1. health and fitness
2. disease
3. diabetes

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: Hans-Ulrich.Haering@med.
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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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.
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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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