribute to the improvement of insulin sensitivity
induced by physical exercise.
E. Molecular events in obesity-related insulin resistance
The negative impact of increased body fat mass on insulin
sensitivity can be clearly shown for the vast majority of
individuals. Furthermore, the insulin-sensitizing effect of
weight reduction and physical training is well documented
(reviewed in Refs. 10 and 11).
1. The role of FFA in obesity-related insulin resistance. Among the
signaling molecules that are derived from adipocytes, FFA
have been implicated in the pathogenesis of insulin resistance (40, 126). FFA are generated via lipolysis mainly in fat
cells. In insulin resistant and obese subjects increased FFA
release into plasma can occur. Obesity-related insulin resistance leads to reduced antilipolytic effect of insulin (123).
Another mechanism by which obesity could contribute to
increased FFA production is overactivity of the sympathetic
nervous system, which has been demonstrated in obese human subjects and type 2 diabetic patients (127–129). FFA are
taken up by liver and skeletal muscle cells. They counteract
the effects of insulin by increasing hepatic gluconeogenesis
and by inhibiting glucose uptake and oxidation in skeletal
muscle (130 –132). This fatty acid-induced insulin resistance
in liver and skeletal muscle has been suggested to be a result
of increased acetyl-CoA production and inhibition of glucose
oxidation by FFA (130, 133). The concept of a glucose-fatty
acid cycle, which was originally described by Randle et al.
(130), has now been called into question by Wolfe (134).
While Randle et al. suggested that increased availability of
TABLE 1. Genome scan studies for susceptibility of insulin resistance and type 2-diabetes
Population group
Chromosomal location
Reference
Pima Indians
Pima Indians
Mexican Americans
Mexican Americans
Botnian Finnish
Utah Caucasians
North American Caucasians
North American Caucasians
French families
Pima Indians
Pima Indians
Utah Caucasians
Finnish families
4q
1p
2q
11p, 6
12q
11q
20q
20q
20q
3q, 4p, 9q, 22q
11q, 1q, 7q
1q
20q
Prochazka et al., 1993 (103)
Thompson et al., 1995 (104)
Hanis et al., 1996 (105)
Stern et al., 1996 (106)
Mahtani et al., 1996 (107)
Elbein et al., 1996 (108)
Ji et al., 1997 (109)
Bowden et al., 1997 (110)
Zouali et al., 1997 (111)
Pratley et al., 1998 (112)
Hanson et al., 1998 (113)
Elbein et al., 1999 (114)
Ghosh et al., 1999 (115)
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592
MATTHAEI ET AL.
FFA and fatty acid oxidation regulates glucose oxidation,
Wolfe has developed a vice versa concept in which the rate
of glycolysis rather than the availability of fatty acids regulates fatty acid oxidation. Evidence that glucose oxidation
could directly regulate fatty acid oxidation by inhibition of
fatty acid transport to the mitochondria was provided by this
group recently (134). Nevertheless, increased fatty acids can
regulate this process by reducing intracellular glucose availability through inhibition of glucose uptake. Therefore, the
initiating effect of fatty acids to induce insulin resistance
could be inhibition of glucose uptake, which would be followed by a decrease of intracellular glucose availability and
glucose oxidation. This would consequently lead to increased fatty acid oxidation according to the concept of
Wolfe.
2. The role of leptin in obesity-related insulin resistance. Leptin
has gained much attention recently in the study of the underlying mechanisms of insulin resistance in obesity. In 1994,
it was identified as an adipocyte-derived hormone in by
Friedman and colleagues (135). Leptin reduces body weight
via specific receptors in hypothalamic areas regulating energy expenditure and satiety (136 –138). Secretion of leptin
from fat cells is strongly dependent on body fat mass (reviewed in Ref. 138). Leptin deficiency and receptor defects in
rodents cause marked obesity as well as hyperinsulinemia
and hyperglycemia (139). Thus, many studies have focused
on the effects of leptin on insulin resistance and insulin
secretion. Both inhibition and stimulation of insulin action
have been shown by leptin in different cell systems (140 –
143). In addition, several groups have shown inhibitory effects of leptin on insulin secretion in isolated cell lines and
perfused pancreatic islets (128), while others have found that
leptin stimulates insulin secretion (144 –150). Therefore, the
conclusion that leptin causes a defect in the insulin-signaling
chain or that it is capable of improving ␤-cell dysfunction in
human subjects cannot yet be made on the basis of these
studies.
In human subjects congenital leptin deficiency or mutations of the leptin receptor occur in extremely rare cases.
These mutations have been associated with severe obesity
but not with diabetes (151–153). However, it must be considered that these few cases reported recently were of young
age, and it remains to be seen whether IGT or diabetes may
still develop with advancing age.
3. The role of tumor necrosis factor-␣ (TNF␣) in obesity-related
insulin resistance. A great number of studies have been performed in the last years to elucidate the role of TNF␣ for
obesity-related insulin resistance. Spiegelman and co-workers recently proposed that TNF␣ may contribute to insulin
resistance in obese subjects (reviewed in Ref. 154). Several
studies have shown that TNF␣ is able to impair insulin signaling through serine kinase and tyrosine phosphatasedependent modulation of the insulin-signaling chain (155–
157). However, these studies have been performed in isolated
cell systems, and to date there is no evidence that these
mechanisms are relevant in type 2 diabetic patients. While
the data from isolated cell systems and animal models provide a plausible molecular basis for TNF␣-induced insulin
Vol. 21, No. 6
resistance, clinical results from different insulin-resistant
populations so far do not support a major role of TNF␣ on
insulin resistance in humans (158, 159). However, one study
has shown increased adipose tissue expression of TNF␣ in
obese premenopausal women when compared with control
subjects (506).
4. The peroxisome proliferator-activated receptor-␥ (PPAR␥): potential role for insulin resistance and ␤-cell function. Thiazolidinediones are pharmacological compounds that reduce
insulin resistance both in prediabetic as well as diabetic individuals (see also Section III.C.). Thiazolidinediones are ligands of the PPAR␥2 (160). PPAR␥2 is predominantly expressed in adipocytes, intestine, and macrophages (161).
There is some evidence that a low level expression might also
occur in muscle cells. The PPAR␥ receptor is a transcription
factor that controls the expression of numerous genes. It is
assumed that the effect of thiazolidinediones on insulin sensitivity is mediated through altered expression of PPAR␥2dependent genes (reviewed in Refs. 162 and 163). Recently,
the Pro12Ala and two other polymorphisms were described
in the PPAR␥2 receptor (164). It appears that the Pro12Ala
polymorphism in its heterozygous form occurs in approximately 30% of humans. Auwerx and colleagues (165) have
shown that this polymorphism appears to be functionally
relevant, leading to a reduced transcriptional activity and
improved insulin sensitivity (165). In our studies, an obese
subgroup with a body mass index (BMI) ⬎35 kg/m2 carrying
this polymorphism in the heterozygous form appears to be
less insulin resistant compared with individuals without this
PPAR␥2 mutation (166). Although the total number of subjects studied is still very low, it might be speculated that this
polymorphism protects against the negative influences of
obesity on insulin sensitivity. Interestingly, we also found
differences in insulin secretion measured during an oral glucose tolerance test. Individuals carrying the polymorphism
showed lower insulin secretion at 60 and 120 min. The lower
secretion might be interpreted as a consequence of the increased insulin sensitivity of these individuals. Alternatively, it might be speculated that the PPAR␥2 polymorphism directly interferes with ␤-cell function. In agreement
with this, direct effects of PPAR␥ agonists on ␤-cells have
been demonstrated. Studies on isolated pancreatic islets and
on a hamster ␤-cell line have shown that thiazolidinediones
could enhance glucose- and glibenclamide-induced insulin
release (167). Although the underlying mechanism for this
direct effect on ␤-cells is not completely clear, it has been
suggested that thiazolidinediones stimulate insulin release
by increase of glucose uptake in the ␤-cell (167). In animal
studies, treatment with thiazolidinediones resulted in improvement of pancreatic islet cell integrity and hyperplasia
(168, 169). Moreover, it has been demonstrated that PPAR␥
activation reduces triglyceride content in islets of Zucker
diabetic fatty rats, leading to a significant increase in insulin
secretion (170). However, in humans only preliminary data
are available concerning a direct effect of PPAR␥ agonists on
pancreatic islets. One study demonstrated that troglitazone
treatment in humans could increase glucose-stimulated insulin secretion (171). Thus, in addition to the insulin-sensitizing effects, PPAR␥ agonists may directly improve ␤-cell
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December, 2000
TREATMENT OF INSULIN RESISTANCE
dysfunction in humans. However, clearly more studies are
needed to investigate direct effects of PPAR␥ agonists on
pancreatic ␤-cells in humans.
593
with insulin, metformin, or sulfonylureas causes a reduction
of HbA1c levels between 0.5 and 0.8%. This beneficial effect
seems to last for at least 3 yr as has been recently shown in
the UKPDS study. During the last 3 yr of this long-term trial,
379 patients were additionally treated with acarbose in a
placebo-controlled design. This resulted in a mean reduction
of the HbA1c by 0.5% in the group of patients who still took
acarbose after 3 yr. This significant effect was sustained over
the 3-yr time period (205). However, at 3 yr a significant
lower proportion of patients were taking acarbose compared
with placebo (39 vs. 58%), the main reasons for noncompliance being flatulence and diarrhea. Intention to treat analysis
showed that all patients allocated to acarbose, compared
with placebo, had 0.2% significantly lower HbA1c at 3 yr
(205).
III. Pharmacological Treatment
In the following section the available antihyperglycemic
agents known to ameliorate insulin resistance will be discussed. One major mechanism of action to increase insulin
sensitivity, which all antihyperglycemic agents have in common, is reducing the deleterious effects of chronic hyperglycemia on insulin action and insulin secretion. This concept
of “glucose toxicity” plays a pivotal role in glucose homeostasis, and excellent reviews have been published during
the last decade (172–174) . In addition to the effect on insulin
sensitivity by reducing glucose toxicity, the evidence of a
primary effect of the respective agents on insulin action will
be reviewed.
3. Effect of ␣-glucosidase-inhibitors on insulin sensitivity. Eight
randomized placebo-controlled studies have been published
examining the effect of ␣-glucosidase inhibitors on insulin
sensitivity in patients with IGT or type 2 diabetes mellitus
(Table 2). In subjects with IGT, Chiasson et al. (206) demonstrated that acarbose (100 mg three times daily) for 4 months
caused a 21% decrease in steady-state plasma glucose (SSPG)
during an insulin suppression test using somatostatin, glucose, and insulin infusions. Similar results were obtained by
Laube et al. (207), who reported that 12 weeks of acarbose
treatment (100 mg three times daily) increased steady-state
glucose infusion rate (SSGIR) by 45%. In addition, Shinozaki
et al. (208) treated subjects with IGT with a different ␣glucosidase inhibitor, voglibose (0.2 mg three times daily),
for 12 weeks, and showed that SSPG levels decreased significantly after voglibose treatment. Thus, these data suggest
that ␣-glucosidase inhibitors improve insulin sensitivity in
subjects with IGT and hyperinsulinemia possibly secondary
to an amelioration of glucose-induced insulin resistance by
reducing hyperglycemia in the postprandial period. In contrast to studies in subjects with IGT, studies examining the
effect of ␣-glucosidase inhibitors on insulin sensitivity in
patients with type 2 diabetes showed no amelioration of
insulin resistance despite decreased postprandial glycemia
(209 –213). Thus, these data are in support of the notion that
␣-glucosidase inhibitors improve insulin sensitivity in subjects with IGT but have no effect on insulin sensitivity in
subjects with overt type 2 diabetes.
A. ␣-Glucosidase inhibitors
1. Mechanism of action. These agents delay digestion of complex carbohydrates and disaccharides (starch, dextrin, sucrose) to absorbable monosaccharides by reversibly inhibiting ␣-glucosidases within the intestinal brush border
(glucoamylase, sucrase, maltase, and isomaltase). This leads
to a reduction of glucose absorption and, subsequently, the
rise of postprandial hyperglycemia is attenuated. The currently available ␣-glucosidase inhibitors are acarbose, miglitol, and voglibose. Extensive and excellent reviews about
their pharmacology have been published (175–183).
2. Effect of ␣-glucosidase inhibitors on hyperglycemia in patients
with type 2 diabetes mellitus. The effect of monotherapy with
␣-glucosidase inhibitors (usually 100 mg three times daily)
on postprandial hyperglycemia is well documented in numerous randomized placebo-controlled studies, and the decrease of postprandial glycemia averages about 3 mmol/liter
(184 –203). The effect of ␣-glucosidase inhibitors on fasting
plasma glucose levels is less pronounced and averages ⫺1.3
mmol/liter. The overall effect of ␣-glucosidase inhibitors on
glycemia of diet-pretreated subjects with type 2 diabetes, as
determined by HbA1c-measurements, averages 0.9% (range,
0.6 –1.4), as recently reviewed by Lebovitz (204).
Addition of acarbose to type 2 diabetic subjects pretreated
TABLE 2. Effect of ␣-glucosidase inhibitors on insulin sensitivity
Study
n
Subjects
Drug
Dose (mg/day)
Duration
Chiasson et al. (206)
18
IGT
Acarbose
300
4 months
Laube et al. (207)
12
IGT
Acarbose
300
3 months
Shinozaki et al. (208)
16
IGT
Voglibose
Schnack et al. (209)
Reaven et al. (210)
Jenney et al. (211)
Johnson and Taylor (212)
15
12
6
21
Type
Type
Type
Type
2
2
2
2
Miglitol
Acarbose
Acarbose
Miglitol
Matsumoto et al. (213)
27
Type 2
Voglibose
0.6
300
450
75
150
0.6
12 weeks
8
3
3
8
weeks
months
months
weeks
4 weeks
Method
Insulin suppression-test,
SSPG
Hyperglycemic clamp
Insulin suppression test,
SSPG
Euglycemic clamp
Euglycemic clamp
Hyperglycemic clamp
MCR during glucose/insulin
sensitivity test
Insulin tolerance test
Results
21% Decrease
of SSPG
45% Increase
of SSGIR
20% Decrease
of SSPG
No effect
No effect
No effect
No effect
No effect
IGT, Impaired glucose tolerance; Type 2, diabetes mellitus type 2; SSPG, steady-state plasma glucose; SSGIR, steady-state glucose infusion
rate.
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594
MATTHAEI ET AL.
4. ␣-Glucosidase inhibitors in type 2 diabetes prevention studies.
Currently, three type 2 diabetes prevention trials examining
the effect of acarbose on the conversion rate from IGT to type
2 diabetes are under way. The Early Diabetes Intervention
Trial (EDIT), the Dutch Acarbose Intervention Trial (DAISI),
and the Study to Prevent NIDDM (STOP-NIDDM). The
STOP-NIDDM is the largest trial including more than 1,400
IGT-subjects recruited until February 1998. The study has a
randomized double-blind placebo-controlled design, and the
recently published preliminary screening data (214) provide
interesting information on the population under study. In a
preliminary subset of 3,919 screened subjects, preselected by
known risk factors to develop type 2 diabetes (BMI ⬎ 27
kg/m2, history of diabetes, hypertension, dyslipidemia, and
gestational diabetes in women) 13.3% had previously undetected diabetes and 17.3% had IGT. A total of 1.418 IGT
subjects identified during the screening procedure were included in the study for a predictive median follow-up period
of 3.9 yr. The results will be available by 2002, and it will be
interesting to see whether treatment with acarbose is able to
decrease the conversion rate of IGT to manifest type 2 diabetes mellitus in a higher proportion than nonpharmacological intervention protocols including dietary advice and
exercise in the Da Qing study (215).
In addition, two other multicenter studies are investigating the effect of diet, increased physical activity or metformin
[Diabetes Prevention Program (DPP)] and diet, increased
physical activity and sulfonylurea [Fasting Hyperglycemia
Study (216)] to prevent type 2 diabetes mellitus. The results
of these long-term studies will be available between 2002 and
2004.
5. Adverse effects of ␣-glucosidase inhibitors. ␣-Glucosidase inhibitors have not been associated with life-threatening adverse effects, possibly due to the low systemic absorption.
a. Gastrointestinal adverse effects. The major adverse effects
associated with acarbose therapy are gastrointestinal complaints, including flatulence and abdominal discomfort, resulting from malabsorption and consequently increased fermentation of carbohydrates. Depending on the acarbose
dosage used (300 –900 mg/day), the frequency of gastrointestinal effects was as high as 56 –76% (placebo, 32–37%) in
earlier studies (217). When the new recommendations for use
of ␣-glucosidase inhibitors were considered in the study
protocols (low acarbose starting dose of 50 mg/day, slow
increase of dosage over weeks, maximum dose 100 mg three
times daily), the incidence of gastrointestinal adverse effects
were reported to be as low as 7.5% (203). Furthermore, it has
been shown that the incidence of gastrointestinal side effects
decreased during long-term treatment (218).
b. Systemic effects. The systemic availability of nonmetabolized acarbose is reported to be 0.5–1.7% (217, 219, 220). Due
to the low systemic absorption of acarbose, systemic effects
are rare. However, liver transaminase elevations [defined as
treatment-induced increases of alanine aminotransferase
(ALT) and/or aspartate aminotransferase (AST) ⬎ 1.8-fold
the upper limit of the normal range] were documented in
3.8% of acarbose recipients (placebo 0.9%) in the early studies
carried out in the United States, using high acarbose daily
Vol. 21, No. 6
dosage (900 mg/day) (221). Animal studies on ethanolinduced hepatotoxicity revealed that high-dose acarbose
treatment augmented ethanol-induced hepatotoxicity (222).
However, in all major acarbose trials using 100 mg three
times daily as the maximum dose, hepatic transaminase elevations were extremely rare (203, 223) and in the five cases
published, transaminase levels were reversible upon withdrawal of the drug (224 –227). Furthermore, a recent study
from Japan demonstrated that acarbose treatment in patients
with chronic liver disease and diabetes mellitus was effective
and caused no significant alterations in hepatic transaminase
levels after 8 weeks of treatment (228). Recently, it has been
reported that acarbose induced a generalized erythema multiforme in a middle-aged Japanese type 2 diabetic patient
(229).
6. Guidelines for the clinical use of ␣-glucosidase inhibitors.
a. Selection of the most appropriate patients. Postprandial hyperglycemia represents a major metabolic disturbance of carbohydrate metabolism in IGT and early phase type 2 diabetic
subjects. Since ␣-glucosidase inhibitors decrease postprandial glycemia these patients are suitable candidates for treatment with ␣-glucosidase inhibitors, provided that the individual therapeutic goal was not achieved by dietary advice
and increased physical activity. In type 2 diabetic patients
suffering predominantly from fasting hyperglycemia, ␣glucosidase inhibitors are less effective but may be used in
combination with other antihyperglycemic agents, such as
metformin, sulfonylureas, or insulin. The results of the UKPDS have shown that combination therapy using these drugs
is effective and safe over at least 3 yr. In patients remaining
on their allocated therapy, the HbA1c-difference at 3 yr was
0.5% lower in the acarbose study group compared with
placebo (205).
B. Biguanides
1. Introduction. There is now a large body of data documenting the clinical efficacy of metformin in the treatment
of type 2 diabetes (230), and most of its clinical, pharmacological, and basic cellular aspects have been addressed
in several excellent reviews published during the past 20
yr (231–238). Recently, the UKPDS showed that metformin
is particularly effective in overweight type 2 diabetic subjects, a condition usually characterized by insulin resistance (239). Moreover, in essentially all clinical studies the
improvement of hyperglycemia with metformin occurred
in the presence of unaltered or reduced plasma insulin
concentrations (e.g., Refs. 240 and 241). Taken collectively,
these findings indicate the potential of metformin as an
insulin-sensitizing or insulin-mimetic drug, which is the
focus of the following.
Despite almost 40 yr of research, the precise cellular mechanism of metformin action is still not entirely understood.
Several cellular mechanisms have been described but a single
unifying site of action, such as a receptor, an enzyme, or a
transcription factor, has yet to be identified. Nevertheless, it
is generally undisputed that metformin has no effect on the
pancreatic ␤-cell in stimulating insulin secretion (234). Mild
increases in glucose-stimulated insulin secretion after met-
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December, 2000
TREATMENT OF INSULIN RESISTANCE
formin treatment (242) are thought to be the result of reduced
glucose toxicity on the ␤-cell secondary to improved glycemic control (243).
2. Mechanisms of action in humans.
a. Glucose production. Accelerated endogenous glucose production is thought to be a key factor in the development of
fasting hyperglycemia in type 2 diabetes (244, 245). In patients with type 2 diabetes, metformin has been shown to
inhibit endogenous glucose production in most studies (246 –
252). This could be accounted for largely by inhibition of
gluconeogenesis (247), although an additional inhibitory effect of metformin on glycogen breakdown is likely (247, 248).
The observation in many studies that, in the basal postabsorptive state, overall glucose disposal (metabolic plasma
clearance rate of glucose) did not change while endogenous
glucose production decreased (246 –248, 251–253) suggests
that the improvement in glycemic control is largely attributable to the effect of metformin on glucose production.
b. Peripheral glucose metabolism. Many (246, 249, 251, 252,
254 –256), but not all, studies (248, 250, 253, 257) using the
hyperinsulinemic-euglycemic clamp technique have shown
a metformin-induced increase in insulin-stimulated glucose
disposal in patients with type 2 diabetes. Since muscle represents a major site of insulin-mediated glucose uptake (244,
258), metformin must, either directly or via indirect mechanisms, have an insulin-like or insulin-sensitizing effect on
this tissue. In humans, the increase in insulin-stimulated
glucose disposal is mostly accounted for by nonoxidative
pathways (252, 255, 259). Nonoxidative glucose metabolism
includes storage as glycogen, conversion to lactate, and incorporation into triglycerides. While no effect on lactate production is observed (247, 248), implications on net triglyceride synthesis cannot be drawn. Nevertheless, it appears
reasonable to propose that in human muscle glucose transport and, possibly as a consequence, glycogen synthesis are
the major targets of metformin action in the insulin-stimulated state. However, in the basal state, metformin had no
effect on glucose clearance or whole-body glucose oxidation,
although the proportion of glucose turnover undergoing oxidation was increased (247). Moreover, forearm glucose uptake in the postabsorptive state was not significantly altered
(247).
c. Metabolic effects independent of improved glycemia. The
interpretation of the above experiments is limited by the fact
that treatment with metformin was always accompanied by
improvement in glycemic control and sometimes also by
reduction of body weight. It cannot be excluded, therefore,
that the effects on endogenous glucose production and glucose disposal, at least in part, were secondary to reduced
glucose toxicity (243) and/or weight loss (260) rather than
metformin per se. Only four studies have examined the metabolic actions of metformin in the absence of any changes in
glycemic control or body weight.
In one study, 1 g of metformin was administered acutely
to patients with type 2 diabetes; after 12 h no effect on
insulin-stimulated glucose disposal was seen while the excessive endogenous glucose production in the basal state was
significantly reduced (253). This suggests that in patients
595
with type 2 diabetes, improvement in insulin-stimulated glucose disposal is predominantly due to alleviation of glucose
toxicity while endogenous glucose production is immediately affected by metformin. In another study, lean, normal
glucose-tolerant, insulin-resistant first-degree relatives of patients with type 2 diabetes acutely received 1 g of metformin
and the opposite effect was observed (259). In subjects with
IGT, 6-week metformin treatment improved basal (HOMA)
but not insulin-stimulated glucose disposal or glucose oxidation (261). In this study both fasting glucose and insulin
decreased significantly. In android obese subjects with IGT,
increased insulin sensitivity (using an iv glucose tolerance)
was observed after only 2 days of metformin treatment (1,700
mg/day) (262). In obese women with the polycystic ovary
syndrome (PCOS) 6 months treatment with metformin also
significantly improved insulin-stimulated glucose disposal
(263, 264). In another study in obese women with PCOS, the
decrease in serum insulin levels was associated with an increased ovulatory response to clomiphene (265). Glucose
production was not assessed in the latter study. These apparent discrepancies could be explained by differences in the
type of insulin resistance. In the highly selected group of
lean, first-degree relatives and women with PCOS, mechanisms may contribute to insulin resistance that are different
than those in garden-variety type 2 diabetes in which insulin
resistance is predominantly the result of obesity and longstanding hyperglycemia. Moreover, the reduction in endogenous glucose production after metformin treatment may
only be seen in subjects in whom it was increased to begin
with, such as patients with type 2 diabetes. The latter is
supported by observations showing that metformin alone
does not cause hypoglycemia or lower blood glucose in nondiabetic subjects (266, 267). The effect of metformin on endogenous glucose production in nondiabetic humans has not
yet been studied.
Additional evidence for improved insulin action comes
from studies combining insulin therapy and metformin. It
was shown that requirements of exogenous insulin are reduced (by ⬃30%) by addition of metformin in obese patients
with type 2 diabetes (268 –270) and in some patients with type
1 diabetes in whom glycemic control was unaltered (271–
273).
d. Other mechanisms of action. It has been suggested that part
of the antihyperglycemic effect of metformin is due to decreased release of FFA from adipose tissue and/or decreased
lipid oxidation (253, 274). However, reduced FFA levels after
metformin treatment have been shown in some (251, 257,
274) but not all studies (247, 248, 259). Moreover, in vitro
studies have shown that metformin does not enhance the
antilipolytic action of insulin on adipose tissue (275). Only
two studies have examined FFA turnover using isotope techniques and found either no difference (247) or a 17% reduction (255) after metformin treatment. In the latter study, the
effect was seen in the basal state but not in the insulinstimulated state in which FFA flux was largely suppressed.
Thus, the metformin effect on peripheral glucose uptake
may, at least in part, be mediated by suppression of FFA and
lipid oxidation. In contrast, a causal relationship with endogenous glucose production is unlikely, since distinctly
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596
MATTHAEI ET AL.
greater reductions in circulating FFA levels with acipimox
failed to lower glucose production (276, 277).
Evidence for other proposed mechanisms of metformin
action is less convincing. Increased intestinal utilization of
glucose has been suggested by animal studies (278 –280).
More recently, in vivo treatment with metformin increased
gene expression of the energy-dependent sodium-glucose
cotransporter (SGLT1) in rat intestine (281). However, such
a mechanism has not been confirmed in humans (250).
e. Weight loss. Unlike other pharmacological therapies for
type 2 diabetes (sulfonylureas, insulin), metformin treatment
is not associated with weight gain. Clinical studies have
consistently shown either a small but significant decrease in
body weight (240, 251) or a significantly smaller increase in
body weight compared with other forms of treatment (268).
One study has shown that weight loss during metformin
treatment was largely accounted for by loss of adipose tissue
(247). This was explained by differential effects of metformin
on adipose tissue and muscle. While metformin improves
insulin sensitivity in muscle, it does not affect the antilipolytic action of insulin on adipose tissue (282). The overall
effect of metformin on body weight is attributed to a reduction in caloric intake (268, 283) rather than an increase in
energy expenditure (247, 253, 284). Since reduction in body
weight per se reduces insulin resistance, this may also represent a mechanism by which metformin improves insulin
resistance.
To summarize, the partly divergent observations from the
numerous metabolic studies regarding metformin’s effect on
muscle and liver (Table 3, A and B) may reflect different
mechanisms of metformin action in the basal vs. the insulinstimulated state. In the basal, postabsorptive state, the improvement of fasting hyperglycemia is mostly due to a decrease of the accelerated endogenous glucose production.
This results from inhibition of both gluconeogenesis and
glycogen breakdown. Direct or indirect effects on regulatory
enzymes are likely to be involved. No data are available for
suppression of glucose production during experimental hyperinsulinemia. However, the fact that reduction in basal
glucose production occurs in the presence of lower or unaltered insulin levels suggests that glucose production in
liver and kidney (285, 286) is more sensitive to the restrictive
action of insulin after treatment with metformin.
In the insulin-stimulated state during the clamp, peripheral glucose disposal is increased even in the absence of
improved fasting glycemia, indicating a reduction in insulin
resistance. This is thought to be mainly a result of enhanced
glucose transport and storage in muscle. The effect on glucose transport is most likely due to a potentiation of insulinstimulated translocation of glucose transporters and an increase in their intrinsic activity (287, 288). Glycogen synthesis
is increased as a result of stimulatory effects of metformin on
the signaling chain to activation of glycogen synthase. Moreover, the in vivo effect on muscle may, in part, be due to a
reduction in FFA oxidation. Finally, in insulin-resistant subjects the effect on muscle appears to be more pronounced,
suggesting a reversal of insulin resistance rather than a mere
improvement in insulin sensitivity.
Vol. 21, No. 6
3. Clinical efficacy of metformin in patients with type 2 diabetes
mellitus.
a. Glycemic control. The glucose-lowering effect of metformin, monotherapy or in combination, has been extensively reviewed (231–233). In a recent meta-analysis (230), all
randomized, controlled clinical trials comparing metformin
with placebo (239, 240, 252, 289 –294) and sulfonylurea (239,
240, 295–301) were evaluated. The weighted mean difference
between metformin and placebo after treatment (median
treatment duration, 4.5 months) for fasting blood glucose
was ⫺2.0 mm and for HbA1c ⫺0.9%. Body weight was not
significantly changed after treatment. Sulfonylureas and
metformin lowered blood glucose (⫺2.0 and ⫺1.8 mm, respectively) and HbA1c (⫺1.1 and ⫺1.3%, respectively)
equally (median treatment duration, 6 months). However,
whereas after sulfonylurea treatment body weight increased
by 2.9 kg, there was a decrease of 1.2 kg after metformin. In
a retrospective study of 9,875 patients with type 2 diabetes
mellitus who attended a large health maintenance organization, metformin treatment improved the mean HbA1c by
1.41% over a 20-month period (302). Among obese patients
treated by intensive blood glucose control within the UKPDS, metformin showed a significantly greater effect than
chlorpropamide, glibenclamide, or insulin for any diabetesrelated endpoint, all-cause mortality, and stroke (239). In
summary, metformin is as effective as sulfonylureas in improving glycemic control but, especially in overweight/
obese patients, advantageous with respect to body weight,
diabetes-related endpoints, and frequency of hypoglycemia.
b. Lipid profile and cardiovascular system. In addition to improving glycemic control, metformin has been shown to reduce serum lipid levels. Metformin treatment results in a
moderate (10 –20%) reduction in circulating triglyceride levels, particularly in patients with marked hypertriglyceridemia and hyperglycemia (247, 257, 303), but also in nondiabetic subjects (304, 305). This has been attributed to a
reduction in hepatic very low density lipoprotein (VLDL)
synthesis (257, 292, 306). Small (5–10%) decreases in total
circulating cholesterol have also been reported (286, 289 –
291) that were essentially attributed to reductions in low
density lipoprotein (LDL) levels (307–309) since high-density
lipoprotein (HDL) cholesterol levels were either increased
(304) or unchanged (309).
In addition to the improvement of the lipid profile, metformin appears to have potentially beneficial hemostaseological effects. Fibrinolysis is increased (305, 307, 308) and the
fibrinolysis inhibitor plasminogen-activator inhibitor 1
(PAI1) is decreased (292, 305, 310). Moreover, a decrease in
platelet aggregability and density has been demonstrated
(296, 311). These additional effects of metformin, which have
been extensively reviewed elsewhere (231, 232), may explain
the advantage of metformin over sulfonylurea or insulin
treatment with respect to macrovascular endpoints shown in
the UKPDS (239).
c. Combination therapies: metformin plus sulfonylureas and
metformin plus insulin. Metformin is also used in combination
with other antihyperglycemic agents. Because of its unique
mechanisms of action, a synergistic effect on glycemic control
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TREATMENT OF INSULIN RESISTANCE
597
TABLE 3A. Metabolic studies in humans with type 2 diabetes: effects of metformin
Author
N
Prager et al. (249)
Nosadini et al. (246)
Jackson et al. (250)
Hother-Nielsen et al. (254)
Wu et al. (257)
DeFronzo et al. (251)
Riccio et al. (255)
McIntyre et al. (256)
Johnson et al. (252)
Perriello et al. (253)
Stumvoll et al. (247)
Cusi et al. (248)
Abbasi et al. (274)
12,
7,
10,
9,
12,
14,
6,
12,
8,
21,
10,
20,
11,
Obese
Obese
Lean
Obese
Obese
Lean/obese
Nonobese
Obese
Obese
Lean/obese
Obese
Obese
Lean/obese
Dose, duration
(g daily, wks)
1.7/4
2.55/4
2.0 –2.5/12
2.0 –2.5/12
2.5/⬎12
2.5/12
1.7/4
3/6
2.55/12
1.0/acute
2.55/15
2.55/16
2.5/12
FG (mg/dl)
FI (␮U/ml)
Basal
MCR
244 3 160
156 3 113a
172 3 103a
205 3 184a
⬃220b 3 ⬃180ab
207 3 158a
⬃163b 3 ⬃143ab
175 3 103a
149 3 122a
15 3 9a
23 3 23
50 3 43
⬃13b 3 ⬃11b
19 3 13a
NC
14.9 3 15.7
15.8 3 11.3
NC
220 3 155a
196 3 152a
224 3 175a
12 3 10a
17 3 14
13 3 12
Insulin-stimulated
MCR
Basal glucose
production
1
1
NC
1
NC
1
1
1
1
NC
2
2
2
1
NC
NC
NC
NC
NC
1
NC
2
NC
2
2
2
2
TABLE 3B. Metabolic studies in humans without type 2 diabetes: effects of metformin
Author
Morel et al. (261)
Nestler et al. (265)
Moghetti et al. (264)
Widen et al. (259)
Diamanti et al. (263)
n
19,
35,
23,
9,
16,
Obese, IGT
Obese, PCO
Obese PCO
Lean (FDR)
PCO
Dose, duration
(g daily, wks)
1.7/6
0.5/5
1.5/26
1.0/acute
1.7/26
FG (mg/dl)
FI (␮U/ml)
112 3 104
78 3 81
85 3 79
15.9 3 11.9
19 3 14
15 3 10a
86 3 88
Basal
MCR
21 3 19
Insulin-stimulated
MCR
Basal glucose
production
NC
NC
1
1
1
NC
FDR, First degree relatives of patients with type 2 diabetes; FG, fasting glucose; FI, fasting insulin; NC, no change; PCO, women with
polycystic ovary syndrome.
a
Significant change.
b
⬃ Indicates values taken from a figure.
has been observed in combination with sulfonylureas (e.g.,
Refs. 240, 312, and 313), troglitazone (Ref. 314 and see next
chapter), and insulin where a dose-sparing effect was consistently demonstrated (268 –270, 314 –316). Interestingly, in
patients in whom sulfonylurea therapy has failed to satisfactory glycemic control, the combination of bedtime NPHinsulin with metformin was advantageous compared with
other combinations (316). In contrast to insulin alone, insulin
plus sulfonylurea, and sulfonylurea alone, when bedtime
NPH-insulin was combined with metformin, a decrease in
HBA1c was achieved without significant weight gain (315,
316).
4. Adverse effects. While mild gastrointestinal disturbances are
the most common side effects, lactic acidosis, although rare,
is the most serious side effect of metformin treatment (317).
In 9,875 patients one case of probable lactic acidosis was
observed in 20 treatment months (302). The incidence of lactic
acidosis is 10 to 20 times lower than with phenformin. This
is explained by the necessity to hydroxylate phenformin
before renal excretion, a step that is genetically defective in
10% of whites (318, 319). Metformin, in contrast, is excreted
unmetabolized. In addition, in contrast to phenformin (320),
metformin neither increases peripheral lactate production
nor decreases lactate oxidation (247, 248), making lactate
accumulation unlikely. One study investigating individual
cases of metformin-associated lactic acidosis showed that in
these patients metformin should never have been started or
should have been discontinued with the onset of acute illness
(321). Thus, strict adherence to the exclusion criteria of metformin treatment (renal and hepatic disease, cardiac or respiratory insufficiency, severe infection, alcohol abuse, his-
tory of lactic acidosis, pregnancy, use of intravenous
radiographic contrast; reviewed in Refs. 213 and 216) should
minimize the risk of metformin-induced lactic acidosis.
5. Guidelines for the clinical use of metformin. As recently reviewed (231) metformin or sulfonylurea therapy can be initiated when patients with NIDDM continue to have hyperglycemia despite diet and exercise. Metformin appears to be
the drug of choice to start pharmacological treatment in
insulin-resistant and overweight/obese diabetic subjects
(239, 322). However, since the antihyperglycemic effects of
metformin are similar in lean and obese subjects, it can also
be recommended as first-line treatment in the absence of
obesity. Addition of metformin to sulfonylureas in patients
with secondary sulfonylurea failure appears reasonable in
view of their synergistic mechanisms of action and has been
shown to improve glycemic control. Furthermore, especially
in overweight/obese patients, the addition of metformin to
insulin is advantageous compared with insulin alone (507).
Finally, metformin is not recommended for patients with
type 1 diabetes, or in insulin-resistant states in the absence of
overt type 2 diabetes. However, metformin is currently under investigation as an agent to prevent type 2 diabetes in
subjects with IGT as one of the three arms (vs. diet and
intensive life-style modification) of the Diabetes Prevention
Program (322), but it is not yet approved for use in subjects
with IGT.
C. Thiazolidinediones
1. Introduction. The thiazolidinediones are a new class of
hypoglycemic agents that were originally developed in the
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598
MATTHAEI ET AL.
early 1980s in Japan as antioxidants (323). Soon after the
synthesis of the first thiazolidinedione, ciglitazone, the blood
glucose-lowering potential of these compounds was observed in animals, with particularly pronounced effects in
animals with genetic insulin resistance such as the KK, db/db,
and ob/ob mice, and fa/fa rats (324 –326). The observation that
glycemia improved in the absence of increasing insulin and
the lack of effect in insulin-deficient animals (327) led to the
conclusion that thiazolidinediones improved insulin resistance and resulted in the nickname “insulin sensitizers.”
However, due to an unacceptable side effect profile, ciglitazone and, later, englitazone never proceeded to human studies. Troglitazone became the first thiazolidinedione available
for clinical use and was released in 1997 in the United States
and Japan followed by rosiglitazone and pioglitazone (both
marketed in 1999 in the United States). In Europe, except for
the United Kingdom, where it was available for a few
months, troglitazone has not been approved and, due to an
untoward risk-benefit ratio (hepatotoxic side effects), was
withdrawn from the US market by the Food and Drug Administration (FDA) in March 2000. Thus, at the present time
rosiglitazone and pioglitazone are the two members of the
thiazolidinedione class available for clinical use in some
countries including the United States, Japan, and Europe.
Since the majority of clinical data originate from studies
using troglitazone, however, this substance will be included
in this review.
2. Mechanism of action. The cellular mechanism of action of the
thiazolidinediones is not precisely understood. However, the
body of evidence indicating that a subtype of the PPAR␥ is
the principal receptor mediating the antidiabetic activity of
the thiazolidinediones is substantial and has recently been
reviewed (328, 329). Expression levels of the nuclear receptor
PPAR␥ are highest in adipocytes, intestinal cells, and macrophages but very low in most other tissues including muscle. PPAR␥ activated by specific agonists, including thiazolidinediones, heterodimerizes with the retinoid X receptor to
bind to specific DNA repeats, resulting in transcription of
thiazolidinedione-responsive genes. In various cell models
(preadipocytes, fibroblasts, myoblasts), thiazolidinedione
treatment resulted in expression of a number of adipocytespecific genes (lipoprotein lipase, fatty-acid binding protein,
GLUT4, acyl-CoA synthetase, etc.) so that PPAR␥ activation
and/or overexpression has essentially been associated with
adipose-cell differentiation and adipogenesis (330 –332).
Therefore, the clinical observations that treatment with thiazolidinediones improves insulin-stimulated (i.e., muscle)
glucose uptake and endogenous (i.e., essentially hepatic) glucose production while PPAR␥ is mainly expressed in fat cells
makes it difficult to link cellular and metabolic mechanisms
of action. In addition, considering the well known connection
between obesity and insulin resistance, it seems paradoxical
that an agent that promotes adipogenesis should improve
insulin sensitivity.
A number of hypothetical schemas to reconcile these
apparent quandaries and explain the overall mode of action of thiazolidinediones have been put forward. First, the
minute quantities of PPAR␥ expressed in muscle may be
sufficient or alternatively might be induced during treat-
Vol. 21, No. 6
ment with thiazolidinediones, leading to a direct PPAR␥mediated response. This is supported by the recent observation in a lipoatrophic mouse model in which
thiazolidinedione treatment improved insulin sensitivity
in the absence or near absence of adipose tissue (333).
Prevention of hyperglycemia-mediated inhibition of the
insulin receptor tyrosine kinase, as demonstrated in rat-1
fibroblasts, represents a potential mechanism (334). Second, the effect of thiazolidinediones may also be mediated
by FFA, which have been shown to interfere with muscle
glucose metabolism and contribute to the impaired insulin-stimulated glucose disposal (335, 336). Since thiazolidinediones have been shown to selectively stimulate lipogenic activities in fat cells, a thiazolidinedione/PPAR␥mediated “fatty-acid-steal phenomenon” has been
proposed leaving less FFAs available for muscle (328).
Third, thiazolidinediones have been shown to reduce expression levels in fat cells of both TNF␣ (337) and leptin
(338, 339), both of which have been implicated in obesityrelated insulin resistance. Although the definite role of the
cytokine TNF␣ for human insulin resistance remains to be
determined, TNF␣ has been shown to interfere with proximal insulin signaling events of (Ref. 340 and Section
II.E.3.). In addition, leptin has been shown to impair insulin signaling in isolated rat adipocytes (341). Since thiazolidinediones have been shown to reduce expression levels of both TNF␣ (337) and leptin (338, 339) in fat cells, they
could contribute to alleviating obesity-related insulin resistance. Which of these mechanisms plays the most important role in vivo is unclear at present, but since they are
not mutually exclusive all of them may be involved.
Parenthetically, a mechanism of action independent of
PPAR␥ was recently demonstrated for inhibition of cholesterol synthesis by troglitazone in various models of liver,
muscle, and fat cells (342).
3. Clinical efficacy of thiazolidinediones in patients with type 2
diabetes mellitus.
a. Glycemic control. Controlled clinical trials assessing the
efficacy of rosiglitazone and pioglitazone as single therapeutic agent in patients with type 2 diabetes showed an average
decrease of fasting plasma glucose levels by about 45 mg/dl
and of HbA1c by about 1.0% (343–346). Taking into account
differences in study design (pretreatment glycemic control,
duration, dose), rosiglitazone and pioglitazone appear to be
similarly efficacious (Table 4). To date no study has directly
compared the clinical efficacy of two or more thiazolidinediones. The effect on glycemic control was dose dependent and leveled off with daily doses greater than 8 mg
for rosiglitazone and exceeding 30 mg for pioglitazone (347).
The effect of troglitazone on glycemic control was slightly
less pronounced, resulting in a decrease in fasting glucose
and HbA1c of approximately 35 mg/dl and 0.7% (347–349).
It thus appears that improvement in glycemic control using
a single agent is slightly less with thiazolidinediones than
with sulfonylureas or metformin.
b. Lipid profile. Interestingly, other abnormalities commonly associated with insulin resistance, such as dyslipidemia and arterial hypertension, also appeared to be im-
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December, 2000
TREATMENT OF INSULIN RESISTANCE
599
TABLE 4. Comparison of troglitazone, rosiglitazone, and pioglitazone
Dosage (mg/dl)
Frequency of administration
Elimination half-life (h)
Decrease of FPG (mg/dl)
Decrease of HbA1c (%)
Decrease of insulin (␮U/ml)
Effect on serum lipids
Adverse effects
Hepatotoxicity
CK elevation
Cardiac hypertrophy
Interaction with CPY 3A4
Troglitazone
Rosiglitazone
200 – 600
od
⬃20
25– 40
⬃0.7
2–5
TG2, Chol nc, HDL1,
LDL(1)
2– 8
od, bd
3– 4
30 –50
⬃1.0
⬃3
FFA2, TG nc, Chol nc, HDL1,
LDL1
15–30
od
5– 6
30 –50
⬃1.0
Pioglitazone
Yes
nd
No
Yes
Noa
No
No
No
No
Yes
No
Yes
FFA nc, TG2, Chol nc, HDL1,
LDL nc
od, Once daily; bd, twice daily; nd, not determined; nc, no change; CK, creatine kinase.
The troglitazone data are based on references of Table 5. The rosiglitazone data are based on: Patel et al. (343); Patel et al. (388); Raskin
and Rappaport (389); Raskin et al. (390); Chabonnel et al. (391); Mathews et al. (392); Grunberger et al. (344); and Salzman and Patel (376).
The pioglitazone data are based on: Mathisen et al. (345); Rubin et al. (355); Schneider et al. (368).
a
Two case reports, questionable causality (374, 375).
proved by thiazolidinediones (343, 345, 350). While none
of the compounds reduced total cholesterol, differential
effects on lipoproteins were noted. All three thiazolidinediones increased HDL cholesterol. However, while
troglitazone and rosiglitazone increased LDL cholesterol,
this was not the case with pioglitazone. No significant
effect on triglyceride levels was reported for either of the
compounds. In healthy volunteers, troglitazone, which,
unlike other thiazolidinediones, carries an antioxidant vitamin E moiety, also reduced the amount of LDL lipid
hydroperoxides (351), which are thought to be of particular atherogenic potential (352).
c. Combination therapy with sulfonylurea, insulin, and metformin. While thiazolidinedione monotherapy turned out
to be disappointing compared with sulfonylureas or metformin, combinations with other forms of pharmacological
treatment appeared to be more promising. In a carefully
designed study, addition of various doses of troglitazone
(200 – 600 mg) to the sulfonylurea compound Glynase in
patients with secondary sulfonylurea failure has been
shown to reduce fasting plasma glucose by 79 mg/dl and
HbA1c by 2.65% (absolute numbers) below sulfonylurea
alone in the highest dosage group. An additive effect with
sulfonylureas was also reported for pioglitazone (353). In
keeping with the concept that thiazolidinediones enhance
insulin action are reports showing a marked reduction in
exogenous insulin requirements in insulin-treated obese
patients. Troglitazone reduced HbA1c by 1.3% below placebo while insulin dosage was reduced by 30% (354). Similarly, addition of pioglitazone in insulin-pretreated patients with type 2 diabetes resulted in an improvement of
glycemic control vs. insulin only (355). The combination of
all three available thiazolidinediones with metformin also
showed significant additive effects (346, 356, 357). One
study suggested that troglitazone improved peripheral
insulin sensitivity while metformin preferentially acted on
the liver in an insulin-mimetic or insulin-sensitizing way
(356). It is somewhat unexpected in this study, however,
that metformin had no effect on glucose production when
added to troglitazone.
4. Effect of thiazolidinediones on insulin sensitivity.
a. Animal studies. Initial studies of chronic administration
of troglitazone showed an improvement of insulin sensitivity
and hyperinsulinemia in rats (325). Using the hyperinsulinemic clamp technique, an increase in insulin-stimulated glucose disposal was demonstrated in obese rats (358). In contrast to the effects of prolonged troglitazone administration
several studies in animals have demonstrated that troglitazone also has acute effects that are both insulin like and
insulin sensitizing (359). In addition to improving insulinstimulated glucose uptake, which is essentially attributed to
muscle, thiazolidinediones were shown to enhance insulin’s
action on glucose production, which occurs predominantly
in the liver. In rats, troglitazone increased the sensitivity to
the suppressive effects of insulin on endogenous glucose
production, i.e., mainly on hepatic glucose output (327, 359).
In diabetic mice and starved rats, troglitazone suppressed
gluconeogenesis, possibly by inhibition of long-chain fatty
acid oxidation (325, 360 –362). Thus, animal studies provide
ample evidence that thiazolidinediones sensitize both muscle and liver tissues to the hypoglycemic action of insulin.
b. Human studies. A series of more mechanistically designed studies, employing oral glucose and meal tolerance
tests, hyperinsulinemic clamps, and isotopic glucose turnover determinations, were performed to elucidate the metabolic mode of action of the thiazolidinediones (at the time
troglitazone), in humans with and without type 2 diabetes
(Table 5). No such data are available for rosiglitazone or
pioglitazone at the present time.
During oral glucose and meal tolerance tests, a 25% reduction of postchallenge blood glucose was observed in
some studies after troglitazone treatment accompanied by a
similar reduction in plasma insulin levels (363, 364). In addition, a slight but significant improvement of these parameters was observed in nondiabetic individuals (365, 366).
Using the hyperinsulinemic-euglycemic clamp technique, a
significant improvement in insulin-stimulated glucose uptake (by 41–97%) was shown not only in patients with type
2 diabetes (356, 363, 364) but also in normal glucose-tolerant,
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600
MATTHAEI ET AL.
insulin-resistant subjects (by 10% with insulin given at a rate
of 40 mU/kg䡠min and 27% with insulin given at a rate of 300
mU/kg䡠min) (365). In patients with type 2 diabetes treated
with troglitazone 400 mg daily, endogenous glucose production, as determined by the isotope dilution technique,
decreased by 30% in one study, approaching the mean normal rate (363). In another study, however, a significant reduction in glucose production was reported only for the
group treated with the highest dose (600 mg daily) but not
with 100, 200, or 400 mg (364). In insulin-resistant women
with PCOS, troglitazone treatment resulted in improved insulin resistance (assessed by minimal model), which was
associated with significant decreases in testosterone, dehydroepiandrosterone sulfate, estradiol, and estrone (367). It
was concluded that treatment of insulin resistance and hyperinsulinemia in PCOS may reduce the accelerated steroidogenesis and release of LH characteristic for this disease.
5. Adverse effects of thiazolidinediones. Adverse events of both
rosiglitazone and pioglitazone occurring with greater frequency than in the placebo group are edema and fluid retention (368, 369). The most commonly reported side effect
with rosiglitazone is upper respiratory tract infection (343).
Pioglitazone has been associated with significant, as yet unexplained, elevations of creatine kinase (Takeda, Japan; Actos package insert).
In the early studies troglitazone was generally well tolerated and in the United States, in 2,510 patients enrolled in
clinical trials, reversible increases in liver enzymes more than
3 times the upper limit of normal occurred in 1.9% of troglitazone-treated patients vs. 0.6% of placebo-treated patients. At this time, 20 patients had treatment discontinued
because of liver function abnormalities (370). However, prescription on a larger scale has led to 43 known cases to date
(9/99) of severe liver damage associated with troglitazone
resulting in 28 deaths (371–373). It is currently unclear to
what extent the liver damage in those patients resulted from
the drug vs. other factors and whether the hepatotoxicity was
substance specific, i.e., PPAR␥-mediated vs. idiosyncratic.
Recently, two cases of hepatocellular injuries were reported
in patients taking rosiglitazone (374, 375). However, the
causal relationship is open to question. In large cohorts,
transaminases were not found to be significantly higher with
rosiglitazone compared with placebo (376). On the basis of
the available data, there is currently no evidence for hepatotoxicity with pioglitazone.
Vol. 21, No. 6
The adipogenic potential of thiazolidinediones in preadipocytes in vitro and in therapeutic doses in animals in vivo
(377) has been of some concern. However, clinical use in
patients has not revealed weight gain beyond that seen with
other agents such as sulfonylurea or insulin (378). To explain
this discrepancy, it has been suggested that preadipocytes in
adult humans could be relatively resistant to the adipogenic
effect of thiazolidinediones or, alternatively, that increased
adipogenesis per se need not necessarily cause obesity (329).
Nevertheless, the concern regarding the potential of these
agents to promote differentiation has been rekindled by the
observation that PPAR␥-activation causes fatty transformation of bone marrow stromal cells, which is considered to be
a serious condition (379). Furthermore, PPAR␥s were recently shown to be involved in differentiation and uptake of
oxidized LDL by macrophages/monocytes, suggesting that
endogenous PPAR␥ ligands are important regulators of gene
expression during atherogenesis (380 –382). Moreover, in
mice, PPAR␥-agonists were shown to promote carcinomatous growth in colon epithelium (383, 384) while human
colonic cancer cells transplanted into mice showed a significant growth retardation after treatment with thiazolidinediones (385). However, at present, lack of data makes
it impossible to determine the clinical relevance in humans
for any of these regulatory mechanisms.
In rodents exposed to more than 10 times the dose of
troglitazone used in humans cardiac enlargement was observed (unpublished data cited in Ref. 349). In contrast, in
patients with type 2 diabetes treated with troglitazone for 2
yr no increase in left ventricular mass was reported (349) and
in controlled clinical trials no increase in cardiac events was
observed in troglitazone-treated patients.
6. Guidelines for the clinical use of thiazolidinediones. The only
approved indication of both rosiglitazone and pioglitazone
at the present time is type 2 diabetes mellitus especially in
patients where insulin resistance rather than insulin deficiency is the leading pathogenic mechanism. In Europe the
approval of rosiglitazone at present is limited to combination
therapy with metformin or sulfonylureas. The recommended
dosage is 4 – 8 mg for rosiglitazone and 15–30 mg for pioglitazone to be taken with meals.
Because of the liver toxicity associated with troglitazone,
the American FDA recommends the monitoring of liver function for patients taking rosiglitazone or pioglitazone. Liver
TABLE 5. Metabolic studies in humans: effects of troglitazone
Author
n
Subjects studied
Dose, duration
(mg/day, wk)
Postchallenge
glucose
Postchallenge
insulin
Basal glucose
production
Peripheral insulin
sensitivity
Nolan et al. (365)
Antonucci et al. (366)
Suter et al. (363)
Berkowitz et al. (387)
Dunaif et al. (367)
Mimura et al. (350)
Maggs et al. (364)
Inzucchi et al. (356)
18
25
11
33
21
8
77
13
Obese, NGT ⫹ IGT
IGT
DM2
Women, exGDM
Women, PCOS
DM2
DM2
DM2
400/12
400/12
400/12
200 – 400/12
200 – 400/13
400/13
100 – 600/26
400/13
2
2
2
⫽
⫽
2
2
2
2
2
2
⫽
2
No data
2
⫽
⫽
No data
2
No data
No data
No data
(Only with 600 mg)
⫽
1EC
No data
1EC
No data
MM
1EC
1 (EC)
1 (EC)
n, number of patients treated; NGT, normal glucose tolerance; IGT, impaired glucose tolerance; DM2, type 2 diabetes mellitus; exGDM,
formerly gestational diabetes mellitus; EC, euglycemic-hyperinsulinemic clamp; MM, minimal model; PCOS, polycystic ovary syndrome;
postchallenge represents values obtained during or at the end of an oral glucose tolerance test or meal tolerance test.
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TREATMENT OF INSULIN RESISTANCE
enzymes should be measured at the start of therapy, every
2 months during the first year, and periodically thereafter.
There is insufficient data regarding use in pregnant or
breast-feeding women as well as in children. Therefore, these
drugs should not be used in any of these populations. Regarding development of colon cancer, no human data are
available. However, it seems prudent not to prescribe
thiazolidinediones in the setting of familial adenomatosis
polyposis coli (386).
D. Insulinotropic agents
1. Introduction. The hypoglycemic potency of sulfonamides
was discovered twice. In 1942 the French physician Jambon
recognized severe hypoglycemia in patients treated with
sulfonamides for typhoid fever, but the potential implications for the treatment of type 2 diabetes mellitus were disregarded possibly due to World War II and the associated
low incidence of type 2 diabetes mellitus caused by widespread malnutrition. In 1955 Franke and Fuchs (393) tested
a newly developed sulfonamide (carbutamide) on themselves and experienced tremor and sweating, which they
correctly interpreted as a hypoglycemic reaction. Between
1955 and 1966 sulfonylureas of the first generation were in
clinical use (tolbutamide, chlorpropamide, tolazamide, and
acetohexamide). In 1966 the sulfonylurea derivatives of the
second generation were introduced into clinical practice, i.e.,
Glyburide (in Europe, glibenclamide), glipizide, and gliclazide. In 1996 the first member of the third generation of
sulfonylureas, glimepiride, was approved.
The pharmacology (394 –398), the molecular mechanism of
action (399 – 415), and the clinical efficacy of sulfonylureas
(416 – 419) have been extensively described. The principal
mode of the antihyperglycemic action of sulfonylureas is
based on its ability to stimulate insulin secretion in the pancreatic ␤-cell. Whether or not sulfonylureas possess additional extrapancreatic effects to increase peripheral insulin
action and in vivo insulin sensitivity is far less clear. Since
there is a lot of evidence from in vitro studies that sulfonylureas have an effect on cellular insulin action [e.g., increase
of insulin-stimulated glucose transport and lipogenesis
(420 – 433)], the current evidence of the effect of sulfonylureas
on in vivo insulin action will be briefly summarized.
2. Effect of sulfonylurea on in vivo insulin sensitivity. Although
the first evidence for an extrapancreatic effect of sulfonylureas was the demonstration of potentiated insulin action in
pancreatectomized dogs (434, 435), the discussion about the
effect of sulfonylureas on in vivo insulin sensitivity will be
focused on studies in human subjects utilizing the glucose
clamp technique.
a. Effect of sulfonylurea on endogenous glucose production. A
total of six studies examining the effect of various sulfonylureas on endogenous glucose production in type 2 diabetic
subjects have been published (417, 436) and are summarized
in Table 6. All of them found a mild reduction of endogenous
glucose output due to sulfonylurea treatment, averaging 18%
(range, 7–27%). Thus, from this set of data it is tempting to
conclude that sulfonylurea treatment potentiates insulininduced suppression of endogenous glucose production.
601
However, looking at the effect of sulfonylurea treatment on
fasting plasma insulin levels before and after the treatment
period in the different studies, it becomes evident that posttreatment fasting plasma insulin levels were increased by an
average of 20% (range, 0 –38%). Thus, these data suggest that
at least the vast majority of the effect of sulfonylureas to
reduce endogenous glucose production is mediated by increased plasma insulin levels induced by the insulinotropic
action of sulfonylureas. Whether or not there is any additional intrinsic activity of sulfonylurea compounds on endogenous glucose production remains to be proven by specifically designed clamp studies maintaining constant insulin
levels under which the effect of sulfonylureas per se can be
examined. However, until those studies are available, the
conclusion that sulfonylureas per se reduce endogenous glucose production is not justified on the basis of the results of
the studies published. Furthermore, in a study examining the
effect of glyburide on endogenous glucose production in
type 1 diabetic subjects, Simonson et al. (437) reported that
treatment with this sulfonylurea compound did not influence endogenous glucose production. These results suggest
that there is neither a direct effect of sulfonylureas on endogenous glucose production nor is there a synergistic action
of the drug together with insulin to decrease endogenous
glucose production. In addition, Lisato et al. (438) demonstrated no effect of gliclazide on endogenous glucose production in type 2 diabetic subjects under clamp conditions
designed to inhibit endogenous insulin secretion by continuous infusion of somatostatin and simultaneously maintain
constant plasma insulin and glucagon levels by infusion of
the hormones.
b. Effect of sulfonylureas on glucose utilization. Several studies
have examined the effect of sulfonylureas on peripheral glucose utilization in type 1 as well as in type 2 diabetic subjects
(Table 7). In type 1 diabetic subjects, the majority of the
studies failed to demonstrate any effect of sulfonylureas on
glucose utilization (439, 441– 443), while one short-term
study revealed an increased glucose utilization due to chlorpropamide as well as glipizide treatment (440).
The effect of sulfonylureas on glucose utilization in IGTand type 2 diabetic subjects were examined in six studies
(439, 444 – 448), which are summarized in Table 7. All of these
studies revealed that sulfonylureas increase peripheral glucose utilization by an average of 29%, ranging from nonsignificant (10%) to significant (52%). This improved peripheral
insulin sensitivity was associated with a mean increase of
plasma insulin levels averaging 33% in these studies (range,
18 – 63%). Thus, the effect of sulfonylureas to increase peripheral glucose utilization is accompanied by an augmented
insulin secretion of similar magnitude. Although this does
not exclude an extrapancreatic effect of sulfonylureas to improve peripheral glucose utilization, the above mentioned
studies were not designed to specifically answer the question
of whether sulfonylureas have an intrinsic extrapancreatic
mode of action to improve peripheral insulin action. Those
studies would have to exclude interfering variables, such as
nonstable concentrations of insulin, glucose, and FFA, as well
as other metabolites and hormones, known to influence peripheral insulin action. Consequently, based on the existing
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602
MATTHAEI ET AL.
data, the evidence of an extrapancreatic action of sulfonylureas is rather indirect and based on studies not vigorously
designed to answer this question.
Glimepiride is a recently introduced sulfonylurea that has
some interesting pharmacokinetic and pharmacodynamic
properties (449, 450). The molecular mechanism of action
(451– 455) as well as the clinical efficacy of glimepiride (456 –
463) have been recently described. One advantage of this
drug is that, due to its pharmacokinetic properties, it can be
taken once daily. Furthermore, this compound is of special
interest in the treatment of insulin resistance, since its antihyperglycemic potency is of similar magnitude compared
with sulfonylureas of the second generation, i.e., glibenclamide, although the insulinotropic action of glimepiride is
less pronounced than that of glibenclamide, as has been
demonstrated in animal models of insulin resistance (454).
These data indicate that glimepiride may have an intrinsic
extrapancreatic activity. However, until human clamp data
using intravenous formulations of glimepiride are available,
the clinical relevance of these findings remains speculative.
In addition, it has been suggested that glimepiride has less
cardiovascular activity compared with conventional sulfonylureas, which may be advantageous in the light of possible
adverse effects of sulfonylureas on the cardiovascular system
(464). However, these preliminary results must be proven in
large-scale randomized controlled clinical trials.
The efficacy of glimepiride has been shown in numerous
controlled clinical trials, demonstrating that glimepiride decreased HbA1c by 1.2–1.9% in patients with type 2 diabetes
mellitus not sufficiently controlled by diet and exercise. Furthermore, like the other sulfonylureas, glimepiride can be
used in combination with other antidiabetic agents, i.e., acarbose, metformin, and insulin.
3. Adverse effects. Safety aspects of sulfonylureas have been
recently reviewed (465, 466). Adverse reactions of sulfonylureas are infrequent, occurring in about 4% of the patients
taking first-generation sulfonylureas and slightly less in patients on second-generation agents (467). Rare adverse events
include allergic reactions, gastrointestinal intolerance, cholestatic jaundice due to hepatotoxicity, severe dermatitis,
hemolytic anemia, and effects on bone marrow, i.e., thrombocytopenia and agranulocytosis. However, the most common adverse effect of sulfonylureas is hypoglycemia. In the
UKPDS, the rates for any hypoglycemic episode per year
were 11.0% for chlorpropamide, 17.7% for glibenclamide,
36.5% for insulin, and 1.2% for diet-treated patients (468).
Comparing glimepiride with placebo, US trials have shown
that hypoglycemia occurred at a cumulative incidence of 13.9
Vol. 21, No. 6
vs. 2% (469). Furthermore, in a comparative study, hypoglycemia occurred in 10% of 289 patients receiving glimepiride
and 16.3% of 288 patients receiving glibenclamide, suggesting that the hypoglycemic potency of glibenclamide may be
more pronounced than that of glimepiride (470). Furthermore, in vitro studies suggest that glimepiride has less severe
effects on cardiovascular parameters (464, 471). However,
the clinical significance of these findings remains to be examined in a large-scale randomized controlled study.
It is noteworthy that a study by Campbell (472) demonstrated that the relative mortality risk of sulfonylureainduced hypoglycemia is similar compared with the mortality risk of biguanide-induced lactic acidosis. Thus, to prevent severe hypoglycemic reactions, the use of sulfonylureas
should be well indicated, and clinical situations in which
regular carbohydrate intake is potentially not warranted
should be recognized early.
4. Guidelines for the clinical use of sulfonylureas. Sulfonylureas
should be used in type 2 diabetic patients when nonpharmacological treatment modalities and the use of noninsulinotropic antidiabetic agents (acarbose, metformin,
thiazolidinediones) are insufficient to reach the individual
therapeutic goal. When sulfonylureas are used as a firstline drug in the hyperinsulinemic phase of type 2 diabetes,
further weight gain and perpetuation of the vicious circle
would result: insulin resistance ⬎⬎ hyperinsulinemia ⬎⬎
hyperphagia ⬎⬎ further weight gain ⬎⬎ worsening of
insulin resistance, etc. Thus, insulinotropic agents are not
first-line drugs in these overweight/obese type 2 diabetic
patients, as has been recently demonstrated by the UKPDS
(239). However, sulfonylureas represent first-line drugs in
nonobese type 2 diabetic patients whose main pathophysiological problem is impaired insulin secretion. Due to the
above mentioned characteristics (i.e., once daily medication, potential extrapancreatic effect, less cardiovascular
adverse effects in vitro, lower hypoglycemic potency) the
use of glimepiride may be advantageous over sulfonylureas of the first and second generation; however, more
data from controlled randomized trials are needed to verify these preliminary results.
E. Insulin
Several studies have shown that insulin therapy improves
peripheral insulin sensitivity and decreases endogenous glucose production in subjects with type 1 (473, 474) as well as
type 2 diabetes, which are summarized in Table 8. Even
short-term intensive insulin therapy for 2–3 weeks using
TABLE 6. Effect of sulfonylureas on endogenous glucose production
Reference
n
Subjects
Drug
Duration
Best et al. (436)
Simonson et al. (501)
Kolterman et al. (502)
Mandarino and Gerich (503)
Hother-Nielsen et al. (504)
Firth et al. (505)
15
10
17
18
8
8
Type-2
Type-2
Type-2
Type-2
Type-2
Type-2
Chlorpropamide
Glyburide
Glyburide
Tolazamide
Glibenclamide
Tolazamide
3– 6 months
3 months
3 months
4 months
3 months
3 months
Method
Euglycemic
Euglycemic
Euglycemic
Euglycemic
Euglycemic
Euglycemic
clamp
clamp
clamp
clamp
clamp
clamp
Results
EGP,
EGP,
EGP,
EGP,
EGP,
EGP,
⫺23%, Insulin, ⫹14%
⫺27%, Insulin, ⫹16%
⫺23%, Insulin, ⫹24%
⫺15%, Insulin, ⫾0%
⫺7%, Insulin, ⫹38%
⫺13%, Insulin, ⫹29%
Mean: ⫺18%
Mean: ⫹20%
EGP, Endogenous glucose production.
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December, 2000
TREATMENT OF INSULIN RESISTANCE
603
TABLE 7. Effect of sulfonylureas on glucose utilization in IGT- and type 2 diabetic subjects
Study
Reference
n
Subjects
Drug
Schulz et al.
Simonson
Simonson
(444)
(439)
(439)
9
10
8
Tolbutamide
Glyburide
Glyburide
Kolterman and Olefsky
Greenfield et al.
Kolterman
Ward et al.
(445)
(446)
(447)
(448)
9
20
17
6
IGT
Type-2
Type-2
(insulin-tx)
Type-2
Type-2
Type-2
Type-2
Glyburide
Glipizide
Glyburide
Gliclazide
Duration
3 hours
3 months
2 months
18
3
3
3
months
months
months
months
Method
Results
Glucose utilization/Insulin secretion
Biostator
Euglycemic clamp
Euglycemic clamp
⫹32%a
⫹22%
⫹10%d
⫹21%b
⫹34%c
⫹2.3-folde
Euglycemic
Euglycemic
Euglycemic
Euglycemic
⫹32%
⫹52%
⫹23%
⫹30%f
Mean: ⫹29%
⫹18%
⫹63%
⫹38%
⫹21%
Mean: ⫹33%
clamp
clamp
clamp
clamp
a
Insulin infusion rate to maintain glycemia was reduced by 32%.
C-peptide concentration during first hour of clamp.
Mean of increase of first and second insulin secretion phase.
d
Not significant.
e
Basal C-peptide concentration after glyburide treatment.
f
Mean of 100 and 300 mU/kg/h insulin-infusion rate; no effect at 40 mU/kg/h insulin-infusion rate.
b
c
large amounts of insulin per day to attain normoglycemia
ameliorates both peripheral insulin resistance as well as endogenous glucose production quite substantially (475, 476).
Interestingly, these beneficial effects were maintained after
withdrawal of insulin therapy for at least 2 weeks (477).
Furthermore, the study by Garvey et al. (476) suggests that
second-phase insulin secretion is enhanced by about 6-fold
after restoration of normoglycemia using continuous subcutaneous insulin infusion, while first-phase insulin secretion
was not significantly affected. These results indicate that
short-term restoration of normoglycemia is able to reduce the
detrimental effects of glucose toxicity on both peripheral
glucose disposal and hepatic glucose production, as well as
insulin-secretory capacity. In addition, the study by Henry et
al. (478) is in support of the notion that these beneficial effects
of intensive insulin therapy aiming at normoglycemia last at
least 6 months, although the effect on the peripheral glucose
disposal rate (GDR) was less pronounced compared with the
short-term studies (475, 476) [GDR ⫹ 17% vs. GDR ⫹
74%], while the effects on endogenous glucose production
were similar. One important message of the study by Henry
et al. is their finding that the improvements in glucose homeostasis were accompanied by inducing peripheral hyperinsulinemia (average insulin dose, 100 U/day) causing
marked weight gain in their type 2 diabetic subjects (⫹ 8.7
kg during 6 months) (478). It would be of great clinical
importance to determine whether the degree of body weight
gain could be decreased by using a different insulin therapeutic regimen than that used by Henry et al. (478). Taking
into account the predominant defect in insulin secretion of
type 2 diabetes mellitus— defective first-phase insulin secretion, while second phase insulin secretion is often even increased in these still overweight/obese patients—the portion
of approximately 75% NPH-insulin in the total daily insulin
dose is certainly not based on the underlying pathophysiology. In most insulin-requiring but still overweight/obese
type 2 diabetic subjects, basal insulin requirements during
daytime are negligible to zero. Thus, it is tempting to speculate, and should be examined in controlled studies, whether
restoration of normoglycemia by using meal-adapted fast
acting insulin preparations during daytime (and, if required,
NPH-insulin at bedtime) is able to attain normoglycemia
using less units of insulin/day and, thereby preventing excessive weight gain and its known deleterious effects on
human health.
IV. Perspectives
Optimal treatment of patients with insulin-resistant type
2 diabetes mellitus includes normalization of weight, glycemia, lipidemia, and blood pressure (468, 482, 483). In addition, according to the American Diabetes Association guidelines, aspirin therapy should be considered as primary
prevention strategy in high-risk patients with type 1 or type
2 diabetes. During the last years, antihyperglycemic agents
have been expanded by the introduction of drugs known to
ameliorate hyperglycemia without increasing insulin secretion, i.e., metformin, acarbose (US market), and thiazolidinediones (troglitazone, rosiglitazone, pioglitazone), as
well as novel insulinotropic agents, i.e., glimepiride and meglitinides (repaglinide and nateglinide; insulin-secreting
drugs with short duration of action suitable for meal-adapted
dosage). Are there any other drugs for oral treatment of type
2 diabetics on the horizon?
A. Agents to enhance insulin action
The trace metal vanadium, a phosphotyrosine phosphatase inhibitor, has been shown to have antihyperglycemic
potency in animal models of diabetes (484, 485) as well as in
type 2 diabetic patients (486 – 488). These studies have shown
that vanadium compounds decrease endogenous glucose
production, increase peripheral glucose disposal, and reduce
lipolysis. However, the antihyperglycemic efficacy of vanadyl sulfate measured by reduced fasting glucose (⫺2 mmol/
liter) and HbA1c (⫺0.5%) after taking 150 mg/day for 6
weeks was relatively mild in 12 type 2 diabetic subjects. It
remains to be seen whether the antihyperglycemic efficacy
can be improved by increasing intestinal absorption using
modified vanadium compounds, such as bis-(maltolato)oxovanadium (489).
Another example of a compound that enhances insulin
signaling by activating insulin receptor tyrosine kinase activity has recently been described by Moller and colleagues
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604
MATTHAEI ET AL.
Vol. 21, No. 6
TABLE 8. Effect of insulin therapy on peripheral glucose disposal and endogenous glucose production in subjects with type 2
diabetes mellitus
Reference
No.
Subjects
(n)
478
475
476
477
479
480
481
14
6
14
13
7
15
19
BMI
(kg/m2)
Ideal body weight
(%)
31
112
119
42
⬎30
107
125
Insulin-Tx
(weeks)
Insulin
(U/day)
Body weight
(kg)
Glucose disposal
(%)
Endogenous glucose
production (%)
24
2
3
4
2
1– 8
4
100
?
140
?
?
?
0.75 U/kg
⫹8.7
?
?
⫾0
?
?
⫹1.3
⫹17
⫹72
⫹74
⫹34
⫹13
⫺38 (SSPG)
⫹42
⫺44
⫺33
⫺43
?
⫺22
⫺25
⫺32
BMI, Body mass index, Insulin-TX, insulin treatment; SSPG, steady state plasma glucose.
(490). By using a screening approach, this group has identified a nonpeptidyl fungal metabolite that selectively activates the insulin receptor tyrosine kinase. Moreover, these
authors showed that oral administration of this small molecule to db/db and ob/ob mouse models of diabetes caused
amelioration of hyperglycemia and hyperinsulinemia. However, numerous studies especially focusing on the possible
mitogenicity of this compound must be performed before the
potential clinical value can be assessed.
Prospectively, the engineering of drugs enhancing insulin
action will be greatly stimulated and facilitated as soon as the
molecular mechanism of insulin-stimulated glucose transport has been completely resolved.
B. Agents to increase insulin secretion
Glucagon-like peptide 1 (GLP-1) acts as an incretin to
increase meal-stimulated insulin secretion by binding to
GLP-1 receptors in the ␤-cell membrane. Studies by Nauck
et al. (491) and others have demonstrated that subcutaneous
administration of GLP-1 in type 2 diabetic subjects lowered
plasma glucose by increasing insulin secretion and decreasing glucagon secretion. However, due to its short plasma
half-life of less than 5 min and the need for parenteral administration, more stable nonpeptidyl GLP-1 receptor agonists are being developed for oral administration.
Recently, BTS 67582, a morpholinoguanidine substance
with insulinotropic activity, was tested in type 2 diabetic
patients (492). BTS 67582 stimulates insulin secretion by closing K⫹- ATP channels in ␤-cell membranes. The binding site
of BTS 67582 is different compared with glibenclamide. Interestingly, BTS 67582 was still active in animals that were no
longer responsive to glibenclamide (493). Whether or not BTS
67582 has extrapancreatic effects due to its guanidine moiety
has not been examined in clamp studies, although in vitro
evidence mitigates against this tempting speculation (494).
C. Agents to inhibit fatty acid oxidation
Inhibitors of carnitine palmitoyltransferase 1 (CPT-1),
which is the rate-limiting enzyme for transfer of long-chain
fatty acyl-CoA into the mitochondria, like etomoxir, have
been shown to have antihyperglycemic activity in type 2
diabetic patients, predominantly due to inhibiting hepatic
gluconeogenesis and decreasing plasma triglyceride concentrations (495). Furthermore, in the spontaneously hypertensive rat model, acute etomoxir treatment improved glucose
tolerance and blood pressure significantly, suggesting an
increased insulin sensitivity (496). However, Hubinger et al.
(497) failed to demonstrate any effect of etomoxir treatment
(100 mg/day) for 3 days in a placebo-controlled, randomized, double-blind study of 12 type 2 diabetic subjects. Prospectively, the slow reversibility of the antigluconeogenic
effect of CPT-1 inhibitors and the resulting interrupted defense against hypoglycemia may limit the clinical usefulness
of these compounds (498). Thus, based on the currently available data, agents to inhibit fatty acid oxidation do not have
a marked antihyperglycemic potency.
V. Summary and Conclusion
Peripheral insulin resistance, ␤-cell dysfunction, and increased endogenous glucose production are the major pathophysiologically abnormalities in type 2 diabetes mellitus. The
oral antihyperglycemic agents known to ameliorate one or
more of these processes, which are discussed in this review,
are shown in Fig. 4. Agents that may eventually supplement
our therapeutic potential are included.
As proposed in Fig. 5 the currently available antihyperglycemic agents should be selected for treatment of type 2
diabetic subjects, based on the dynamic pathophysiologically
abnormalities of the disease, needless to say, keeping in mind
the respective contraindications.
As the essential part of the nonpharmacological treatment
basis, type 2 diabetic patients should participate in a structured diabetes education program. During this program, the
patients learn everything important about diabetes, especially self-measurement of blood glucose, and the impact of
nutrition and physical activity on the progression of the
disease. The patient should be taught that he/she is suffering
from a chronic and progressive disease probably requiring
different modes of therapy including, eventually, insulin
and, importantly, that the speed of disease progression is
largely dependent upon exogenous effects such as body
weight and level of physical activity. Thus, the patient should
get the message that he/she can actively combat disease
progression and in this regard the physician should empower the self-responsibility of the patient.
If the individual HbA1c-treatment goal has not been
reached after 3 months and the patient is still overweight/
obese (BMI ⬎ 25 kg/m2), antihyperglycemic agents should
be selected, which do not cause appreciable weight gain by
increasing the preexisting hyperinsulinemia, i.e., ␣-glucosidase inhibitors, metformin, or thiazolidinediones. Selecting
these agents during this stage of the disease utilizes the
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December, 2000
TREATMENT OF INSULIN RESISTANCE
endogenous hyperinsulinemia to improve insulin action and
does not impede the goal of weight reduction by further
increasing hyperinsulinemia/insulin resistance due to insulinotropic agents. If necessary during the course of the disease, combinations of these noninsulinotropic compounds
can be selected, which have been proven to be efficacious
(356, 499, 500).
If combinations of these noninsulinotropic agents are no
longer effective during the progression of the disease, insulinotropic agents such as sulfonylureas or meglitinides
should be started. If, at this point, obesity is still present,
combination therapy with noninsulinotropic agents is indicated.
If oral insulinotropic agents are not sufficient to reach the
HbA1c-goal, insulin therapy must be initiated. The study by
Yki-Ja¨rvinen et al. (316) examining different treatment protocols for type 2 diabetic subjects suffering from secondary
sulfonylurea failure has indicated that bedtime NPH-insulin
combined with metformin during daytime is superior to
other combinations of metformin, sulfonylurea, and insulin
protocols to obtain the highest reduction in HbA1c and the
lowest gain in body weight. Thus, this treatment option
should be used preferentially when type 2 diabetic patients
enter this stage of the disease. With advancing disease duration associated with progressive deterioration of ␤-cell
function, insulin substitution also during daytime is often
605
required to achieve near-normoglycemia. In this respect, the
introduction of fast-acting insulin analogs such as insulin
lispro (1996) and insulin aspart (1999) has made it possible
to optimize our treatment of the insulin-requiring and often
still overweight/obese type 2 diabetic patient with as minimal
as possible exogenous, meal-adapted insulin during daytime.
Since in the vast majority of overweight/obese insulinrequiring type 2 diabetic patients, endogenous insulin secretion is still sufficient to maintain basal insulinemia, generally there is no need for basal insulin supplementation
during the day. Moreover, unnecessary daytime basal insulin supplementation may cause weight gain and increased
frequency of hypoglycemia. Thus, although data from largescale randomized controlled clinical trials are currently not
available, the pathophysiological guided daytime insulin therapy of the insulin-requiring and still overweight/obese type
2 diabetic patient should strive to substitute the deficient
meal-related insulin-secretory response by using fast-acting
insulin analogs. Unfortunately, however, until now most of
these diabetic patients still get either daytime basal insulin
supplementation or some kind of fixed insulin mixtures containing 70 – 80% basal insulin. In this context, randomized
controlled clinical trials are urgently needed to compare insulin treatment protocols for overweight/obese type 2 diabetic subjects used so far with meal-adapted protocols using
fast-acting analogs with respect to units of insulin per day
FIG. 4. Antihyperglycemic agents. Summary of hyperglycemic agents currently available and potential new therapeutic targets and substances.
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606
MATTHAEI ET AL.
Vol. 21, No. 6
FIG. 5. Starling’s curve of the pancreas and rational treatment of type 2 diabetes mellitus. Starling’s curve of the pancreas as originally described
by DeFronzo et al. (245), indicating the relationship of mean plasma insulin levels during an oral glucose tolerance test (OGTT) and fasting
plasma glucose levels of subjects with normal glucose tolerance, IGT, and type 2 diabetes. The depicted therapeutic options should be selected
according to the pathophysiological stage of the individual patient. SU, Sulfonylureas.
needed to achieve near-normoglycemia and the corresponding effect on weight gain. Based on the nature of the ␤-cell
defect in the still overweight/obese type 2 diabetes patient,
it is tempting to speculate that the protocol using mealadapted fast-acting insulin analogs might achieve nearnormoglycemia with lower total daily insulin dosage accompanied by significantly less weight gain. In this regard, the
results of these trails would have a tremendous impact on the
insulin-treatment recommendations for the subjects with
type 2 diabetes entering this stage of the disease. In addition,
to further decrease the exogenous insulin dose in the treatment of overweight/obese insulin-requiring type 2 diabetic
subjects, additional therapy with noninsulinotropic agents
has been shown to reduce the insulin dose by 20 –30%, and
the possible clinical benefit should be evaluated in the individual patient (507).
In conclusion, the optimal therapy of patients with type 2
diabetes mellitus requires a multifaceted therapeutic approach including patient education, life style changes, and
pharmacological antihyperglycemic and antihypertensive,
as well as antihyperlipidemic, therapy. Future efforts should
focus on preventive strategies using educational and possibly (dependent upon the outcome of ongoing studies) phar-
macological interventions in an attempt to lower the number
of patients with the metabolic syndrome, IGT, and overt type
2 diabetes mellitus, thereby reducing the disabling individual and socioeconomic burden for society.
References
1. Gerich JE 1998 The genetic basis of type 2 diabetes mellitus: impaired insulin secretion vs. impaired insulin sensitivity. Endocr Rev
19:491–503
2. DeFronzo RA 1992 Pathogenesis of type 2 (non-insulin dependent)
diabetes mellitus: a balanced overview. Diabetologia 35:389 –397
3. Yki-Ja¨rvinen H 1994 Pathogenesis of non-insulin-dependent diabetes mellitus. Lancet 343:91–95
4. Ferrannini E 1998 Insulin resistance vs. insulin deficiency in noninsulin-dependent diabetes mellitus: problems and prospects. Endocr Rev 19:477– 490
5. Kahn CR 1994 Banting Lecture. Insulin action, diabetogenes, and
the cause of type II diabetes. Diabetes 4:1066 –1084
6. Olefsky JM 1993 Insulin resistance and the pathogenesis of noninsulin-dependent diabetes mellitus: cellular and molecular mechanisms. Adv Exp Med Biol 334:129 –150
7. Ha¨ring HU 1999 Pathogenesis of type II diabetes: are there common
causes for insulin resistance and secretion failure? Exp Clin Endocrinol Diabetes 107[Suppl.2]:S17–S23
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 09 September 2014. at 05:56 For personal use only. No other uses without permission. . All rights reserved.
December, 2000
TREATMENT OF INSULIN RESISTANCE
8. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus 1999 Diabetes Care 22[Suppl 1]:S5–S19
9. Beck Nielsen H, Groop LC 1994 Metabolic and genetic characterization of prediabetic states. Sequence of events leading to noninsulin-dependent diabetes mellitus. J Clin Invest 94:1714 –1721
10. Kelley DE 1995 Effects of weight loss on glucose homeostasis in
NIDDM. Diabetes Rev 3:366 –377
11. Schneider SH, Morgado A 1995 Effects of fitness and physical
training on carbohydrate metabolism and associated cardiovascular risk factors in patients with diabetes. Diabetes Rev 3:378 – 407
12. Levy J, Atkinson AB, Bell PM, McCance DR, Hadden DR 1998
Beta-cell deterioration determines the onset and rate of progression
of secondary dietary failure in type 2 diabetes mellitus: the 10 year
follow-up of the Belfast Diet Study. Diabet Med 15:290 –296
13. Turner RC, Cull CA, Frighi V, Holman RR 1999 Glycemic control
with diet, sulfonylurea, metformin, or insulin in patients with type
2 diabetes mellitus: progressive requirement for multiple therapies
(UKPDS 49). JAMA 281:2005–2012
14. Fox C 1999 Diabetes and hypertension: an era of clarity or confusion. J Hum Hypertens 13[Suppl 2]:S9 –S17
15. UKPDS-Study Group 1998 Tight blood pressure control and risk
of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J 317:703–713
16. UKPDS-Study Group 1998 Efficacy of atenolol and captopril in
reducing risk of macrovascular and microvascular complications in
type 2 diabetes: UKPDS 39. Br Med J 317:713–720
17. Taskinen MR 1999 Strategies for the management of diabetic dyslipidemia. Drugs 58[Suppl 1]:47–51
18. Howard BV 1999 Insulin resistance and lipid metabolism. Am J
Cardiol 84 (1A):28J–32J
19. Vague P, Juhan-Vague I 1997 Fibrinogen, fibrinolysis and diabetes
mellitus: a comment. Diabetologia 40:738 –740
20. Tschoepe D, Roesen P 1998 Heart disease in diabetes mellitus: a
challenge for early diagnosis and intervention. Exp Clin Endocrinol
Diabetes 106:16 –24
21. Gerich JE 1991 Is muscle the major site of insulin resistance in
type 2 (non-insulin-dependent) diabetes mellitus? Diabetologia
34:607– 610
22. Moller DE, Flier JS 1991 Insulin resistance–mechanisms, syndromes, and implications. N Engl J Med 325:938 –948
23. Garvey WT, Birnbaum MJ 1993 Cellular insulin action and insulin
resistance. Baillieres Clin Endocrinol Metab 7:785– 873
24. DeFronzo RA, Tobin JD, Andres R 1979 Glucose clamp technique:
a method for quantifying insulin secretion and resistance. Am J
Physiol 237:E214 –E223
25. Mitrakou A, Kelley D, Veneman T, Jenssen T, Pangburn T, Reilly
J, Gerich J 1990 Contribution of abnormal muscle and liver glucose
metabolism to postprandial hyperglycemia in NIDDM. Diabetes
39:1381–1390
26. Kelley D, Mitrakou A, Marsh H, Schwenk F, Benn J, Sonnenberg
G, Arcangeli M, Aoki T, Sorensen J, Berger M, Sonksen P, Gerich
J 1988 Skeletal muscle glycolysis, oxidation, and storage of an oral
glucose load. J Clin Invest 81:1563–1571
27. Ferrannini E, Bjorkman O, Reichard Jr GA, Pilo A, Olsson M,
Wahren J, DeFronzo RA 1985 The disposal of an oral glucose load
in healthy subjects. A quantitative study. Diabetes 34:580 –588
28. Pimenta W, Korytkowski M, Mitrakou A, Jenssen T, Yki-Ja¨rvinen
H, Evron W, Dailey G, Gerich J 1995 Pancreatic ␤-cell dysfunction
as the primary genetic lesion in NIDDM. Evidence from studies in
normal glucose-tolerant individuals with a first-degree NIDDM
relative. JAMA 273:1855–1861
29. Volk A, Renn W, Overkamp D, Mehnert B, Maerker E, Jacob S,
Balletshofer B, Haring HU, Rett K 1999 Insulin action and secretion in healthy, glucose tolerant first degree relatives of patients
with type 2 diabetes mellitus. Influence of body weight. Exp Clin
Endocrinol Diabetes 107:140 –147
30. Finegood DT, Bergman RN, Vranic M 1987 Estimation of endogenous glucose production during hyperinsulinemic-euglycemic
glucose clamps. Comparison of unlabeled and labeled exogenous
glucose infusates. Diabetes 36:914 –924
31. Stumvoll M, Meyer C, Mitrakou A, Nadkarni V, Gerich JE 1997
Renal glucose production and utilization: new aspects in humans.
Diabetologia 40:749 –757
607
32. Perriello G, Pampanelli S, Del-Sindaco P, Lalli C, Ciofetta M,
Volpi E, Santeusanio F, Brunetti P, Bolli GB 1997 Evidence of
increased systemic glucose production and gluconeogenesis in an
early stage of NIDDM. Diabetes 46:1010 –1016
33. DeFronzo RA, Simonson D, Ferrannini E 1982 Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetes mellitus.
Diabetologia 23:313–319
34. Campbell PJ, Mandarino LJ, Gerich JE 1988 Quantification of the
relative impairment in actions of insulin on hepatic glucose production and peripheral glucose uptake in non-insulin-dependent
diabetes mellitus. Metabolism 37:15–21
35. Bogardus C, Lillioja S, Howard BV, Reaven G, Mott D 1984
Relationships between insulin secretion, insulin action, and fasting
plasma glucose concentration in nondiabetic and noninsulindependent diabetic subjects. J Clin Invest 74:1238 –1246
36. Ferrannini E, Smith JD, Cobelli C, Toffolo G, Pilo A, DeFronzo
RA 1985 Effect of insulin on the distribution and disposition of
glucose in man. J Clin Invest 76:357–364
37. Mitrakou A, Kelley D, Veneman T, Jenssen T, Pangburn T, Reilly
J, Gerich J 1990 Contribution of abnormal muscle and liver glucose
metabolism to postprandial hyperglycemia in NIDDM. Diabetes
39:1381–1390
38. Randle PJ, Priestman DA, Mistry SC, Halsall A 1994 Glucose fatty
acid interactions and the regulation of glucose disposal. J Cell
Biochem 55[Suppl]:1–11
39. Saloranta C, Groop L 1996 Interactions between glucose and FFA
metabolism in man. Diabetes Metab Rev 12:15–36
40. Boden G 1997 Role of fatty acids in the pathogenesis of insulin
resistance and NIDDM [published erratum appears in Diabetes
1997 Mar;46(3):536]. Diabetes 46:3–10
41. Foley JE 1992 Rationale and application of fatty acid oxidation
inhibitors in treatment of diabetes mellitus. Diabetes Care 15:
773–784
42. Nurjhan N, Consoli A, Gerich J 1992 Increased lipolysis and its
consequences on gluconeogenesis in non-insulin-dependent diabetes mellitus. J Clin Invest 89:169 –175
43. Campbell PJ, Mandarino LJ, Gerich JE 1988 Quantification of the
relative impairment in actions of insulin on hepatic glucose production and peripheral glucose uptake in non-insulin-dependent
diabetes mellitus. Metabolism 37:15–21
44. Groop LC, Bonadonna RC, Del Prato S, Ratheiser K, Zyck K,
Ferrannini E, DeFronzo RA 1989 Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for
multiple sites of insulin resistance. J Clin Invest 84:205–213
45. Bonadonna RC, Groop L, Kraemer N, Ferrannini E, Del Prato S,
DeFronzo RA 1990 Obesity and insulin resistance in humans: a
dose-response study. Metabolism 39:452– 459
46. Campbell PJ, Carlson MG, Hill JO, Nurjhan N 1992 Regulation of
free fatty acid metabolism by insulin in humans: role of lipolysis
and reesterification. Am J Physiol 263:E1063–E1069
47. Campbell PJ, Carlson MG, Nurjhan N 1994 Fat metabolism in
human obesity. Am J Physiol 266:E600 –E605
48. Nurjhan N, Campbell PJ, Kennedy FP, Miles JM, Gerich JE 1986
Insulin dose-response characteristics for suppression of glycerol
release and conversion to glucose in humans. Diabetes 35:1326 –
1331
49. Groop LC, Bonadonna RC, Simonson DC, Petrides AS, Shank M,
DeFronzo RA 1992 Effect of insulin on oxidative and nonoxidative
pathways of free fatty acid metabolism in human obesity. Am J
Physiol 263:E79 –E84
50. Mitrakou A, Kelley D, Mokan M, Veneman T, Pangburn T, Reilly
J, Gerich J 1992 Role of reduced suppression of glucose production
and diminished early insulin release in impaired glucose tolerance.
N Engl J Med 326:22–29
51. Berrish TS, Hetherington CS, Alberti KG, Walker M 1995 Peripheral and hepatic insulin sensitivity in subjects with impaired
glucose tolerance. Diabetologia 38:699 –704
52. Kellerer M, Lammers R, Haring HU 1999 Insulin signal transduction: possible mechanisms for insulin resistance. Exp Clin Endocrinol Diabetes 107:97–106
53. Kasuga M, Karlsson FA, Kahn CR 1982 Insulin stimulates the
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 09 September 2014. at 05:56 For personal use only. No other uses without permission. . All rights reserved.
608
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
MATTHAEI ET AL.
phosphorylation of the 95,000-dalton subunit of its own receptor.
Science 215:185–187
Thies RS, Molina JM, Ciaraldi TP, Freidenberg GR, Olefsky JM
1990 Insulin-receptor autophosphorylation and endogenous substrate phosphorylation in human adipocytes from control, obese,
and NIDDM subjects. Diabetes 39:250 –259
Freidenberg GR, Henry RR, Klein HH, Reichart DR, Olefsky JM
1987 Decreased kinase activity of insulin receptors from adipocytes
of non-insulin-dependent diabetic subjects. J Clin Invest 79:240 –250
Caro JF, Sinha MK, Raju SM, Ittoop O, Pories WJ, Flickinger EG,
Meelheim D, Dohm GL 1987 Insulin receptor kinase in human
skeletal muscle from obese subjects with and without noninsulin
dependent diabetes. J Clin Invest 79:1330 –1337
Klein HH, Vestergaard H, Kotzke G, Pedersen O 1995 Elevation
of serum insulin concentration during euglycemic hyperinsulinemic clamp studies leads to similar activation of insulin receptor
kinase in skeletal muscle of subjects with and without NIDDM.
Diabetes 44:1310 –1317
Bak JF, Moller N, Schmitz O, Saaek A, Pedersen O 1992 In vivo
insulin action and muscle glycogen synthase activity in type 2
(non-insulin-dependent) diabetes mellitus: effects of diet treatment. Diabetologia 35:777–784
Obermaier-Kusser B, White MF, Pongratz DE, Su Z, Ermel B,
Muhlbacher C, Haring HU 1989 A defective intramolecular autoactivation cascade may cause the reduced kinase activity of the
skeletal muscle insulin receptor from patients with non-insulindependent diabetes mellitus. J Biol Chem 264:9497–9504
Nyomba BL, Ossowski VM, Bogardus C, Mott DM 1990 Insulinsensitive tyrosine kinase: relationship with in vivo insulin action in
humans. Am J Physiol 258:E964 –E974
Maegawa H, Shigeta Y, Egawa K, Kobayashi M 1991 Impaired
autophosphorylation of insulin receptors from abdominal skeletal
muscles in nonobese subjects with NIDDM. Diabetes 40:815– 819
Nolan JJ, Freidenberg G, Henry R, Reichart D, Olefsky JM 1994
Role of human skeletal muscle insulin receptor kinase in the in vivo
insulin resistance of noninsulin-dependent diabetes mellitus and
obesity. J Clin Endocrinol Metab 78:471– 477
Freidenberg GR, Reichart D, Olefsky JM, Henry RR 1988 Reversibility of defective adipocyte insulin receptor kinase activity in
non-insulin-dependent diabetes mellitus. Effect of weight loss.
J Clin Invest 82:1398 –1406
White MF, Maron R, Kahn CR 1985 Insulin rapidly stimulates
tyrosine phosphorylation of a Mr-185,000 protein in intact cells.
Nature 318:183–186
Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA,
Cahill DA, Goldstein BJ, White MF 1991 Structure of the insulin
receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352:73–77
Sun XJ, Wang LM, Zhang Y, Yenush L, Myers-MG J, Glasheen E,
Lane WS, Pierce JH, White MF 1995 Role of IRS-2 in insulin and
cytokine signalling. Nature 377:173–177
Lavan BE, Fantin VR, Chang ET, Lane WS, Keller SR, Lienhard
GE 1997 A novel 160-kDa phosphotyrosine protein in insulintreated embryonic kidney cells is a new member of the insulin
receptor substrate family. J Biol Chem 272:21403–21407
Lavan BE, Lane WS, Lienhard GE 1997 The 60-kDa phosphotyrosine protein in insulin-treated adipocytes is a new member of the
insulin receptor substrate family. J Biol Chem 272:11439 –11443
Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa
T, Terauchi Y, Ueki K, Kaburagi Y, Satoh S, Sekihara H, Yoshioka
S, Horikoshi H, Furuta Y, Ikawa Y, Kasuga M, Yazaki Y, Aizawa
S 1994 Insulin resistance and growth retardation in mice lacking
insulin receptor substrate-1. Nature 372:182–186
Araki E, Lipes MA, Patti ME, Bruning JC, Haag B, Johnson RS,
Kahn CR 1994 Alternative pathway of insulin signalling in mice
with targeted disruption of the IRS-1 gene. Nature 372:186 –190
Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S,
Zhang Y, Bernal D, Pons S, Shulman GI, Bonner WS, White MF
1998 Disruption of IRS-2 causes type 2 diabetes in mice. Nature
391:900 –904
Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese
CB, Cohen P 1997 Characterization of a 3-phosphoinositide-
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
Vol. 21, No. 6
dependent protein kinase which phosphorylates and activates protein kinase B␣. Curr Biol 7:261–269
Marte BM, Downward J 1997 PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. Trends Biochem Sci
22:355–358
Chou MM, Hou W, Johnson J, Graham LK, Lee MH, Chen CS,
Newton AC, Schaffhausen BS, Toker A 1998 Regulation of protein
kinase C zeta by PI 3-kinase and PDK-1. Curr Biol 8:1069 –1077
Le-Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker
PJ 1998 Protein kinase C isotypes controlled by phosphoinositide
3-kinase through the protein kinase PDK1. Science 281:2042–2045
Mendez R, Kollmorgen G, White MF, Rhoads RE 1997 Requirement of protein kinase C ␨ for stimulation of protein synthesis by
insulin. Mol Cell Biol 17:5184 –5192
Standaert ML, Galloway L, Karnam P, Bandyopadhyay G, Moscat
J, Farese RV 1997 Protein kinase C-␨ as a downstream effector of
phosphatidylinositol 3-kinase during insulin stimulation in rat adipocytes. Potential role in glucose transport. J Biol Chem 272:30075–
30082
Kotani K, Ogawa W, Matsumoto M, Kitamura T, Sakaue H, Hino
Y, Miyake K, Sano W, Akimoto K, Ohno S, Kasuga M 1998
Requirement of atypical protein kinase clambda for insulin stimulation of glucose uptake but not for Akt activation in 3T3–L1
adipocytes. Mol Cell Biol 18:6971– 6982
Krook A, Roth RA, Jiang XJ, Zierath JR, Wallberg-Henriksson H
1998 Insulin-stimulated Akt kinase activity is reduced in skeletal
muscle from NIDDM subjects. Diabetes 47:1281–1286
Kim YB, Nikoulina SE, Ciaraldi TP, Henry RR, Kahn BB 1999
Normal insulin-dependent activation of Akt/protein kinase B, with
diminished activation of phosphoinositide 3-kinase, in muscle in
type 2 diabetes. J Clin Invest 104:733–741
Bjornholm M, Kawano Y, Lehtihet M, Zierath JR 1997 Insulin
receptor substrate-1 phosphorylation and phosphatidylinositol
3-kinase activity in skeletal muscle from NIDDM subjects after in
vivo insulin stimulation. Diabetes 46:524 –527
Goodyear LJ, Giorgino F, Sherman LA, Carey J, Smith RJ, Dohm
GL 1995 Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. J Clin Invest 95:2195–2204
Taylor SI 1992 Lilly Lecture: molecular mechanisms of insulin
resistance. Lessons from patients with mutations in the insulinreceptor gene. Diabetes 41:1473–1490
Kahn CR, Vicent D, Doria A 1996 Genetics of non-insulin-dependent (type-II) diabetes mellitus. Annu Rev Med 47:509 –531
O’Rahilly S, Choi WH, Patel P, Turner RC, Flier JS, Moller DE
1991 Detection of mutations in insulin-receptor gene in NIDDM
patients by analysis of single-stranded conformation polymorphisms. Diabetes 40:777–782
Cocozza S, Porcellini A, Riccardi G, Monticelli A, Condorelli G,
Ferrara A, Pianese L, Miele C, Capaldo B, Beguinot F, Varrone S
1992 NIDDM associated with mutation in tyrosine kinase domain
of insulin receptor gene. Diabetes 41:521–526
Hart LM, Stolk RP, Heine RJ, Grobbee DE, van-der-Does FE,
Maassen JA 1996 Association of the insulin-receptor variant Met985 with hyperglycemia and non-insulin-dependent diabetes mellitus in the Netherlands: a population-based study. Am J Hum
Genet 59:1119 –1125
Almind K, Bjorbaek C, Vestergaard H, Hansen T, Echwald S,
Pedersen O 1993 Aminoacid polymorphisms of insulin receptor
substrate-1 in non-insulin-dependent diabetes mellitus. Lancet 342:
828 – 832
Bernal D, Almind K, Yenush L, Ayoub M, Zhang Y, Rosshani L,
Larsson C, Pedersen O, White MF 1998 Insulin receptor substrate-2
amino acid polymorphisms are not associated with random type 2
diabetes among Caucasians. Diabetes 47:976 –979
Almind K, Inoue G, Pedersen O, Kahn CR 1996 A common amino
acid polymorphism in insulin receptor substrate-1 causes impaired
insulin signaling. Evidence from transfection studies. J Clin Invest
97:2569 –2575
Clausen JO, Hansen T, Bjorbaek C, Echwald SM, Urhammer SA,
Rasmussen S, Andersen CB, Hansen L, Almind K, Winther K,
Haraldsdo`ttir J, Borch-Johnsen K, Pedersen O 1995 Insulin resis-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 09 September 2014. at 05:56 For personal use only. No other uses without permission. . All rights reserved.
December, 2000
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
106.
TREATMENT OF INSULIN RESISTANCE
tance: interactions between obesity and a common variant of insulin receptor substrate-1. Lancet 346:397– 402
Zhang Y, Wat N, Stratton IM, Warren PM, Orho M, Groop L,
Turner RC 1996 UKPDS 19: heterogeneity in NIDDM: separate
contributions of IRS-1 and beta 3-adrenergic-receptor mutations to
insulin resistance and obesity respectively with no evidence for
glycogen synthase gene mutations. UK Prospective Diabetes Study.
Diabetologia 39:1505–1511
Koch M, Rett K, Volk A, Maerker E, Haist K, Deninger M, Renn
W, Ha¨ring HU 1999 Amino acid polymorphism Gly972Arg in IRS-1
is not associated to clamp-derived insulin sensitivity in young
healthy first degree relatives of patients with Type 2-diabetes. Exp
Clin Endocrinol Diabetes 107:318 –322
Porzio O, Federici M, Hribal ML, Lauro D, Accili D, Lauro R,
Borboni P, Sesti G 1999 The Gly972–⬎Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells.
J Clin Invest 104:357–364
Bektas A, Warram JH, White MF, Krolewski AS, Doria A 1999
Exclusion of insulin receptor substrate 2 (IRS-2) as a major locus
for early-onset autosomal dominant type 2 diabetes. Diabetes
48:640 – 642
Shepherd PR, Withers DJ, Siddle K 1998 Phosphoinositide 3kinase: the key switch mechanism in insulin signalling. Biochem
J 333:471– 490
Shepherd PR, Nave BT, Rincon J, Nolte LA, Bevan AP, Siddle K,
Zierath JR, Wallberg HH 1997 Differential regulation of phosphoinositide 3-kinase adapter subunit variants by insulin in human
skeletal muscle. J Biol Chem 272:19000 –19007
Terauchi Y, Tsuji Y, Satoh S, Minoura H, Murakami K, Okuno A,
Inukai K, Asano T, Kaburagi Y, Ueki K, Nakajima H, Hanafusa
T, Matsuzawa Y, Sekihara H, Yin Y, Barrett JC, Oda H, Ishikawa
T, Akanuma Y, Komuro I, Suzuki M, Yamamura K, Kodama T,
Suzuki H, Koyasu S, Aizawa S, Tobe K, Fukni Y, Yazaki Y,
Kadowaki T, et al 1999 Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 ␣ subunit of phosphoinositide
3-kinase. Nat Genet 21:230 –235
Hansen T, Andersen CB, Echwald SM, Urhammer SA, Clausen
JO, Vestergaard H, Owens D, Hansen L, Pedersen O 1997 Identification of a common amino acid polymorphism in the p85alpha
regulatory subunit of phosphatidylinositol 3-kinase: effects on glucose disappearance constant, glucose effectiveness, and the insulin
sensitivity index. Diabetes 46:494 –501
Kawanishi M, Tamori Y, Masugi J, Mori H, Ito C, Hansen T,
Andersen CB, Pedersen O, Kasuga M 1997 Prevalence of a polymorphism of the phosphatidylinositol 3-kinase p85 alpha regulatory subunit (codon 326 Met–⬎Ile) in Japanese NIDDM patients
[letter]. Diabetes Care 20:1043
Baier LJ, Wiedrich C, Hanson RL, Bogardus C 1998 Variant in the
regulatory subunit of phosphatidylinositol 3-kinase (p85alpha):
preliminary evidence indicates a potential role of this variant in the
acute insulin response and type 2 diabetes in Pima women. Diabetes 47:973–975
Kahn CR, Vicent D, Doria A 1996 Genetics of non-insulin-dependent (type-II) diabetes mellitus. Annu Rev Med 47:509 –531
Prochazka M, Lillioja S, Tait JF, Knowler WC, Mott DM, Spraul
M, Bennett PH, Bogardus C 1993 Linkage of chromosomal markers
on 4q with a putative gene determining maximal insulin action in
Pima Indians. Diabetes 42:514 –519
Thompson DB, Janssen RC, Ossowski VM, Prochazka M,
Knowler WC, Bogardus C 1995 Evidence for linkage between a
region on chromosome 1p and the acute insulin response in Pima
Indians. Diabetes 44:478 – 481
Hanis CL, Boerwinkle E, Chakraborty R, Ellsworth DL, Concannon P, Stirling B, Morrison VA, Wapelhorst B, Spielman RS,
Gogolin EK, Shepard JM, Williams SR, Risch N, Hinds D,
Iwasaki N, Ogata M, Omori Y, Petzold C, Rietzch H, Schroder HE,
Schulze J, Cox NJ, Menzel S, Boriraj VV, Chen X, Lim LR, Lindner
T, Mereu LE, Wang YQ, Xiang K, Yamagata K, Yang Y, Bell GI
1996 A genome-wide search for human non-insulin-dependent
(type 2) diabetes genes reveals a major susceptibility locus on
chromosome 2. Nat Genet 13:161–166
Stern MP, Duggirala R, Mitchell BD, Reinhart LJ, Shivakumar S,
Shipman PA, Uresandi OC, Benavides E, Blangero J, O’Connell
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
609
P 1996 Evidence for linkage of regions on chromosomes 6 and 11
to plasma glucose concentrations in Mexican Americans. Genome
Res 6:724 –734
Mahtani MM, Widen E, Lehto M, Thomas J, McCarthy M, Brayer
J, Bryant B, Chan G, Daly M, Forsblom C, Kanninen T, Kirby A,
Kruglyak L, Munnelly K, Parkkonen M, Reeve DM, Weaver A,
Brettin T, Duyk G, Lander ES, Groop LC 1996 Mapping of a gene
for type 2 diabetes associated with an insulin secretion defect by a
genome scan in Finnish families. Nat Genet 14:90 –94
Elbein SC, Bragg KL, Hoffman MD, Mayorga RA, Leppert MF
1996 Linkage studies of NIDDM with 23 chromosome 11 markers
in a sample of whites of northern European descent. Diabetes
45:370 –375
Ji L, Malecki M, Warram JH, Yang Y, Rich SS, Krolewski AS 1997
New susceptibility locus for NIDDM is localized to human chromosome 20q. Diabetes 46:876 – 881
Bowden DW, Sale M, Howard TD, Qadri A, Spray BJ, Rothschild
CB, Akots G, Rich SS, Freedman BI 1997 Linkage of genetic markers on human chromosomes 20 and 12 to NIDDM in Caucasian sib
pairs with a history of diabetic nephropathy. Diabetes 46:882– 886
Zouali H, Hani EH, Philippi A, Vionnet N, Beckmann JS, Demenais F, Froguel P 1997 A susceptibility locus for early-onset
non-insulin dependent (type 2) diabetes mellitus maps to chromosome 20q, proximal to the phosphoenolpyruvate carboxykinase
gene. Hum Mol Genet 6:1401–1408
Pratley RE, Thompson DB, Prochazka M, Baier L, Mott D, Ravussin E, Sakul H, Ehm MG, Burns DK, Foroud T, Garvey WT,
Hanson RL, Knowler WC, Bennett PH, Bogardus C 1998 An
autosomal genomic scan for loci linked to prediabetic phenotypes
in Pima Indians. J Clin Invest 101:1757–1764
Hanson RL, Ehm MG, Pettitt DJ, Prochazka M, Thompson DB,
Timberlake D, Foroud T, Kobes S, Baier L, Burns DK, Almasy L,
Blangero J, Garvey WT, Bennett PH, Knowler WC 1998 An autosomal genomic scan for loci linked to type II diabetes mellitus and
body-mass index in Pima Indians. Am J Hum Genet 63:1130 –1138
Elbein SC, Hoffman MD, Teng K, Leppert MF, and Hasstedt SJ
1999 A genome-wide search for type 2 diabetes susceptibility genes
in Utah Caucasians. Diabetes 48:1175–1182
Ghosh S, Watanabe RM, Hauser ER, Valle T, Magnuson VL,
Erdos MR, Langefeld CD, Balow J, Ally DS, Kohtamaki K, Chines
P, Birznieks G, Kaleta HS, Musick A, Te C, Tannenbaum J,
Eldridge W, Shapiro S, Martin C, Witt A, So A, Chang J, Shurtleff
B, Porter R, Boehnke M, et al 1999 Type 2 diabetes: evidence for
linkage on chromosome 20 in 716 Finnish affected sib pairs. Proc
Natl Acad Sci USA 96:2198 –2203
Stern MP, Mitchell BD, Blangero J, Reinhart L, Krammerer CM,
Harrison CR, Shipman PA, O’Connell P, Frazier ML, MacCluer
JW 1996 Evidence for a major gene for type II diabetes and linkage
analyses with selected candidate genes in Mexican-Americans. Diabetes 45:563–568
Hager J, Dina C, Francke S, Dubois S, Houari M, Vatin V, Vaillant
E, Lorentz N, Basdevant A, Clement K, Guy GB, Froguel P 1998
A genome-wide scan for human obesity genes reveals a major
susceptibility locus on chromosome 10. Nat Genet 20:304 –308
Wolford JK, Bogardus C, Prochazka M 1999 Genome-wide scan
for CAG/CTG repeat expansions in Pimas with early onset of type
2 diabetes mellitus. Mol Genet Metab 66:62– 67
Hegele RA, Sun F, Harris SB, Anderson C, Hanley AJ, Zinman B
1999 Genome-wide scanning for type 2 diabetes susceptibility in
Canadian Oji-Cree, using 190 microsatellite markers. J Hum Genet
44:10 –14
Goodyear LJ, Kahn BB 1998 Exercise, glucose transport, and insulin sensitivity. Annu Rev Med 49:235–261
Perseghin G, Price TB, Petersen KF, Roden M, Cline GW, Gerow
K, Rothman DL, Shulman GI 1996 Increased glucose transportphosphorylation and muscle glycogen synthesis after exercise
training in insulin-resistant subjects. N Engl J Med 335:1357–1362
Hespel P, Vergauwen L, Vandenberghe K, Richter EA 1995 Important role of insulin and flow in stimulating glucose uptake in
contracting skeletal muscle. Diabetes 44:210 –215
Kishi K, Muromoto N, Nakaya Y, Miyata I, Hagi A, Hayashi H,
Ebina Y 1998 Bradykinin directly triggers GLUT4 translocation via
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 09 September 2014. at 05:56 For personal use only. No other uses without permission. . All rights reserved.
610
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
MATTHAEI ET AL.
an insulin-independent pathway [published erratum appears in
Diabetes 1998 Jul;47(7):1170]. Diabetes 47:550 –558
DeFronzo RA, Sherwin RS, Kraemer N 1987 Effect of physical
training on insulin action in obesity. Diabetes 36:1379 –1385
Koivisto VA, Yki-Ja¨rvinen H 1987 Effect of exercise on insulin
binding and glucose transport in adipocytes of normal humans.
J Appl Physiol 63:1319 –1323
Stumvoll M, Jacob S 1999 Multiple sites of insulin resistance:
muscle, liver and adipose tissue [comment]. Exp Clin Endocrinol
Diabetes 107:107–110
Grassi G, Seravalle G, Cattaneo BM, Bolla GB, Lanfranchi A,
Colombo M, Giannattasio C, Brunani A, Cavagnini F, Mancia G
1995 Sympathetic activation in obese normotensive subjects. Hypertension 25:560 –563
Scherrer U, Randin D, Tappy L, Vollenweider P, Jequier E, Nicod
P 1994 Body fat and sympathetic nerve activity in healthy subjects.
Circulation 89:2634 –2640
Hilsted J, Richter E, Madsbad S, Tronier B, Christensen NJ,
Hildebrandt P, Damkjaer M, Galbo H 1987 Metabolic and cardiovascular responses to epinephrine in diabetic autonomic neuropathy. N Engl J Med 317:421– 426
Randle PJ, Garland PB, Hales CN, Newsholme EA 1963 The
glucose fatty-acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1:785–789
Gonzalez MC, Ayuso MS, Parrilla R 1989 Control of hepatic gluconeogenesis: role of fatty acid oxidation. Arch Biochem Biophys
271:1–9
Felley CP, Felley EM, van-Melle GD, Frascarolo P, Jequier E,
Felber JP 1989 Impairment of glucose disposal by infusion of triglycerides in humans: role of glycemia. Am J Physiol 256:E747–E752
Boden G, Chen X, Ruiz J, White JV, Rossetti L 1994 Mechanisms
of fatty acid-induced inhibition of glucose uptake. J Clin Invest
93:2438 –2446
Wolfe RR 1998 Metabolic interactions between glucose and fatty
acids in humans. Am J Clin Nutr 67:519S–526S
Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman
JM 1994 Positional cloning of the mouse obese gene and its human
homologue [published erratum appears in Nature 1995 Mar 30;
374(6521):479] [see comments]. Nature 372:425– 432
Tartaglia LA, Dembski M, Weng X, Deng NH, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C,
Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Woolf EA,
Monroe CA, Tepper RI 1995 Identification and expression cloning
of a leptin receptor, OB-R. Cell 83:1263–1271
White DW, Tartaglia LA 1996 Leptin and OB-R: body weight
regulation by a cytokine receptor. Cytokine Growth Factor Rev
7:303–309
Friedman JM, Halaas JL 1998 Leptin and the regulation of body
weight in mammals. Nature 395:763–770
Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ,
Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM,
Tepper RI, Morgenstern JP 1996 Evidence that the diabetes gene
encodes the leptin receptor: identification of a mutation in the leptin
receptor gene in db/db mice. Cell 84:491– 495
Cohen B, Novick D, Rubinstein M 1996 Modulation of insulin
activities by leptin. Science 274:1185–1188
Berti L, Kellerer M, Capp E, Haring HU 1997 Leptin stimulates
glucose transport and glycogen synthesis in C2C12 myotubes: evidence for a PI3-kinase mediated effect. Diabetologia 40:606 – 609
Muller G, Ertl J, Gerl M, Preibisch G 1997 Leptin impairs metabolic actions of insulin in isolated rat adipocytes. J Biol Chem
272:10585–10593
Kieffer TJ, Keller RS, Leech CA, Holz GG, Habener JF 1997 Leptin
suppression of insulin secretion by the activation of ATP-sensitive
K⫹ channels in pancreatic ␤-cells. Diabetes 46:1087–1093
Shimizu H, Ohtani K, Tsuchiya T, Takahashi H, Uehara Y, Sato
N, Mori M 1997 Leptin stimulates insulin secretion and synthesis
in HIT-T 15 cells. Peptides 18:1263–1266
Tanizawa Y, Okuya S, Ishihara H, Asano T, Yada T, Oka Y 1997
Direct stimulation of basal insulin secretion by physiological concentrations of leptin in pancreatic ␤ cells. Endocrinology 138:4513–
4516
Fehmann HC, Berghofer P, Brandhorst D, Brandhorst H, Hering
147.
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
161.
162.
163.
164.
165.
166.
Vol. 21, No. 6
B, Bretzel RG, Goke B 1997 Leptin inhibition of insulin secretion
from isolated human islets. Acta Diabetologica 34:249 –252
Harvey J, McKenna F, Herson PS, Spanswick D, Ashford MLJ
1997 Leptin activates ATP-sensitive potassium channels in the rat
insulin-secreting cell line, CRI-G1. J Physiol (Lond) 504:527–535
Seufert J, Kieffer TJ, Leech CA, Holz GG, Moritz W, Ricordi C,
Habener JF 1999 Leptin suppression of insulin secretion and gene
expression in human pancreatic islets: implications for the development of adipogenic diabetes mellitus. J Clin Endocrinol Metab
84:670 – 676
Ookuma M, Ookuma K, York DA 1998 Effects of leptin on insulin
secretion from isolated rat pancreatic islets. Diabetes 47:219 –223
Zhao AZ, Bornfeldt KE, Beavo JA 1998 Leptin inhibits insulin
secretion by activation of phosphodiesterase 3B. J Clin Invest 102:
869 – 873
Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D,
Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A,
Bougneres P, Lebouc Y, Froguel P, Guy GB 1998 A mutation in the
human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392:398 – 401
O’Rahilly S 1998 Life without leptin [news; comment]. Nature
392:330 –331
Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA,
Cheetham CH, Earley AR, Barnett AH, Prins JB, O’Rahilly S 1997
Congenital leptin deficiency is associated with severe early-onset
obesity in humans. Nature 387:903–908
Peraldi P, Spiegelman B 1998 TNF-␣ and insulin resistance: summary and future prospects. Mol Cell Biochem 182:169 –175
Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF,
Spiegelman BM 1996 IRS-1-mediated inhibition of insulin receptor
tyrosine kinase activity in TNF-␣- and obesity-induced insulin
resistance. Science 271:665– 668
Kanety H, Hemi R, Papa MZ, Karasik A 1996 Sphingomyelinase
and ceramide suppress insulin-induced tyrosine phosphorylation
of the insulin receptor substrate-1. J Biol Chem 271:9895–9897
Kroder G, Bossenmaier B, Kellerer M, Capp E, Stoyanov B,
Muhlhofer A, Berti L, Horikoshi H, Ullrich A, Haring H 1996
Tumor necrosis factor-␣- and hyperglycemia-induced insulin resistance. Evidence for different mechanisms and different effects on
insulin signaling. J Clin Invest 97:1471–1477
Kellerer M, Rett K, Renn W, Groop L, Haring HU 1996 Circulating TNF-␣ and leptin levels in offspring of NIDDM patients
do not correlate to individual insulin sensitivity. Horm Metab
Res 28:737–743
Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R 1996 Effects of
an engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM.
Diabetes 45:881– 885
Harris PK, Kletzien RF 1994 Localization of a pioglitazone response element in the adipocyte fatty acid-binding protein gene.
Mol Pharmacol 45:439 – 445
Lemberger T, Braissant O, Juge AC, Keller H, Saladin R, Staels
B, Auwerx J, Burger AG, Meier CA, Wahli W 1996 PPAR tissue
distribution and interactions with other hormone-signaling pathways. Ann NY Acad Sci 804:231–251
Spiegelman BM 1998 PPAR-␥: adipogenic regulator and thiazolidinedione receptor. Diabetes 47:507–514
Auwerx J 1999 PPAR␥, the ultimate thrifty gene. Diabetologia
42:1033–1049
Yen CJ, Beamer BA, Negri C, Silver K, Brown KA, Yarnall DP,
Burns DK, Roth J, Shuldiner AR 1997 Molecular scanning of the
human peroxisome proliferator activated receptor ␥ (hPPAR␥)
gene in diabetic Caucasians: identification of a Pro12Ala PPAR ␥
2 missense mutation. Biochem Biophys Res Commun 241:270 –274
Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J 1998 A Pro12Ala substitution in PPAR␥2 associated with decreased receptor activity,
lower body mass index and improved insulin sensitivity. Nat Genet
20:284 –287
Koch M, Rett K, Maerker E, Volk A, Deninger M, Renn W, Ha¨ring
HU 1999 The PPAR␥2 amino acid polymorphism Pro 12 Ala is
prevalent in offspring of Type II diabetic patients and is associated
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 09 September 2014. at 05:56 For personal use only. No other uses without permission. . All rights reserved.
December, 2000
167.
168.
169.
170.
171.
172.
173.
174.
175.
176.
177.
178.
179.
180.
181.
182.
183.
184.
185.
186.
187.
188.
189.
TREATMENT OF INSULIN RESISTANCE
to increased insulin sensitvitiy in a subgroup of obese subjects.
Diabetologia 42:758 –762
Masuda K, Okamoto Y, Tsuura Y, Kato S, Miura T, Tsuda K,
Horikoshi H, Ishida H, Seino Y 1995 Effects of Troglitazone (CS045) on insulin secretion in isolated rat pancreatic islets and HIT
cells: an insulinotropic mechanism distinct from glibenclamide.
Diabetologia 38:24 –30
Fujiwara T, Wada M, Fukuda K, Fukami M, Yoshioka S, Yoshioka
T, Horikoshi H 1991 Characterization of CS-045, a new oral antidiabetic agent. II. Effects on glycemic control and pancreatic islet
structure at a late stage of the diabetic syndrome in C57BL/KsJdb/db mice. Metabolism 40:1213–1218
Buckingham RE, Al-Barazanji KA, Toseland CD, Slaughter M,
Connor SC, West A, Bond B, Turner NC, Clapham JC 1998 Peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats. Diabetes 47:1326 –1334
Shimabukuro M, Zhou YT, Lee Y, Unger RH 1998 Troglitazone
lowers islet fat and restores ␤ cell function of Zucker diabetic fatty
rats. J Biol Chem 273:3547–3550
Rossetti L, Giaccari A, DeFronzo RA 1990 Glucose toxicity. Diabetes Care 13:610 – 630
Yki-Ja¨rvinen H 1992 Glucose toxicity. Endocr Rev 13:415– 431
Unger RH, Grundy S 1985 Hyperglycaemia as an inducer as well
as a consequence of impaired islet cell function and insulin resistance: implications for the mangement of diabetes. Diabetologia
28:119 –121
Cavaghan MK, Ehrmann DA, Byrne MM, Polonsky KS 1997
Treatment with the oral antidiabetic agent troglitazone improves ␤
cell responses to glucose in subjects with impaired glucose tolerance. J Clin Invest 100:530 –537
Balfour JA, McTavish D 1993 Acarbose. An update of its pharmacology and therapeutic use in diabetes mellitus. Drugs 46:1025–
1054
Clissold SP, Edwards C 1988 Acarbose. A preliminary review of
its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs 35:214 –243
Salvatore T, Giugliano D 1996 Pharmacokinetic-pharmacodynamic relationships of Acarbose. Clin Phamacokinet 30:94 –106
Bischoff H 1994 Pharmacology of ␣-glucosidase inhibition. Eur
J Clin Invest 24[Suppl 3]:3–10
Harrower AD 1996 Pharmacokinetics of oral antihyperglycaemic
agents in patients with renal insufficiency. Clin Phamacokinet 31:
111–119
Yee HS, Fong NT 1996 A review of the safety and efficacy of acarbse
in diabetes mellitus. Pharmacotherapy 16:792– 805
Campbell LK, White JR, Campbell RK 1996 Acarbose: its role in
the treatment of diabetes mellitus. Ann Pharmacother 30:1255–1262
Puls W 1996 Phamacology of glucosidase inhibitors. In: Kuhlmann
J, Puls W (eds) Handbook of Experimental Pharmacology: Oral
Antidiabetics. Springer, Berlin, vol 119:497–525
Lebovitz HE 1997 ␣-Glucosidase inhibitors. Endocrinol Metab Clin
North Am 26:539 –551
Hanefeld M, Fischer S, Schulze J, Spengler M, Wargenau M,
Schollberg K, Fu¨cker K 1991 Therapeutic potentials of acarbose as
first-line drug in NIDDM insufficiently treated with diet alone.
Diabetes Care 14:732–737
Lindstrom J, Tuomilehto J, Spengler M 1996 The effect of acarbose
on dietary nutrient intake and metabolic control in NIDDM patients. (Abstract) Diabetologia 39[Suppl 1]:739
Coniff RF, Shapiro JA, Seaton TB 1994 Long-term efficacy and
safety of acarbose in the treatment of obese subjects with noninsulin-dependent diabetes mellitus. Arch Intern Med 154:2442–
2448
Coniff RF, Shapiro JA, Seaton TB, Bray GA 1995 Multicenter,
placebo-controlled trial comparing acarbose with placebo, tolbutamde and tolbutamide plus acarbose in non-insulin-dependent
diabetes mellitus. Am J Med 98:443– 451
Matsumoto K, Yano M, Miyake S, Ueki Y, Yamaguchi Y, Akazama S, Tominaga Y 1998 Effects of voglibose on glycemic excursions, insulin secretion and insulin sensitivity in non-insulin
treated NIDDM patients. Diabetes Care 21:256 –260
Segal P, Feig PU, Schernthaner G, Ratzmann KP, Rybka J, Petz-
190.
191.
192.
193.
194.
195.
196.
197.
198.
199.
200.
201.
202.
203.
204.
205.
206.
207.
208.
209.
611
inna D, Berlin C 1997 The efficacy and safety of miglitol therapy
compared with glibenclamide in patients with NIDDM inadequately controlled by diet alone. Diabetes Care 20:687– 691
Coniff RF, Shapiro JA, Robbins D, Kleinfield R, Seaton TB,
Beisswenger P, McGill JB 1995 Reduction in glycosylated hemoglobin and postprandial hyperglycemia by acarbose in patients
with NIDDM: a placebo-controlled dose comparison study. Diabetes Care 18:817– 824
Johnston PS, Feig PU, Coniff RF, Krol A, Kelley DE, Mooradian
D 1998 Chronic treatment of African-American type 2 diabeic patients with ␣-glucosidase inhibition. Diabetes Care 21:416 – 422
Braun D, Schonherr U, Mitzkat HJ 1996 Efficacy of acarbose monotherapy in patients with type 2 diabetes: a double-blind study
conducted in general practice. Endocrinol Metab 3:275–280
Johnston PS, Feig PU, Coniff RF, Krol A, Davidson JA, Haffner
SM 1998 Long-term titrated-dose alpha-glucosidase inhibition in
non-insulin requiring hispanic NIDDM patients. Diabetes Care
21:409 – 415
Hoffman J, Spengler M 1997 Efficacy of 24 week monotherapy
with acarbose, metformin or placebo in dietary-treated NIDDM
patients: the Essen II Study. Am J Med 103:483– 490
Pagano G, Marena S, Corgiat-Mansin L, Cravero F, Giordia C,
Bozza M, Ross CM 1995 Comparison of miglitol and glibenclamide
in diet-treated type 2 diabetic patients. Diabete Metab 21:162–167
Santeusanio F, Ventura MM, Contandini S, Compagnucci P,
Moriconi V, Zaccarini P 1993 Efficacy and safety of two different
doses of acarbose in non-insulin-dependent diabetic patients
treated by diet alone. Diabetes Nutr Metab 6:147–154
Hotta N, Kakutta H, Sano T, Masumae H, Yamada H, Kitazawa
S, Sakamoto N 1993 Long-term effect of acarbose on glycemic
control in non-insulin-dependent diabetes mellitus: a placebo controlled double-blind study. Diabet Med 10:134 –138
Johnston PS, Lebovitz HE, Coniff RF, Simonson DC, Raskin P,
Munera CL 1998 Advantages of ␣-glucosidase inhibition as monotherapy in eldely type 2 diabetic patients. J Clin Endocrinol Metab
83:1515–1522
Hasche H, Mertes G 1998 Efficacy of acarbose in patients receiving
dietary training and counselling: a 2-year placebo-controlled, double-blind study (Abstract) Diabetes 47 [Suppl 1]:351
Kawagishi T, Nshizawa Y, Taniwaki H, Tanaka S, Okuno Y,
Inaba M, Ishimura E, Emoto M, Morii H 1997 Relationship between gastric emptying and ␣-glucosidase inhibitor effect on postprandial hyperglycemia in NIDDM patients. Diabetes Care 20:
1529 –1532
Chiasson JL, Josse RG, Hunt JA, Palmason C, Rodger NW, Ross
SA, Ryan EA, Tan MN, Wolever TMS 1994 The efficacy of acarbose
in the treatment of patients with non-insulin-dependent diabetes
mellitus: a multicenter controlled clinical trial. Ann Intern Med
121:928 –935
Hoffmann J, Spengler M 1994 Efficacy of 24 week monotherapy
with acabose, glibenclamide or placebo in NIDDM patients. Diabetes Care 17:561–566
Mertes G 1998 Efficacy and safety of acarbose in the treatment of
Type 2 diabetes: data from a 2-year surveillance study. Diabetes Res
Clin Pract 40:63–70
Lebovitz HE 1998 @-Glucosidase inhibitors as agents in the treatment of diabetes. Diabetes Rev 6:132–145
Holman RR, Cull C, Turner R 1999 A randomized double-blind
trial of acarbose in type 2 diabetes shows improved glycemic control over three years. Diabetes Care 22:960 –964
Chiasson JL, Josse RG, Leiter L, Mihic M, Nathan DM, Palmason
C, Cohen RM, Wolever TMS 1996 The effect of acarbose on insulin
sensitivity in subjects with impaired glucose tolerance. Diabetes
Care 19:1190 –1193
Laube H, Linn T, Heyen P 1998 The effects of acarbose on insulin
sensitivity and proinsulin in overweight subjects with impaired
glucose tolerance. Exp Clin Endocrinol Diabetes 106:231–233
Shinozaki K, Suzuki M, Ikebuchi M, Hirose J, Hara Y, Harano Y
1996 Improvement of insulin sensitivity and dyslipidemia with a
new ␣-glucosidase inhibitor, voglibose, in nondiabetic hyperinsulinemic subjects. Metabolism 45:731–737
Schnack C, Prager RJF, Winkler J, Klauser RM, Schneider BG,
Schernthaner G 1989 Effects of 8-wk ␣-glucosidase inhibition on
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 09 September 2014. at 05:56 For personal use only. No other uses without permission. . All rights reserved.
612
210.
211.
212.
213.
214.
215.
216.
217.
218.
219.
220.
221.
222.
223.
224.
225.
226.
227.
228.
229.
MATTHAEI ET AL.
metabolic control, C-peptide secretion, hepatic glucose output, and
peripheral insulin sensitvity in poorly controlled type II diabetic
patients. Diabetes Care 12:537–543
Reaven GM, Lardinois CK, Greenfield MS, Schwarzt HC, Vreman HJ 1990 Effect of acarbose on carbohydrate and lipid metabolism in NIDDM patients poorly controlled by sufonylureas. Diabetes Care 13[Suppl 3]:32–36
Jenney A, Proietto J, OⴕDea K, Nankervis A, Traianedes K,
D‘Embden H 1993 Low-dose acarbose improves glycemic control
in NIDDM patients without changes in insulin sensitivity. Diabetes
Care 16:499 –502
Johnson AB, Taylor R 1996 Does suppression of postprandial
blood glucose excursions by the ␣-glucosidase inhibitor miglitol
improve insulin sensitivity in diet-treated type II diabetic patients?
Diabetes Care 19:559 –563
Matsumoto K, Yano M, Miyake S, Ueki Y, Yamaguchi Y, Akazawa
S, Tominaga Y 1998 Effects of voglibose on glycemic excursions,
insulin secretion, and insulin sensitivity in non-insulin-treated
NIDDM patients. Diabetes Care 21:256 –260
Chiasson JL, Gomis R, Hanefeld M, Josse RG, Karasik A, Laakso
M and the STOP-NIDDM Trial Research Group 1998 The STOPNIDDM Trial: an international study on the efficacy of an ␣glucosidase inhibitor to prevent type 2 diabetes in a population
with impaired glucose tolerance: rationale, design, and preliminary
screening data. Diabetes Care 21:1720 –1725
Pan X, Li G, Hu YH, Wang J, Yang W, Zuo A, Ze H, Lin J, Xiao
JZ, Cao H, Liu PA, Jiang X, Jiang Y, Wang J, Zheng H, Zhang H,
Bennett PH, Howard BV 1997 Effects of diet and exercise in preventing NIDDM in people with impaired glucose toleance: the Da
Qing IGT and Diabetes Study. Diabetes Care 20:537–544
Karunakaran S, Hammersley MS, Morris RJ, Turner RC, Holman
RR 1997 The Fasting Hyperglycemia Study. III. Randomized Trial
of sulfonylurea therapy in subjects with increased but not diabetic
fasting plasma glucose. Metabolism 46[Suppl 1]:55– 60
Clissold SP, Edwards C 1988 Acarbose. A preliminary review of
its pharmacodynamic and pharmacokinetic properties and
theapeutic potential. Drugs 35:214 –243
Spengler M, Cagatay M 1992 Assessment of efficacy and tolerability of acarbose in diabetic patients 5–16 years of age. In: Lefebvre
PJ, Standl E (eds) New Aspects in Diabetes. Treatment Strategies
with ␣-Glucosidase Inhibitors. De Gruyter, Berlin, pp 290 –294
Ahr HJ, Boberg M, Krause HP, Maul W, Mu¨ller FO 1989 Pharmacokinetics of acarbose. I. Absorption, concentration in plasma
metabolism and excretion after single administration of [14C]acarbose to rats, dogs and man. Arzneimittelforschung 39:1254 –1260
Ahr HJ, Krause HP, Siefert HM, Steinke W, Weber H 1989 Pharmacokinetics of acarbose. II. Distributon to and elimination from
tissues and organs following single or repeated administration of
[14C]acarbose to rats and dogs. Arzneimittelforschung 39:1261–
1267
Hollander PA 1996 Acarbose: adverse events and safety profile.
Drug Benefit Trends 8[Suppl E]:46 –54
Wang PY, Kaneko T, Wang Y, Sato A 1999 Acarbose alone or in
combination with ethanol potentiates the hepatotoxicity of carbon
tetrachloride and acetaminophen in rats. Hepatology 29:161–165
Buse J, Hart K, Minasi L 1998 The PROTECT Study: final results
of a large multicenter postmarketing study in patients with type 2
diabetes. Precose Resolution of optimal titration to enhance current
therapies. Clin Ther 20:257–269
Andrade RJ, Lucena M, Vega JL, Torres M, Salmeron FJ, Bellot
V, Garcia-Escano MD, Moreno P 1998 Acarbose-associated hepatotoxicity [letter]. Diabetes Care 21:2029 –2030
Andrade RJ, Lucena M, Rodriguez-Mendizabal M 1996 Hepatic
injury caused by acarbose [letter]. Ann Intern Med 124:931
Carrascosa M, Pascual F, Aresti S 1997 Acarbose-induced severe
hepatotoxicity [letter]. Lancet 349:698 – 699
Diaz-Gtierrez FL, Ladero JM, Diaz-Rubio M 1998 Acarboseinduced acute hepatitis [letter]. Am J Gastroenterol 93:481
Kihara Y, Ogami Y, Tabaru A, Unoki H, Otsuki M 1997 Safe and
effective treatment of diabetes mellitus associated with chronic
liver disease with an ␣-glucosidase inibitor. J Gastroenterol 32:
777–782
Kono T, Hayami M, Kobayashi H, Ishii M, Taniguchi S 1999
230.
231.
232.
233.
234.
235.
236.
237.
238.
239.
240.
241.
242.
243.
244.
245.
246.
247.
248.
249.
250.
251.
252.
253.
254.
Vol. 21, No. 6
Acarbose-induced generalised erythema multiforme. Lancet 354:
396 –397
Johansen K 1999 Efficacy of metformin in the treatment of NIDDM.
Diabetes Care. 22:33–37
Bailey CJ, Turner RC 1996 Metformin. N Engl J Med 334:574 –579
Dunn CJ, Peters DH 1995 Metformin. A review of its pharmacological properties and therapeutic use in non-insulin-dependent
diabetes mellitus. Drugs. 49:721–749
Davidson MB, Peters AL 1997 An overview of metformin in the
treatment of type 2 diabetes mellitus. Am J Med 102:99 –110
Bailey C J 1992 Biguanides and NIDDM. Diabetes Care 15:755–772
Klip A, Leiter L 1990 Cellular mechanism of action of metformin.
Diabetes Care 13:696 –704
Bailey C 1988 Metformin revisited: its actions and indications for
use. Diabetic Med 5:315–320
Hermann L 1990 Biguanides and sulfonylureas as combination
therapy in NIDDM. Diabetes Care 13:37– 41
Bailey C, Nattrass M 1988 Treatment - metformin. Baillieres Clin
Endocrinol Metab 2:455– 476
UK Prospective Diabetes Study Group 1998 Effect of intensive
blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:
854 – 865
DeFronzo RA, Goodman AM, The Multicenter Metformin Study
Group 1995 Efficacy of metformin in patients with non-insulindependent diabetes mellitus. N Engl J Med 333:541–549
Hermann LS, Kjellstro¨m T, Nilsson-Ehle P 1991 Effects of metformin and glibenclamide alone and in combination on serum
lipids and lipoproteins in patients with non-insulin-dependent diabetes mellitus. Diabete Metab 17:174 –179
Ferner RE, Rawlins MD, Alberti K G 1988 Impaired ␤-cell responses improve when fasting blood glucose concentration is reduced in non-insulin-dependent diabetes. Q J Med 66:137–146
Yki-Ja¨rvinen H 1992 Glucose toxicity. Endocr Rev 13:415– 431
Dinneen S, Gerich J, Rizza R 1992 Carbohydrate metabolism
in non-insulin-dependent diabetes mellitus. N Engl J Med 327:
707–713
DeFronzo RA, Bonadonna RC, Ferrannini E 1992 Pathogenesis of
NIDDM. Diabetes Care 15:318 –368
Nosadini R, Avogaro A, Trevisian R, Valerio A, Tessari P, Duner
E, Tiengo A, Velussi M, Del Prato S, De Kreutzenberg S, Muggeo
M, Crepaldi G 1987 Effect of metformin on insulin-stimulated
glucose turnover and insulin binding to receptors in type II diabetes. Diabetes Care 10:62– 67
Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE 1995
Metabolic effects of metformin in non-insulin-dependent diabetes
mellitus. N Engl J Med. 333:550 –554
Cusi K, Consoli A, DeFronzo RA 1996 Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent
diabetes mellitus. J Clin Endocrinol Metab 81:4059 – 4067
Prager R, Schernthaner G, Graf H 1986 Effect of metformin on
peripheral insulin sensitivity in non-insulin-dependent diabetes
mellitus. Diabete Metab 12:346 –350
Jackson RA, Hawa MI, Jaspan JB, Sim BM. Disilvio L, Featherbe
D, Kurtz AB 1987 Mechanism of metformin action in noninsulindependent diabetes. Diabetes 36:632– 640
DeFronzo RA, Barzilai N, Simonson DC 1991 Mechanism of metformin action in obese and lean noninsulin-dependent diabetic
subjects. J Clin Endocrinol Metab 73:1294 –1301
Johnson AB, Webster JM, Sum C-F, Heseltine L, Argyraki M,
Cooper BG, Taylor R 1993 The impact of metformin therapy on
hepatic glucose production and skeletal muscle glycogen synthase
activity in overweight type II diabetic patients. Metabolism 42:
1217–1222
Perriello G, Misericordia P, Volpi E, Santucci A, Santucci C,
Ferrannini E, Ventura MM, Santeusanio F, Brunetti P, Bolli GB
1994 Acute antihyperglycemic mechanisms of metformin in
NIDDM. Evidence for suppression of lipid oxidation and hepatic
glucose production. Diabetes 43:920 –928
Hother-Nielsen O, Schmitz O, Andersen PH, Beck-Nielsen H,
Pedersen O 1989 Metformin improves peripheral but not hepatic
insulin action in obese patients with type II diabetes. Acta Endocrinol (Copenh) 120:257–265
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 09 September 2014. at 05:56 For personal use only. No other uses without permission. . All rights reserved.
December, 2000
TREATMENT OF INSULIN RESISTANCE
255. Riccio A, Del Prato S, Vigili de Kreutzenberg S, Tiengo A 1991
Glucose and lipid metabolism in non-insulin-dependent diabetes.
Effect of metformin. Diabete Metab 17:180 –184
256. McIntyre HD, Ma A, Bird DM, Paterson CA, Ravenscroft PJ,
Cameron DP 1991 Metformin increases insulin sensitivity and
basal glucose clearance in type 2 (non-insulin dependent) diabetes
mellitus. Aust NZ J Med 21:714 –719
257. Wu MS, Johnston P, Sheu WH, Hollenbeck CB, Jeng CY, Goldfine ID, Chen YD, Reaven GM 1990 Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care. 13:1– 8
258. DeFronzo RA 1988 The triumvirate: B-cell, muscle, and liver: a
collusion responsible for NIDDM. Diabetes 37:667– 687
259. Widen EI, Eriksson JG, Groop LC 1992 Metformin normalizes
nonoxidative glucose metabolism in insulin-resistant normoglycemic first-degree relatives of patients with NIDDM. Diabetes 41:
354 –358
260. Wing RR, Koeske R, Epstein LH, Norwalk MP, Gooding W,
Becker D 1987 Long-term effects of modest weight loss in type II
diabetic patients. Arch Intern Med 147:1749 –1753
261. Morel Y, Golay A, Perneger T, Lehmann T, Vadas L, Pasik C,
Reaven GM 1999 Metformin treatment leads to an increase in basal,
but not insulin-stimulated, glucose disposal in obese patients with
impaired glucose tolerance. Diabet Med 16:650 – 655
262. Scheen AJ, Letiexhe MR, Lefebvre PJ 1995 Short administration of
metformin improves insulin sensitivity in android obese subjects
with impaired glucose tolerance. Diabet Med 12:985–989
263. Diamanti Kandarakis E, Kouli C, Tsianateli T, Bergiele A 1998
Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome. Eur J Endocrinol
138:269 –274
264. Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M,
Zanolin E, Muggeo M 2000 Metformin effects on clinical features
endocrine and metabolic pofiles and insulin sensitivity in polycystic ovary syndrome: a randomized double-blind placebocontrolled 6-month trial followed by open long-term clinical evaluation. J Clin Endocrinol Metab 85:139 –146
265. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R 1998 Effects of
metformin on spontaneous and clomiphen-induced ovulation in
the polycystic ovary syndrome. N Engl J Med 338:1876 –1880
266. Hermann LS 1975 Metformin: a review of its pharmacologic properties and therapeutic use. Diabete Metab 5:233–245
267. McLelland J 1985 Recovery from metformin overdose. Diabet Med
2:410 – 411
268. Ma¨kimattila S, Nikkila¨ K, Yki-Ja¨rvinen H 1999 Causes of weight
gain during insulin therapy with and without metformin in patients with type II diabetes. Diabetologia 42:406 – 412
269. Giugliano D, Quatraro A, Consoli G, Mineai A, Ceriello A, De
Rosa N, D’Onofrio F 1993 Metformin for obese, insulin-treated
diabetic patients: improvement in glycaemic control and reduction
of metabolic risk factors. Eur J Clin Pharmacol 44:107–112
270. Robinson AC, Johnston DG, Burke J, Elkeles RS, Robinson S
1998 The effect of metformin on glycemic control and serum lipids
in insulin-treated NIDDM patients with suboptimal metabolic control. Diabetes Care 21:701–705
271. Gin H, Messerchmitt C, Brottier E, Aubertin J 1985 Metformin
improved insulin resistance in type I, insulin-dependent, diabetic
patients. Metabolism. 34:923–925
272. Pagano G, Tagliaferro V, Carta Q, Caselle MT, Bozzo C, vitelli
F, Trovati M, Cocuzza E 1983 Metformin reduces insulin requirements in type 1 (insulin-dependent) diabetes. Diabetologia
24:351–354
273. Gin H, Slama G, Weissbrodt P, Poynard T, Vexiau P, Klein JC,
Tchobroutsky G 1982 Metformin reduces post-prandial insulin
needs in type I (insulin-dependent) diabetic patients: assessment by
the artificial pancreas. Diabetologia. 23:34 –36
274. Abbasi F, Carantoni M, Chen YD, Reaven GM 1998 Further evidence for a central role of adipose tissue in the antihyperglycemic
effect of metformin. Diabetes Care 21:1301–1305
275. Cigolini M, Bosello O, Zancanaro C, Orlandi PG, Fezzi O, Smith
U 1984 Influence of metformin on metabolic effects of insulin in
human adipose tisssue in vitro. Diabete Metab 10:311–315
276. Puhakainen I, Yki-Ja¨rvinen H 1993 Inhibition of lipolysis de-
277.
278.
279.
280.
281.
282.
283.
284.
285.
286.
287.
288.
289.
290.
291.
292.
293.
294.
295.
296.
297.
613
creases lipid oxidation and gluconeogenesis from lactate but not
fasting hyperglycemia or total hepatic glucose production. Diabetes 42:1694 –1699
Saloranta C, Taskinen M, Widen E, Harkonen M, Melander A,
Groop L 1993 Metabolic consequences of sustainded suppression
of free fatty acids by acipimox in patients with NIDDM. Diabetes
42:1559 –1566
Wilcock C, Bailey C J 1990 Sites of metformin-stimulated glucose
metabolism. Biochem Pharmacol 39:1831–1834
Penicaud L, Hitier Y, Ferre P, Girard J 1989 Hypoglycaemic effect
of metformin in genetically obese (fa/fa) rats results from an increased utilization of blood glucose by intestine. Biochem J 262:
881– 885
Bailey CJ, Mynett KJ, Page T 1994 Importance of the intestine as
a site of metformin-stimulated glucose utilization. Br J Pharmacol
112:671– 675
Wilcock C, Bailey CJ 1994 Accumulation of metformin by tissues
of the normal and diabetic mouse. Xenobiotica 24:49 –57
Bellomo R, McGrath B, Boyce N 1991 In vivo catecholamine extraction during continuous hemofiltration in inotrope-dependent
patients. ASAIO Trans 37:M324 –M325
Lee A, Morley JE 1998 Metformin decreases food consumption and
induces weight loss in subjects with obesity with type II noninsulin-dependent diabetes. Obes Res 6:47–53
Leslie P, Jung RT, Isles TE, Baty J 1987 Energy expenditure in
non-insulin dependent diabetic subjects on metformin or sulfonylurea therapy. Clin Sci 73:41– 45
Stumvoll M, Meyer C, Mitrakou A, Nadkarni V, Gerich J 1997
Renal glucose production and utilzation. New aspects in humans.
Diabetologia. 40:749 –757
Meyer C, Stumvoll M, Nadkarni V, Dostou J, Mitrakou A, Gerich
J 1998 Abnormal renal and hepatic glucose metabolism in type 2
diabetes mellitus. J Clin Invest. 102:619 – 624
Matthaei S, Hamann A, Klein HH, Benecke H, Kreymann G, Flier
JS, Greten H 1991 Association of Metformin’s effect to increase
insulin-stimulated glucose transport with potentiation of insulininduced translocation of glucose transporters from intracellular
pool to plasma membrane in rat adipocytes. Diabetes 40:850 – 857
Matthaei S, Reibold JP, Hamann A, Benecke H, Haring HU,
Greten H, Klein HH 1993 In vivo metformin treatment ameliorates
insulin resistance: evidence for potentiation of insulin-induced
translocation and increased functional activity of glucose transporters in obese (fa/fa) Zucker rat adipocytes. Endocrinology 133:
304 –311
Lalor BC, Bhatnagar D, Winocour PH, Ishola M, Arrol S, Brading
M, Durrington PN 1990 Placebo-controlled trial of the effects of
guar gum and metformin on fasting blood glucose and serum lipids
in obese, type 2 diabetic patients. Diabet Med 7:242–245
Teupe B, Bergis K 1991 Prospective randomized two-years clinical
study comparing additional metformin treatment with reducing
diet in type 2 diabetes. Diabete Metab 17:213–217
Dornan T, Heller S, Peck G, Tattersall R 1991 Double-blind evaluation of efficacy and tolerability of metformin in NIDDM. Diabetes Care 14:342–344
Nagi D, Yudkin J 1993 Effects of metformin on insulin resistance,
risk factors for cardiovascular disease, and plasminogen activator
inhibitor in NIDDM subjects. Diabetes Care 16:621– 629
Tessari P, Biolo G, Bruttomesso D, Inchiostro S, Panebianco G,
Vedovato M, Fongher C, Tiengo A 1994 Effects of metformin
treatment on whole-body and splanchnic amino acid turnover in
mild type 2 diabetes. J Clin Endocrinol Metab 79:1553–1560
Grant PJ 1996 The effects of high- and medium-dose metformin
therapy on cardiovascular risk factors in patients with type II
diabetes. Diabetes Care 19:64 – 66
Rains S, Wilson G, Richmond W, Elkeles R 1988 The effect of
glibenclamide and metformin on serum lipoproteins in type 2
diabetes. Diabet Med 5:653– 658
Collier A, Watson HH, Patrick AW, Ludlam CA, Clarke BF 1989
Effect of glycaemic control, metformin and gliclazide on platelet
density and aggregability in recently diagnosed type 2 (non-insulin-dependent) diabetic patients. Diabete Metab 15:420 – 425
Josephkutty S, Potter JM 1990 Comparison of tolbutamide and
metformin in elderly diabetic patients. Diabet Med 7:510 –514
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 09 September 2014. at 05:56 For personal use only. No other uses without permission. . All rights reserved.
614
MATTHAEI ET AL.
298. Noury J, Nandeuil A 1991 Comparative three-month study of the
efficacies of metformin and gliclazide in the treatment of NIDD.
Diabete Metab 17:209 –212
299. Boyd K, Rogers C, Boreham C, Andrews WJ, Hadden DR 1992
Insulin, glibenclamide or metformin treatment for non insulin dependent diabetes: heterogenous responses of standard measures of
insulin action and insulin secretion before and after differing hypoglycaemic therapy. Diabetes Res 19:69 –76
300. Hermann LS, Kjellstro¨m T, Schersten B, Lindga¨rde F, Bitzen P,
Melander A 1994 Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. Diabetes Care 17:
1100 –1109
301. Campbell IW, Menzies DG, Chalmers J, McBain AM, Brown IR
1994 One year comparative trial of metformin and glipizide in type
2 diabetes mellitus. Diabete Metab 20:394 – 400
302. Selby JV, Ettinger B, Swain BE, Brown JB 1999 First 20 months’
experience with use of metformin for type 2 diabetes in a large
health maintenance organization. Diabetes Care 22:38 – 44
303. Reaven G, Johnston P, Hollenbeck CB, Skowronski R, Zhang JC,
Goldfine ID, Chen YD 1992 Combined metformin-sulfonylurea
treatment of patients with noninsulin-dependent diabetes in fair to
poor glycemic control. J Clin Endocrinol Metab 74:1020 –1026
304. Giugliano D, De Rosa N, Di Maro G, Marfella R, Acampora R,
Buoninconti R, D’Onofrio F 1993 Metformin improves glucose,
lipid metabolism, and reduces blood pressure in hypertensive,
obese women. Diabetes Care 16:1387–1390
305. Landin K, Tengborn L, Smith U 1991 Treating insulin resistance
in hypertension with metformin reduces both blood pressure and
metabolic risk factors. J Intern Med 229:181–187
306. Schneider J, Erren T, Zo¨fel P, Kaffarnik H 1990 Metformininduced changes in serum lipids, lipoproteins, and apoproteins
in non-insulin-dependent diabetes mellitus. Atherosclerosis 82:
97–103
307. Landin K, Tengborn L, Smith U 1994 Metformin and metoprolol
CR treatment in non-obese men. J Intern Med 235:335–341
308. Landin K, Tengborn L, Smith U 1994 Effects of metformin and
metoprolol CR on hormones and fibrinolytic variables during a
hyperinsulinemic, euglycemic clamp in man. Thromb Haemost
71:783–787
309. Pentikainen PJ, Voutilainen E, Aro A, Uusitupa M, Penttila I,
Vapaatalo H 1990 Cholesterol lowering effect of metformin in
combined hyperlipidemia: placebo controlled double blind trial.
Ann Med 22:307–312
310. Grant PJ, Stickland MH, Booth NA, Prentice CR 1991 Metformin
causes a reduction in basal and post-venous occlusion plasminogen
activator inhibitor-1 in type 2 diabetic patients. Diabet Med 8:
361–365
311. Gin H, Freyburger G, Boisseau M, Aubertin J 1989 Study of the
effect of metformin on platelet aggregation in insulin-dependent
diabetics. Diabetes Res Clin Pract 6:61– 67
312. Marena S, Tagliaferro V, Montegrosso G, Pagano A, Scaglione L,
Pagano G 1994 Metabolic effects of metformin addition to chronic
glibenclamide treatment in type 2 diabetes. Diabete Metab 20:15–19
313. Groop L, Widen E 1991 Treatment strategies for secondary sulfonylurea failure. Should we start insulin or add metformin? Is there
a place for intermittent insulin therapy? Diabete Metab 17:218 –223
314. Hanuschak LN 1996 Metformin useful in combination with exogenous insulin [letter]. Diabetes Care 19:671– 672
315. Aviles-Santa A, Sinding J, Raskin P 1999 Effects of metformin in
patients with poorly controlled, insulin treated type 2 diabetes. Ann
Intern Med 131:182–188
316. Yki-Ja¨rvinen H, Ryysy L, Nikkila¨ K, Tulokas T, Vanamo R, Heikkila¨ M 1999 Comparison of bedtime insulin regimens in patients
with type 2 diabetes mellitus. Ann Intern Med 130:389 –396
317. Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, Fleming
GA 1998 Lactic acidosis in patients with diabetes treated with
metformin. N Engl J Med 338:265–266
318. Oates NS, Shah RR, Idle JR, Smith R L 1983 Influence of oxidation
polymorphism on phenformin kinetics and dynamics. Clin Pharmacol Ther 34:827– 834
319. Kreisberg R, Pennington L, Boshell B 1970 Lactate turnover and
gluconeogenesis in obesity: effect of phenformin. Diabetes
19:64 – 69
Vol. 21, No. 6
320. Lalau JD, Lacroix C, Compagnon P, de Cagny B, Rigaud JP,
Bleichner G, Chauveau P, Dulbecco P, Guerin C, Haegy JM 1995
Role of metformin accumulation in metformin-associated lactic
acidosis. Diabetes Care 18:779 –784
321. Nathan DM 1999 Some answers, more questions, from UKPDS.
Lancet 352:832– 833
322. The Diabetes Prevention Program Diabetes Group 1999 The Diabetes Prevention Program. Design and methods for a clinical trial
in the prevention of type 2 diabetes. Diabetes Care 22:623– 634
323. Yoshioka T, Fujita T, Kanai T, Aizawa Y, Kurumada T, Hasegawa
K, Horikoshi H 1989 Studies on hindered phenols and analogues.
1. Hypolipidemic and hypoglycemic agents with ability to inhibit
lipid peroxidation. J Med Chem 32:421– 428
324. Fujita T, Sugiyama Y, Taketomi S, Sohda T, Kawamatsu Y, Iwatsuka H, Suzuoki Z 1983 Reduction of insulin resistance in obese
and/or diabetic animals by 5-[4-(1-methylcyclohexylmethoxy)benzyl]-thiazolidine-2,4-dione (ADD-3878, U-63, 287, ciglitazone), a
new antidiabetic agent. Diabetes 32:804 – 810
325. Fujiwara T, Okuno A, Yoshioka S, Horikoshi H 1995 Suppression
of hepatic gluconeogenesis in long-term Troglitazone treated diabetic KK and C57BL/KsJ-db/db mice. Metabolism 44:486 – 490
326. Fujiwara T, Wada M, Fukuda K, Fukami M, Yoshioka S, Yoshioka
T, Horikoshi H 1991 Characterization of CS-045, a new oral antidiabetic agent. II. Effects on glycemic control and pancreatic islet
structure at a late stage of the diabetic syndrome in C57BL/KsJdb/db mice. Metabolism 40:1213–1218
327. Tominaga M, Igarashi M, Daimon M, Eguchi H, Matsumoto M,
Sekikawa A, Yamatani K, Sasaki H 1993 Thiazolidinediones (AD4833 and CS-045) improve hepatic insulin resistance in streptozotocin-induced diabetic rats. Endocr J 40:343–349
328. Schoonjans K, Martin G, Staels B, Auwerx J 1997 Peroxisome
proliferator-activated receptors, orphans with ligands and functions. Curr Opin Lipidol 8:159 –166
329. Spiegelman BM 1998 PPAR-␥: adipogenic regulator and thiazolidinedione receptor. Diabetes 47:507–514
330. Teboul L, Gaillard D, Staccini L, Inadera H, Amri EZ, Grimaldi
PA 1995 Thiazolidinediones and fatty acids convert myogenic cells
into adipose-like cells. J Biol Chem 270:28183–28187
331. Tontonoz P, Hu E, Spiegelman BM 1994 Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 79:1147–1156
332. Tafuri SR 1996 Troglitazone enhances differentiation, basal glucose uptake, and Glut1 protein levels in 3T3–L1 adipocytes. Endocrinology 137:4706 – 4712
333. Burant CF, Sreenan S, Hirano K, Tai TA, Lohmiller J, Lukens J,
Davidson NO, Ross S, Graves RA 1997 Troglitazone action is
independent of adipose tissue. J Clin Invest 100:2900 –2908
334. Kellerer M, Kroder G, Tippmer S, Berti L, Kiehn R, Mosthaf L,
Haring H 1994 Troglitazone prevents glucose-induced insulin resistance of insulin receptor in rat-1 fibroblasts. Diabetes 43:447– 453
335. Saloranta C, Groop L 1996 Interactions between glucose and FFA
metabolism in man. Diabetes Metab Rev 12:15–36
336. Randle PJ, Priestman DA, Mistry SC, Halsall A 1994 Glucose fatty
acid interactions and the regulation of glucose disposal. J Cell Biol
55S:1–11
337. Hofmann C, Lorenz K, Braithwaite SS, Colca JR, Palazuk BJ,
Hotamisligil GS, Spiegelman BM 1994 Altered gene expression
for tumor necrosis factor and its receptor during drug and dietary
modulation of insulin resistance. Endocrinology 134:264 –270
338. De Vos P, Lefebvre AM, Miller SG, Guerre-Millo M, Wong K,
Saladin R, Hamann LG, Staels B, Briggs MR, Auwerx J 1996
Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor gamma.
J Clin Invest 98:1004 –1009
339. Kallen CB, Lazar MA 1996 Antidiabetic thiazolidinediones inhibit
leptin (ob) gene expression in 3T3–L1 adipocytes. Proc Natl Acad
Sci USA 93:5793–5796
340. Kroder G, Bossenmaier B, Kellerer M, Capp E, Stoyanov B,
Muhlhofer A, Berti L, Horikoshi H, Ullrich A, Haring H 1996
Tumor necrosis factor-␣- and hyperglycemia-induced insulin
resistance. Evidence for different mechanisms and different effects
on insulin signaling. J Clin Invest 97:1471–1477
341. Muller G, Ertl J, Gerl M, Preibisch G 1997 Leptin impairs meta-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 09 September 2014. at 05:56 For personal use only. No other uses without permission. . All rights reserved.
December, 2000
342.
343.
344.
345.
346.
347.
348.
349.
350.
351.
352.
353.
354.
355.
356.
357.
358.
359.
360.
361.
TREATMENT OF INSULIN RESISTANCE
bolic actions of insulin in isolated rat adipocytes. J Biol Chem
272:10585–10593
Wang M, Wise SC, Leff T, Su T 1999 Troglitazone, an antidiabetic
agent, inhibits cholesterol biosynthesis through a mechanism independent of peroxisome proliferator-activated receptor-␥. Diabetes 48:254 –260
Patel J, Anderson RJ, Rappaport EB 1999 Rosiglitzone monotherapy improves glycaemic control in patients with type 2 diabetes: a twelve-week, randomized, placebo-controlled study. Diab
Obes Metab 1:165–172
Grunberger G, Weston WM, Patwardhan R, Rappaport EB 1999
Rosiglitazone once or twice daily improves glycemic control in
patients with type 2 diabetes. Diabetes 48[Suppl 1]:A102; 0439
Mathisen A, Geerlof J, Houser V 1999 The effect of pioglitazone
on glucose control and lipid profile in patients with type 2 diabetes.
Diabetes 48[Supp l]:A102; 0441
Egan J, Rubin C, Mathisen A on behalf of the Pioglitazone 027
Study Group 1999 Combination therapy with pioglitazone and
metformin in patients with type 2 diabetes. Diabetes 48[Suppl
1]:A117
Horton ES, Whitehouse F, Ghazzi MN, Venable TC, Whitcomb
RW 1998 Troglitazone in combination with sulfonylurea restores
glycemic control in patients with type 2 diabetes. The Troglitazone
Study Group. Diabetes Care 21:1462–1469
Kumar S, Boulton AJ, Beck Nielsen H, Berthezene F, Muggeo M,
Persson B, Spinas GA, Donoghue S, Lettis S, Stewart-Long P 1996
Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Troglitazone Study Group. Diabetologia
39:701–709
Ghazzi MN, Perez JE, Antonucci TK, Driscoll JH, Huang SM, Faja
BW, Whitcomb RW 1997 Cardiac and glycemic benefits of troglitazone treatment in NIDDM. The Troglitazone Study Group. Diabetes 46:433– 439
Mimura K, Umeda F, Hiramatsu S, Taniguchi S, Ono Y, Nakashima N, Kobayashi K, Masakado M, Sako Y, Nawata H 1994
Effects of a new oral hypoglycaemic agent (CS-045) on metabolic
abnormalities and insulin resistance in type 2 diabetes. Diabet Med
11:685– 691
Cominacini L, Young MMR, Capriati A, Garbin U, Fratta Pasini
A, Campagnola M, Davoli A, Rigoni A, Contessa GB, Lo Cascio
V 1997 Troglitazone increases the resistance of low density lipoprotein to oxidation in healthy volunteers. Diabetologia 40:1211–1218
Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL
1989 Beyond cholesterol. Modifications of low-density lipoprotein
that increase its atherogenicity. N Engl J Med 320:915–924
Schneider R, Egan J, Houser V 1999 Combination therapy with
pioglitazone and sulfonylurea in patients with type 2 diabetes.
Diabetes 48[Suppl 1]:A106
Schwartz S, Raskin P, Fonseca V, Graveline J 1998 Effect of troglitazone in insulin-treated patients with type II diabetes mellitus.
N Engl J Med. 338:861– 866
Rubin C, Egan J, Schneider R on behalf of the Pioglitazone 014
Study Group 1999 Combination therapy with pioglitazone and
insulin in patients with Type 2 diabetes. Diabetes 48[Suppl 1]:A110
Inzucchi SE, Maggs DG, Spollett GR, Page SL, Rife FS, Walton
V, Shulman GI 1998 Efficacy and metabolic effects of metformin
and troglitazone in type II diabetes mellitus. N Engl J Med 338:
867– 872
Fonseca V, Biswas N, Salzman A 1999 Once-daily rosiglitazone
(RSG) in combination with metformin (MET) effectively reduces
hyperglycemia in patients with type 2 diabetes. Diabetes 48[Suppl
1]:A100
Bowen L, Stein PP, Stevenson R, Shulman GI 1991 The effect of
CP 68,722, a thiozolidinedione derivative, on insulin sensitivity in
lean and obese Zucker rats. Metabolism 40:1025–1030
Lee MK, Olefsky JM 1995 Acute effects of troglitazone on in vivo
insulin action in normal rats. Metabolism 44:1166 –1169
Ciaraldi TP, Gilmore A, Olefsky JM, Goldberg M, Heidenreich
KA 1990 In vitro studies on the action of CS-045, a new antidiabetic
agent. Metabolism 39:1056 –1062
Murano K, Inoue Y, Emoto M, Kaku K, Kaneko T 1994 CS-045, a
new oral antidiabetic agent, stimulates fructose-2,6-bisphosphate
production in rat hepatocytes. Eur J Pharmacol 254:257–262
615
362. Fulgencio JP, Kohl C, Girard J, Pegorier JP 1996 Troglitazone
inhibits fatty acid oxidation and sterification, and gluconeogenesis
in isolated hepatocytes from starved rats. Diabetes 45:1556 –1562
363. Suter SL, Nolan JJ, Wallace P, Gumbiner B, Olefsky JM 1992
Metabolic effects of new oral hypoglycemic agent CS-045 in
NIDDM subjects. Diabetes Care 15:193–203
364. Maggs DG, Buchanan TA, Burant CF, Cline G, Gumbiner B,
Hseuh WM, Inzucchi S, Kelley D, Nolan J, Olefsky JM, Polonsky
KS, Silver D, Valiquett TR, Shulman GI 1998 Metabolic effects of
troglitazone monotherapy in type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 128:
176 –185
365. Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J 1994 Improvement in glucose tolerance and insulin resistance in obese
subjects treated with troglitazone. N Engl J Med 331:1188 –1193
366. Antonucci T, Whitcomb R, McLain R, Lockwood D 1997 Impaired
glucose tolerance is normalized by treatment with the thiazolidinedione troglitazone. Diabetes Care 20:188 –193
367. Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R 1996
The insulin-sensitizing agent troglitazone improves metabolic and
reproductive abnormalities in the polycystic ovary syndrome.
J Clin Endocrinol Metab 81:3299 –3306
368. Schneider R, Lessem J, Lekich R 1999 Pioglitazone is effective in
the treatment of patients with type 2 diabetes. Diabetes 48[Suppl
1]:A109
369. Beebe K, Patel J 1999 Rosiglitazone is effective and well tolerated
in patients ⬎ 65 with type 2 diabetes. Diabetes 48[Suppl 1]:A111
(Abstract)
370. Watkins PB, Whitcomb RW 1998 Hepatic dysfunction associated
with troglitazone. N Engl J Med 338:916 –917
371. Food and Drug Administration www.fda.gov\medwatch\
safety\1997\dec97.htm rezuli
372. Gitlin N, Julie NL, Spurr CL, Lim KN, Juarbe HM 1998 Two cases
of severe clinical and histologic hepatotoxicity associated with troglitazone. Ann Intern Med 129:36 –38
373. Neuschwander Tetri BA, Isley WL, Oki JC, Ramrakhiani S, Quiason SG, Phillips NJ, Brunt EM 1998 Troglitazone-induced hepatic
failure leading to liver transplantation. A case report. Ann Intern
Med 129:38 – 41
374. Freid J, Everitt D, Boscia J 2000 Rosiglitazone and hepatic failure.
Ann Intern Med 132:164
375. Al-Salman J, Arjomand H, Kemp DG, Mittal M 2000 Hepatocellular injury in a patient receiving rosiglitazone. A case report. Ann
Intern Med 132:121–124
376. Salzman A, Patel J 1999 Rosiglitazone is not associated with hepatotoxicity. Diabetes 48[Suppl 1]:A95
377. Hallakou S, Doare L, Foufelle F, Kergoat M, Guerre-Millo M,
Berthault MF, Dugail I, Morin J, Auwerz J, Ferre P 1997 Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker
fa/fa rat. Diabetes 46:1393–1399
378. Buse JB, Gumbiner B, Mathias NP, Nelson DM, Faja BW, Whitcomb RW 1998 Troglitazone use in insulin-treated type 2 diabetic
patients. Diabetes Care 21:1455–1461
379. Gimble JM, Robinson CE, Wu X, Kelly KA, Rodriguez BR,
Kliewer SA, Lehmann JM, Morris DC 1996 Peroxisome proliferator-activated receptor-␥ activation by thiazolidinediones induces
adipogenesis in bone marrow stromal cells. Mol Pharmacol 50:
1087–1094
380. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK 1998 The
peroxisome proliferator-activated receptor-␥ is a negative regulator of macrophage activation. Nature 391:79 – 82
381. Nagy L, Tontonoz P, Alvarez JGA, Chen HW, Evans RM 1998
Oxidized LDL regulates macrophage gene expression through ligand activation of PPAR␥. Cell 93:229 –240
382. Tontonoz P, Nagy L, Alvarez JGA, Thomazy VA, Evans RM 1998
PPAR ␥ promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93:241–252
383. Lefebvre AM, Chen I, Desreumaux P, Najib J, Fruchart JC, Geboes K, Briggs M, Heyman R, Auwerz J 1998 Activation of the
peroxisome proliferator-activated receptor gamma promotes the
development of colon tumors in C57BL/6J-APCMin/⫹ mice. Nat
Med 4:1053–1057
384. Saez E, Tontonoz P, Nelson MC, Alvarez JG, Ming UT, Baird SM,
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 09 September 2014. at 05:56 For personal use only. No other uses without permission. . All rights reserved.
616
385.
386.
387.
388.
389.
390.
391.
392.
393.
394.
395.
396.
397.
398.
399.
400.
401.
402.
403.
404.
405.
406.
407.
408.
409.
410.
411.
MATTHAEI ET AL.
Thomazy VA, Evans RM 1998 Activators of the nuclear receptor
PPARgamma enhance colon polyp formation. Nat Med 4:1058 –
1061
Sarraf P, Mueller E, Jones D, King FJ, DeAngelo DJ, Partridge JB,
Holden SA, Chen LB, Singer S, Fletcher C, Spiegelman BM 1998
Differentiation and reversal of malignant changes in colon cancer
through PPAR␥. Nat Med 4:1046 –1052
Seed B 1998 PPARgamma and colorectal carcinoma: conflicts in a
nuclear family. Nat Med 4:1004 –1005
Berkowitz K, Peters R, Kjos SL, Goico J, Marroquin A, Dunn ME,
Xiang A, Azen S, Buchanan TA 1996 Effect of troglitazone on
insulin sensitivity and pancreatic ␤-cell function in women at high
risk for NIDDM. Diabetes 45:1572–1579
Patel J, Miller E, Patwardhan R 1998 Rosiglitazone improves glycaemic control when used as a monotherapy in type 2 diabetic
patients. Diabetic Med 15[Suppl 2]:S37–38
Raskin P, Rappaport EB 1999 Rosiglitazone (RSG) improves fasting and post-prandial plasma glucose in type 2 diabetes. Diabetes
48[Suppl 1]:A95
Raskin P, Dole JF, Rappaport EB 1999 Rosiglitazone improves
glycemic control in poorly controlled, insulin-treated type 2 diabetes. Diabetes 48[Suppl 1]:A94
Chabonnel B, Lo¨nnqvist F, Jones NP, Abel MG, Patwardhan R
1999 Rosiglitazone is superior to glyburide in reducing fasting
plasma glucose after 1 year of treatment in type 2 diabetic patients.
Diabetes 48[Suppl 1]:A114
Mathews DR, Bakst A, Weston WM, Hemyari P 1999 Rosiglitazone decreases insulin resistance and improves ␤-cell function in
patients with type 2 diabetes. Diabetologia 42[Suppl 1]:A228
Franke H, Fuchs J 1955 Ein neues antidiabetisches Prinzip. Dtsch
Med Wochenschr 80:1449 –1453
Skillman TG, Feldman JM 1981 The pharmacology of sulfonylureas. Am J Med 70:361–372
Prendergast BD 1984 Glyburide and glipizide, second-generation
oral sulfonylurea hypoglycemic agents. Clin Pharm 3:473– 485
Feldman JM 1985 Glyburide: a second-generation sulfonylurea
hypoglycemic agent. History, chemistry, metabolism, pharmacokinetics, clinical use and adverse effects. Pharmacotherapy 5:43– 62
Lebovitz HE 1985 Glipizide: a second-generation sulfonylurea hypoglycemic agent. Pharmacology, pharmacokinetics and clinical
use. Pharmacotherapy 5:63–77
Kuhn T 1988 The second generation oral sulfonylureas: glyburide
and glipizide. Am Pharm NS28:55– 61
Groop L 1983 Metabolic effects of sulfonylurea drugs. A review.
Ann Clin Res 15[Suppl 37]:16 –20
Lebovitz HE 1984 Cellular loci of sulfonylurea actions. Diabetes
Care 7[Suppl 1]:67–71
Kolterman OG 1987 The impact of sulfonylureas on hepatic glucose metabolism in type II diabetics. Diabetes Metab Rev 3:399 – 414
Kolterman OG, Olefsky JM 1984 The impact of sulfonylurea treatment upon the mechanisms responsible for the insulin resistance
in type II diabetes. Diabetes Care 7 [Suppl 1]:81– 88
Ammon HP 1988 Molecular mechanism of action of sulfonylureas.
Dtsch Med Wochenschr 113:864 – 870
Panten U 1989 Mechanism of insulin secretion and ist modulation
by sulfonylureas. Contrib Nephrol 73:16 –21
Malaisse WJ, Lebrun P 1990 Mechanisms of sulfonylurea-induced
insulin release. Diabetes Care 13[Suppl 3]:9 –17
Caro JF 1990 Effects of glyburide on carbohydrate metabolism and
insulin action in the liver. Am J Med 89[Suppl 2A]:17S–25S
Boyd AE, Aguilar-Bryan L, Nelson DA 1990 Molecular mechanisms of action of glyburide on the ␤ cell. Am J Med 89[Suppl
2A]:3S–10S
Smith RJ 1990 Effects of the sulfonylureas on muscle glucose homeostasis. Am J Med 89[Suppl 2A]:38S– 43S
Del Prato S, Vigili de Kreutzenberg S, Riccio A, Tiengo A 1991
Hepatic sensitivity to insulin: effects of sulfonylurea drugs. Am J
Med 90[Suppl 6A]:29S–36S
Panten U, Schwanstecher M, Schwanstecher C 1992 Pancreatic
and extrapancreatic sulfonylurea receptors. Horm Metab Res 24:
549 –554
Kramer W, Mu¨ller G, Girbig F, Gutjahr U, Kowalewski S, Hartz
D, Summ HD 1995 The molecular interaction of sulfonylureas with
412.
413.
414.
415.
416.
417.
418.
419.
420.
421.
422.
423.
424.
425.
426.
427.
428.
429.
430.
431.
432.
433.
434.
435.
Vol. 21, No. 6
␤-cell ATP-sensitive K(⫹)-channels. Diabetes Res Clin Pract Suppl:
S67– 80
Panten U, Schwanstecher M, Schwanstecher C 1996 Sulfonylurea
receptors and mechanism of sulfonylurea action. Exp Clin Endocrinol Diabetes 104:1–9
Groop L 1983 Metabolic effects of sulfonylurea drugs. Ann Clin Res
15:16 –20
Kolterman OG, Prince MJ, Olefsky JM 1983 Insulin resistance in
noninsulin-dependent diabetes mellitus: impact of sulfonylurea
agents in vivo and in vitro. Am J Med 82:82–101
Bak JF, Pedersen O 1991 Gliclazide and insulin action in human
muscle. Diabetes Res Clin Pract 14:S61–S64
Zimmerman BR 1997 Sulfonylureas. Endocrinol Metab Clin North
Am 26:511–522
Gerich JE 1985 Sulfonylureas in the treatment of diabetes mellitus–
1985. Mayo Clin Proc 60:439 – 443
Melander A, Lebovitz HE, Faber OK 1990 Sulfonylureas. Why,
which, and how. Diabetes Care 13[Suppl 3]:18 –25
Kolterman OG 1992 Glyburide in non-insulin-dependent diabetes:
an update. Clin Ther 14:196 –213
Martz A, Jo I, Jung CY 1989 Sulfonylurea binding to adipocyte
membranes and potentiation of insulin-stimulated hexose transport. J Biol Chem 264:13672–13678
Maloff BL, Lockwood DH 1981 In vitro effects of a sulfonylurea on
insulin action in adipocytes. Potentiation of insulin-stimulated hexose transport. J Clin Invest 68:85–90
Wang PH, Moller D, Flier JS, Nayak C, Smith RJ 1989 Coordinate
regulation of glucose transporter function, number, and gene expression by insulin and sulfonylureas in L6 rat skeletal muscle cells.
J Clin Invest 84:62– 67
Wang PH, Beguinot F, Smith RJ 1987 Augmentation of the effects
of insulin and insulin-like growth factors I and II on glucose uptake
in cultured rat skeletal muscle cells by sulfonylureas. Diabetologia
30:797– 803
Cooper DR, Vila MC, Watson JE, Nair G, Pollet RJ, Standaert M,
Farese RV 1990 Sulfonylurea-stimulated glucose transport associaton with diacylglycerollike activation of protein kinase C in
BC3H1 myocytes. Diabetes 39:1399 –1407
Rogers BJ, Standaert ML, Pollet RJ 1987 Direct effects of sulfonylurea agents on glucose transport in the BC3H-1 myocyte. Diabetes 36:1292–1296
Pedersen O, Hother-Nielsen O, Bak J, Hjollund E, Beck-Nielsen
H 1991 Effects of sulfonylureas on adipocyte and skeletal muscle
insulin action in patients with non-insulin-dependent diabetes mellitus. Am J Med 90 [Suppl 6A]:22S–28S
Farese RV, Ishizuka T, Standaert ML, Cooper DR 1991 Sulfonylureas activate glucose transport and protein kinase C in rat adipocytes. Metabolism 40:196 –200
Maloff BL, Drake L, Riedy DK, Lockwood DH 1984 Effects of
sulfonylureas on the actions of insulin and insulin-mimickers: potentiation of stimulated hexose transport in adipocytes. Eur J Pharmacol 17:319 –326
McCaleb ML, Maloff BL, Nowak SM, Lockwood DH 1984 Sulfonylurea effects on target tissues for insulin. Diabetes Care 7[Suppl
1]:42– 46
Ba¨hr M, von Holtey M, Mu¨ller G, Eckel J 1994 Direct stimulation
of myocardial glucose transport and glucose transporter-1
(GLUT1) and GLUT4 protein expression by the sulfonylurea
glimepiride. Endocinology 136:2547–2553
Jacobs DB, Jung CY 1985 Sulfonylurea potentiates insulin-induced
recruitment of glucose transport carrier in rat adipocytes. J Biol
Chem 260:2593–2596
Mu¨ller G, Wied S 1993 The sulfonylurea drug, glimepiride, stimulates glucose transport, glucose transporter translocation, and
dephosphorylation in insulin-resistant rat adipocytes in vitro. Diabetes 42:1852–1867
Salhanick AI, Konowitz P, Amatruda JM 1982 Potentiation of
insulin action by a sulfonylurea in primary cultures of hepatocytes
from normal and diabetic rats. Diabetes 32:206 –212
Caren R, Corbo L 1957 The potentiation of exogenous insulin by
tolbutamide in depancreatized dogs. J Clin Invest 36:1546 –1550
Ricketts H, Wildberger HL Schmid H Long-term studies of sul-
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 09 September 2014. at 05:56 For personal use only. No other uses without permission. . All rights reserved.
December, 2000
436.
437.
438.
439.
440.
441.
442.
443.
444.
445.
446.
447.
448.
449.
450.
451.
452.
453.
454.
455.
456.
457.
TREATMENT OF INSULIN RESISTANCE
phonylureas in totally depancreatectomized dogs. Ann NY Acad
Sci 71:170 –176
Best JD, Judzewitsch RG, Pfeifer MA, Beard JC, Halter JB, Porte
D 1982 The effect of chronic sulfonylurea therapy on hepatic glucose production in non-insulin-dependent diabetes. Diabetes 31:
333–338
Simonson DC, Del Prato S, Castellino P, Groop L, DeFronzo RA
1987 Effect of glyburide on glycemic control, insulin requirement,
and glucose metabolism in insulin-treated diabetic patients. Diabetes 36:136 –146
Lisato G, Riccio A, Vigili de Kreutzenberg S, Tiengo A, Del Prato
S 1987 Hepatic action of gliclazide treatment in type 2 (non-insulindependent) diabetes mellitus. Diabetologia 30:550A (Abstract)
Simonson DC 1990 Effects of glyburide on in vivo insulin-mediated
glucose disposal. Am J Med 89[Suppl 2A]:44S–50S
Pontiroli AE, Alberetto M, Bertoletti A, Baio G, Pozza G 1984
Sulfonylureas enhance in vivo the effectiveness of insulin in type 1
(insulin dependent) diabetes mellitus. Horm Metab Res 16:167–170
Pernet A, Trimble ER, Kuntschen F, Assal JP, Hahn C, Renold AE
1985 Sulfonylureas in insulin-dependent (type I) diabetes: evidence
for an extrapancreatic effect in vivo. J Clin Endocrinol Metab 61:
247–251
Keller U, Mu¨ller R, Berger W 1986 Sulfonylurea therapy fails to
diminish insulin resistance in type I-diabetic subjects. Horm Metab
Res 18:599 – 603
Leblanc H, Thote A, Chatellier G, Passa P 1990 Effect of glipizide
on glycemic control and peripheral insulin sensitivity in type 1
diabetics. Diabete Metab 16:93–97
Schulz B, Ratzmann KP, Heinke P, Besch W 1983 A stimulatory
effect of tolbutamide on the insulin-mediated glucose uptake in
subjects with impaired glucose tolerance (IGT). Exp Clin Endocrinol 82:222–231
Kolterman OG, Olefsky JM 1984 The impact of sulfonylurea treatment upon the mechanism responsible for the insulin resistance in
type II diabetes. Diabetes Care 7 [Suppl 1]:81– 88
Greenfield MS, Doberne L, Rosenthal M, Schulz B, Widstrom A,
Reaven GM 1982 Effect of sulfonylurea treatment on in vivo insulin
secretion and action in patients with non-insulin-dependent diabetes mellitus. Diabetes 31:307–312
Kolterman OG 1985 Longituinal evaluation of the effects of sulfonylurea therapy in subjects with type II diabetes mellitus. Am J
Med 79(3B):23–33
Ward G, Harrison LC, Proietto J, Aitken P, Nankervis A 1985
Gliclazide therapy is associated with potentiation of postbinding
insulin action in obese, non-insulin-dependent diabetic subjects.
Diabetes 34:241–245
Langtry HD, Balfour JA 1998 Glimepiride: a review of its use in the
management of type 2 diabetes mellitus. Drugs 55:563–584
Rosenkranz B, Profozic V, Metelko Z, Mrzljak V, Lange C, Malerczyk V 1996 Pharmacokinetics and safety of glimepiride at clinically effective doses in diabetic patients with renal impairment.
Diabetologia 39:1617–1624
Kramer W, Mu¨ller G, Geisen K 1996 Characterization of the molecular mode of action of the sulfonylurea, glimepiride, at ␤-cells.
Horm Metab Res 28:464 – 468
Mu¨ller G, Geisen K 1996 Characterization of the molecular mode
of action of the sulfonylurea, glimepiride, at adipocytes. Horm
Metab Res 28:469 – 487
Ashcroft FM 1996 Mechanism of the glycaemic effects of sulfonylureas. Horm Metab Res 28:456 – 463
Mu¨ller G, Satoh Y, Geisen K 1995 Extrapancreatic effects of sulfonylureas—a comparison between glimepiride and conventional
sulfonylureas. Diabetes Res Clin Pract 28[Suppl]:S115–S137
Clark HE, Matthews DR 1996 The effect of glimepiride on pancreatic beta-cell function under hyperglycaemic clamp and hyperinsulinaemic, euglycaemic clamp conditions in non-insulin-dependent diabetes mellitus. Horm Metab Res 28:445– 450
Rosenstock J, Samolis E, Muchmore DB, Schneider J 1996
Glimepiride, a new once-daily sulfonylurea. Diabetes Care
19:1194 –1199
Dills DG, Schneider J 1996 Clinical evaluation of glimepiride vs.
glyburide in NIDDM in a double-blind comparative study. Horm
Metab Res 28:426 – 429
617
458. Draeger KE, Wernicke-Panten K, Lomp HJ, Schu¨ler E, Ro␤kamp
R 1996 Long-term treatment of type 2 diabetic patients with the new
oral antidiabetic agent glimepiride (Amaryl ®): a double-blind comparison with glibenclamide. Horm Metab Res 28:419 – 425
459. Riddle MC 1996 Combined therapy with a sulfonylurea plus
evening insulin: safe, reliable, and becoming routine. Horm Metab
Res 28:430 – 433
460. Goldberg RB, Holvey SM, Schneider J 1996 A dose-response
study of glimepiride in patients with NIDDM who have previously
received sulfonylurea agents. Diabetes Care 19:849 – 856
461. Roßkamp R, Wernicke-Panten K, Draeger E 1996 Clinical profile
of the novel sulphonylurea glimepiride. Diabetes Res Clin Pract
31[Suppl]:S33–S42
462. Campbell RK 1998 Glimepiride: role of a new sulfonylurea in the
treatment of type 2 diabetes mellitus. Ann Pharmacother 32:1044 –
1052
463. Massi-Benedetti M, Herz M, Pfeiffer C 1996 The effects of acute
exercise on metabolic control in type II diabetic patients treated
with glimepiride or glibenclamide. Horm Metab Res 28:451– 455
464. Geisen K, Vegh A, Krause E, Papp JG 1996 Cardiovascular effects
of conventional sulfonylureas and glimepiride. Horm Metab Res
28:496 –507
465. Rosskamp R 1996 Safety aspects of oral hypoglycemic agents.
Diabetologia 39:1668 –1672
466. Schneider J 1996 An overview of the safety and tolerance of
glimepiride. Horm Metab Res 28:413– 418
467. Paice BJ, Patterson KR, Lawson DH 1985 Undesired effects of
sulfonylurea drugs. Adverse Drug React Acute Poisoning Rev
1:23–36
468. UKPDS Group 1998 Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk
of complications in patients with type 2 diabetes (UKPDS 33).
Lancet 352:837– 853
469. Schneider J, Chaikin P 1997 Glimepiride safety: results of placebocontrolled, dose-regimen, and active-controlled trials [special report]. Postgrad Med 33– 44
470. Dills DG, Schneider J and the Glimepiride/Glyburide Research
Group 1996 Clinical evaluation of glimepiride vs. glyburide in
NIDDM in a double-blind comparative study. Horm Metab Res
28:426 – 429
471. Bijlstra PJ, Lutterman JA, Russel FGM, Thien T, Smits P 1996
Interaction of sulfonylurea derivatives with vascular ATP-sensitive
potassium channels in humans. Diabetologia 39:1083–1090
472. Campbell IW 1985 Metformin and the sulphonylureas: the comparative risk. Horm Metab Res Suppl 15:105–111
473. Yki-Ja¨rvinen H, Koivisto VA 1984 Continuous subcutaneous insulin infusion therapy decreases insulin resistance in type 1 diabetes. J Clin Endocrinol Metab 58:659 – 666
474. Lager I, Lo¨nnroth P, von Schenck H, Smth U 1983 Reversal of
insulin resistance in type I diabetes after treatment with continuous
subcutaneous insulin infusion. Br Med J (Clin Res Ed) 287:1661–
1664
475. Scarlett JA, Gray RS, Griffin J, Olefsky JM, Kolterman OG 1982
Insulin treatment reverses the insulin resistance of type II diabetes
mellitus. Diabetes Care 5:353–363
476. Garvey WT, Olefsky JM, Griffin J, Hamman RF, Kolterman OG
1985 The effect of insulin treatment on insulin secretion and insulin
action in type II diabetes mellitus. Diabetes 34:222–234
477. Andrews WJ, Vasquez B, Nagulesparan M, Klimes I, Foley J,
Unger R, Reaven GM 1984 Insulin therapy in obese non-insulindependent diabetes induces improvements in insulin action and
secretion that are maintained for two weeks after insulin withdrawal. Diabetes 33:634 – 642
478. Henry RR, Gumbiner B, Ditzler T, Wallace P, Lyon R, Glauber
HS 1993 Intensive conventional insulin therapy for type II diabetes.
Diabetes Care 16:21–31
479. Laakso M, Uusitupa M, Takala J, Majander H, Reijonen T, Penttila I 1988 Effects of hypocaloric diet and insulin therapy on metabolic control and mechanisms of hyperglycaemia in obese noninsulin-dependent diabetic subjects. Metabolism 37:1092–1100
480. Ginsberg H, Rayfield EJ 1981 Effect of insulin therapy on insulin
resistance in type II diabetic subjects. Evidence for heterogeneity.
Diabetes 30:739 –745
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 09 September 2014. at 05:56 For personal use only. No other uses without permission. . All rights reserved.
618
MATTHAEI ET AL.
481. Yki-Ja¨rvinen H, Nikkila¨ E, Helve E, Taskinen MR 1988 Clinical
benefits and mechanisms of a sustained response to intermittent
insulin therapy in type 2 diabetic patients with secondary drug
failure. Am J Med 84:185–192
482. UKPDS Group 1999 Tight blood pressure control and risk of macrovasclar and microvascular complications in type 2 diabetes (UKPDS 38). Br Med J 317:703–713
483. Pyo¨ra¨la¨ K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG,
Thorgeirsson G and the 4S-Group 1997 Cholesterol lowering with
simvastatin improves prognosis of diabetic patients with coronary
heart disease. Diabetes Care 20:614 – 620
484. Meyerovitch J, Rothenberg P, Shechter Y, Bonner-Weir SA, Kahn
CR 1991 Vanadate normalises hyperglycaemia in two mouse mdels
of non-insulin dependent diabetes mellitus. J Clin Invest 87:1286 –1294
485. Brichard SM, Ongemba LN, Henquin JC 1992 Oral vanadate decreases muscle insulin resistance in obese fa/fa rats. Diabetologia
35:522–527
486. Goldfine AB, Simonson SC, Folli F, Patti ME, Katin CR 1995
Metabolic effects of sodium metavanadate in humans with insulindependent and non-insulin-dependent diabetes mellitus. J Clin
Endocrinol Metab 80:3311–3320
487. Cohen N, Halberstam M, Stilimovich P, Chang CJ, Shamoon H,
Rosetti L 1995 Oral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 95:2501–2509
488. Halberstam M, Cohen N, Shlimovich P, Rosetti L, Shamoon H
1996 Oral vanadyl sulfate improves insulin sensitivity in NIDDM
but not in obese nondiabetic subjects. Diabetes 45:659 – 666
489. McNeill JH, Yuen VG, Hoveyda HR, Orvig C 1992 Bis-(maltolato)oxovanadium (IV) is a potential mimic. J Med Chem 35:1489 –1491
490. Zhang B, Salituro G, Szalkowski D, Li Z, Zhang Y, Royo I, Vilella
D, Diez MT, Pelaez F, Ruby C, Kendall R, Mao X, Griffin P,
Calaycay J, Zierath JR, Heck JV, Smith RG, Moller DE 1999
Discovery of a small molecule insulin mimetic with antidiabetic
activity in mice. Science 284:974 –977
491. Nauck M, Wollschla¨ger D, Werner J, Holst J, Orskov C,
Creutzfeldt W, Willms B 1996 Effects of subcutaneous glucagonlike peptide 1 (GLP-1[7–36 amide]) in patients with NIDDM. Diabetologia 39:1546 –1553
492. Skillman CA, Raskin P 1997 A double-masked placebo-controlled
trial assessing effects of various doses of BTS 67582, a novel insulinotropic agent on fasting hyperglycaemia in NIDDM patients.
Diabetes Care 20:591–596
493. Jones RB, Dickinson K, Anthny DM, Marita AR, Kaul CL, Buckett WR 1997 Evaluation of BTS 67582, a novel antidiabetic agent,
in normal and diabetic rats. Br J Pharmacol 120:1135–1143
494. Page T, Bailey CJ 1997 Glucose-lowering effect of BTS 67 582. Br J
Pharmacol 122:1464 –1468
Vol. 21, No. 6
495. Ratheiser K, Schneeweis B, Waldha¨usl W, Fasching P, Korn A,
Nowoty P, Rohac M, Wolf HPO 1991 Inhibition by etomoxir of
carnitine palmitoyltransferase 1 reduces hepatic glucose production and plasma lipids in non-insulin-dependent diabetes mellitus.
Metabolism 40:1185–1190
496. Swislocki A, Eason T 1994 Glucose tolerance and blood pressure
are improved in the spontaneously hypertensive rat by ethyl-2-(6(4-chlorophenoxy)-hexyl)oxirane-2-carboxylate (etomoxir), an inhibitor of fatty acid oxidation. Am J Hypertens 7:739 –744
497. Hubinger A, Knode O, Susanto F, Reinauer H, Gries FA 1997
Effects of carnitine-acyltransferase inhibitot etomoxir on insulin
sensitivity, energy expenditure and substrate oxidation in NIDDM.
Horm Metab Res 29:436 – 439
498. Bailey CJ 1999 New pharmacological approaches to glycemic control. Diabetes Rev 7:94 –113
499. Iwamoto Y, Kosaka K, Kuzuya T, Akanuma Y, Shigeta Y, Kaneko
T 1996 Effect of combination therapy of troglitazone and sulphonylureas in patients with Type 2 diabetes who were poorly controlled by sulphonylurea therapy alone. Diabet Med. 13:365–370
500. Haupt E, Knick B, Koschinsky T, Liebemeister H, Schneider J,
Hirche H 1991 Oral antidiabetic combination therapy with sulphonylureas and metformin. Diabete Metab 17:224 –231
501. Simonson DC, Ferrannini E, Bevilacqua S, Smith D, Barrett E,
Carlson R, DeFronzo RA 1984 Mechanism of improvement in
glucose metabolism after chronic glyburide therapy. Diabetes 33:
838 – 845
502. Kolterman OG, Gray RS, Shapiro G, Scarlett JA, Griffin J, Olefsky JM 1984 The acute and chronic effects of sulfonylurea therapy
in type II diabetic subjects. Diabetes 33:346 –354
503. Mandarino LJ, Gerich JE 1984 Prolonged sulphonylurea administration decreases insulin resistance and increases insulin secretion
in non-insulin-dependent diabetes mellitus: evidence for improved
insulin action at a postreceptor site in hepatic as well as extrahepatic tissues. Diabetes Care 7[Suppl 1]:89 –94
504. Hother-Nielsen O, Schmitz O, Andersen PH, Pedersen O, BeckNielsen H 1988 In vivo action of glibenclamide in obese subjects
with mild type 2 (non-insulin dependent) diabetes. Diabetes Res
8:63–70
505. Firth RG, Bell PM, Rizza RA 1986 Effects of tolazamide and exogenous insulin on insulin action in patients with non-insulindependent diabetes mellitus. N Engl J Med 314:1280 –1286
506. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM
1995 Increased adipose tissue expression of tumor necrosis factor-␣
in human obesity and insulin resistance. J Clin Invest 95:2409 –2415
507. Buse J 2000 Combining insulin and oral agents. Am J Med
108[Suppl 1]:23–32
Journees Internationales d’Endocrinologie Clinique
Henri-Pierre Klotz
Socie´te´ Franc¸aise d’Endocrinologie
First Announcement
The 44th Journe´es Internationales d’Endocrinologie Clinique will be held in Paris on May 17–18, 2001 and
will be devoted to: “Obesity: come-back to endocrinology.”
Deadline for submission of abstracts: January 15, 2001
For information, contact
Dr. G. Copinschi
Laboratory of Experimental Medicine
Brussels Free University-CP 618
808 Route de Lennik
B-1070 Brussels
Belgium
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