Annals of Medicine

ISSN: 0785-3890 (Print) 1365-2060 (Online) Journal homepage: www.tandfonline.com/journals/iann20

Glitazones: clinical effects and molecular

mechanisms

Michael Stumvoll & Hans-Ulrich Häring

To cite this article: Michael Stumvoll & Hans-Ulrich Häring (2002) Glitazones: clinical effects
and molecular mechanisms, Annals of Medicine, 34:3, 217-224, DOI: 10.1080/ann.34.3.217.224

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Published online: 08 Jul 2009.

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^ WHAT IS NEW IN MOLECULAR
Glitazones: clinical effects and molecular
mechanisms
Michael Stumvoll and Hans-Ulrich HaÈring
With the thiazolidinediones rosiglitazone and pioglitazone a
novel treatment modality for type 2 diabetes has become
available in many countries. As monotherapy, fasting blood
glucose and glycosylated hemoglobin (HbA1c), on average,
can be improved by approximately 40 mg/dl and almost 1%,
respectively. In combination with other agents their ef®cacy
is additive. Thiazolidinediones reduce insulin resistance not
only in type 2 diabetes but also in non-diabetic conditions
associated with insulin resistance such as obesity. The
mechanism of action involves binding to the peroxisome
(PPAR)g, a transcription
proliferator-activated receptor (PPAR)g
factor that regulates the expression of speci®c genes
especially in fat cells but also in other tissues. It is likely
that thiazolidinediones primarily act in adipose tissue where
PPARg is predominantly expressed. Thiazolidinediones have
PPARg
been shown to interfere with expression and release of
mediators of insulin resistance originating in adipose tissue
(e.g. free fatty acids, adipocytokines such as tumor necrosis
factor a, resistin, adiponectin) in a way that results in net
improvement of insulin sensitivity (i.e. in muscle and liver).
Nevertheless, a direct molecular effect in skeletal muscle
cannot be excluded. Interference with transcription entails a
potential for side-effect risk, that cannot de®nitively be
assessed yet. For example, the in-vitro stimulation of
adipogenic differentiation may underlie the clinical ob-
servation of weight gain. Theoretically, this may turn out to
be counterproductive in the long run. However, there is not
suf®cient evidence from humans at the moment, especially
no long-term data, to allow a conclusive statement. The
hepatotoxicity observed with troglitazone, on the other
PPARg-mediated but secondary
hand, does not seem to be PPARg
to toxic metabolites. Based on differences in drug metab-
olism this problem is relatively unlikely to occur with
rosiglitazone or pioglitazone. Unexplained but not unim-
portant is the propensity for ¯uid retention. In summary,
From the Medizinische Klinik, Abteilung fuÈr Endokrinologie,
Stoffwechsel und Pathobiochemie, Eberhard-Karls-UniversitaÈt,
TuÈbingen, Germany.
Correspondence: Dr. Michael Stumvoll, Medizinische Univer-
sitaÈtsklinik, Otfried-MuÈller-Str. 10, DE-72076 TuÈbingen, Germany.
Fax: +49-7071-295277, Email: michael.stumvoll@med.uni-
tuebingen.de
# 2002 Taylor & Francis. ISSN 0785-3890
ENDOCRINOLOGY? ^
with the thiazolidinediones a novel concept for the
treatment of insulin resistance is available that in theory
could also be used for prevention of type 2 diabetes. Long-
term data are indispensable for a ®nal risk-bene®t assess-
ment of these substances.
Keywords: adipose tissue; insulin resistance; obesity; pioglitazone; peroxisome
proliferator-activated receptor; rosiglitazone; type 2 diabetes.
Ann Med 2002; 34: 217±224
Insulin resistance
Insulin resistance is said to be present in an individual
when the biological effects of insulin are less than
expected. The tissues through which alterations in
insulin sensitivity immediately in¯uence glucose
homeostasis are muscle (glucose disposal), liver and
to a minor extent kidney (suppression of endogenous
glucose production). Thus, the two resulting abnorm-
alities consistently observed in glucose-intolerant
states are increased rates of glucose production and
decreased peripheral glucose disposal (1, 2). Further-
more, suppression of lipolysis in adipose tissue is
highly sensitive to insulin. In patients with type 2
diabetes impaired insulin suppression of lipolysis has
been reported (3). A novel concept recently emerging
from knockout animals also suggests a pathophysio-
logical role of insulin resistance of the central nervous
system (4) (Fig. 1).
Besides disturbing glucose homeostasis, insulin
resistance contributes to the pathogenesis of other
clinically relevant disorders. Hypertension associated
with insulin resistance appears to be a consequence,
among many other causes, also of the impaired
vasodilating effect of insulin (5). Hepatic insulin
resistance contributes to dyslipidemias characterized
by decreased high-density lipoprotein (HDL) concen-
trations and increased low-density lipoprotein (LDL)
(6). (Furthermore, recent results suggest that insulin
resistance is also associated with increased aggreg-
ability of platelets (7) and with endothelial dysfunc-
tion (8). Thus, insulin resistance can be made
responsible, at least in part, for the pro-arteriosclero-
Annals of Medicine 34
218 STUMVOLL . HAÈRING
Figure 1. Insulin secretion and resistance. Organ manifesta-
tions of insulin resistance and metabolic consequences: adipose
tissue — increased lipolysis and excessive FFA release; liver (and
kidney) — increased glucose production; muscle — decreased
glucose uptake. The role of insulin resistance in brain is theoretical
at present since evidence is available only from a brain-specific
insulin receptor knockout mouse (4).
tic milieu of hyperglycemia, arterial hypertension,
dyslipidemia and hypercoagulability seen in type 2
diabetes and related disorders. It therefore represents
a highly rewarding target for pharmacological inter-
vention.
Role of adipose tissue and obesity
The striking association between insulin resistance
and obesity (9) produces the important question Ð
which factors originating from adipose tissue are
responsible and have the potential for pharmacologi-
cal intervention? In addition to free fatty acids (FFAs)
whose role is ®rmly established (10), advances in
molecular biology and genomic research have facili-
tated the identi®cation of peptides released from
adipocytes (so-called adipocytokines) that potentially
in¯uence insulin sensitivity. The ob gene product
leptin whose primary function is to signal replenished
energy stores from the adipocyte to the hypothalamus
(11) has been shown to interfere with insulin signaling
and action in cell models (12±14). Tumor necrosis
factor-a (TNFa) is a cytokine that is primarily
produced in macrophages and involved in host
defense. Since fat tissue is also a signi®cant source
of this cytokine and TNFa expression in adipose
tissue is elevated in obesity (15), it represents a
reasonable candidate for linking obesity to insulin
resistance. However, evidence from euglycemic
clamps showing an effect of circulating TNFa on
insulin sensitivity independent of other factors
released from adipose tissue is lacking. While in
obese rats neutralization of TNFa resulted in
increased insulin sensitivity (16) this was not the case
in patients with type 2 diabetes (17). Nevertheless, the
# 2002 Taylor & Francis. ISSN 0785-3890
Key messages
. With the thiazolidinediones rosiglitazone and
pioglitazone, a novel treatment modality for
type 2 diabetes has become available.
. The mechanism of action of these compounds
involves binding to the peroxisome proliferator-
activated receptor (PPAR) gamma , a transcrip-
tion factor that regulates the expression of
speci®c genes especially in fat cells but also in
other tissues.
. As monotherapy, glycosylated hemoglobin
(HbA1c) on average can be improved by almost
1%.
. Thiazolidinediones reduce insulin resistance
not only in type 2 diabetes but also in non-
diabetic conditions associated with insulin
resistance such as obesity.
fact that local levels of TNFa bound to its circulating
receptor correlates with the degree of adiposity in
humans (18) suggests that paracrine mechanisms may
be operative. Studies in cell models suggest that
molecular mechanisms of TNFa-induced insulin
resistance involve activation of inhibitory serine
kinases (19) or tyrosine phosphatases which lead to
inhibition of the insulin signaling pathway (20, 21).
Resistin, a protein that is increasingly released from
white adipocytes during differentiation was recently
identi®ed. In rodent models of obesity resistin mRNA
is increased in adipose tissue. Intravenous adminis-
tration of the recombinant protein causes glucose
intolerance and insulin resistance in mice. On the
other hand, neutralizing antibodies reduce insulin
resistance and hyperglycemia in a mouse model with
dietary obesity and type 2 diabetes (22). Although
these data appear promising, evidence for the applic-
ability to the human situation is still pending. At
present, it is actually unclear whether a human
resistin homologue is suf®ciently expressed in adipose
tissue and circulates in human plasma.
Recently, a novel adipocyte-derived hormone,
adiponectin was identi®ed and characterized (23,
24). With a concentration of around 5 mg/ml in
human plasma, adiponectin represents one of the
most abundant circulating proteins. Interestingly, in
obesity, a condition highly associated with insulin
resistance, plasma adiponectin levels are signi®cantly
decreased (25, 26). Adiponectin concentrations are
positively correlated with insulin sensitivity, decrease
signi®cantly with deteriorating glucose tolerance (25)
and increase after weight reduction (27). Further-
more, intravenous administration of recombinant
Annals of Medicine 34
 GLITAZONES
Figure 2. Chemical structure of thiazolidinediones and
vitamin E.
adiponectin to rodent models of insulin resistance
restored normal insulin sensitivity (28). Thus, in
contrast to previously discussed adipocytokines,
adiponectin seems to protect from insulin resistance
and type 2 diabetes.
Thiazolidinediones Ð historical aspects and
clinical ef®cacy
For a long time, only biguanides such as metformin,
have been used for the treatment of insulin resistance.
It was not until 1997, when the thiazolidinediones (=
`glitazones’) also became available for treating insulin
resistance. They are a new class of agents which were
originally developed in the early 1980s in Japan as
antioxidants (29). Soon after the synthesis of the ®rst
thiazolidinedione, ciglitazone, the blood glucose low-
ering potential of these compounds was observed in
animals with particularly pronounced effects in
animals with genetic insulin resistance such as KK,
db/db and ob/ob mice and fa/fa rats (30±32). The
observation that glycemia improved in the absence of
increasing insulin and the lack of effect in insulin
de®cient animals (29, 33) led to the conclusion that
thiazolidinediones improved insulin resistance, hence
the nickname `insulin sensitizers’. Due to an unto-
ward risk-bene®t ratio (hepatotoxic side effects),
however, troglitazone had to be withdrawn from
the market and currently the newer compounds
rosiglitazone and pioglitazone are the two thiazolidi-
nediones available in most countries (34) (Fig. 2).
With thiazolidinedione treatment an average
improvement of fasting plasma glucose levels by
about 40 mg/dl was observed in patients with type 2
diabetes accompanied by a signi®cant reduction in
# 2002 Taylor & Francis. ISSN 0785-3890
219
fasting insulin levels ranging from 2 to 10 mU/ml
(35, 36). The alterations in glycemic parameters are
strongly suggestive of an improvement in insulin
sensitivity in patients with type 2 diabetes. Taking
into account differences in study design (pretreatment
glycemic control, duration, dose) rosiglitazone and
pioglitazone are similarly ef®cacious (1). To date no
study has directly compared the clinical ef®cacy of
two or more thiazolidinediones. The effect on
glycemic control was dose dependent and leveled off
with daily doses >600 mg for troglitazone, >8 mg for
rosiglitazone and >30 mg for pioglitazone (35±37).
Overall, the improvement in glycemic control using a
single agent appears to be less pronounced with
thiazolidinediones than with sulfonylureas or metfor-
min.
Interestingly, other abnormalities commonly asso-
ciated with insulin resistance, such as dyslipidemia
and arterial hypertension, also appeared to be
improved by thiazolidinediones (35, 38, 39). While
rosiglitazone did not alter the LDL-HDL ratio (35),
pioglitazone treatment reduced LDL-cholesterol and
increased HDL-cholesterol (36). No signi®cant effect
on triglyceride levels was reported for either of the
compounds. Troglitazone, which unlike other thia-
zolidinediones carries an antioxidant vitamin E
moiety, in healthy volunteers also reduced LDL lipid
hydroperoxides (40) which are thought to be of
particular atherogenic potential (41). Other reported
non-hypoglycemic effects of thiazolidinedines include
improvement of ®brinolysis and decrease in carotid
artery intima media thickness (reviewed in (42)).
Mechanism of action
Metabolic studies
The concept, that a decrease in blood sugar, accom-
panied by a decrease in insulin concentrations,
represents improvement of insulin sensitivity, was
systematically examined in metabolic studies in vivo.
Thus, a 25% decrease in blood sugar and 30% lower
insulin could be shown during a meal-tolerance-test
and an oral glucose tolerance test in patients with
type-2-diabetes and patients with impaired glucose
tolerance after treatment with troglitazone (43, 44).
For pioglitazone a signi®cant improvement of the
insulin sensitivity could also be observed in a clamp
experiment in patients with type-2-diabetes (45). In
non-diabetic, adipose patients treated with troglita-
zone an improvement of insulin sensitivity of about
80% was measured with the hyperinsulinemic-eugly-
cemic clamp in the absence of changes in fasting
glucose (46). The pathologically increased endogen-
ous glucose production in type 2 diabetic patients was
reduced after therapy with troglitazone to near-
normal rates (43). This indicates improved effective-
Annals of Medicine 34
220 STUMVOLL . HAÈRING
Figure 3. Family of PPARs and ligand specificity. Font size
reflects expression levels in specific tissues.
ness of insulin also in glucose producing tissues
(mainly liver). However, this effect seems to be less
pronounced in humans (47) compared to animal
models (48, 49).
In-vitro studies
The cellular mechanism of action of the thiazolidine-
diones is mediated by binding to and activating the
peroxisomal proliferator-activated receptor (PPAR)g.
PPARg is a nuclear receptor that acts as transcription
factor upon activation by regulating the transcription
and expression of speci®c genes. Together with the
isoforms PPARa and PPAR¯ (Fig. 3) it belongs to the
same superfamily as thyroid hormone and steroid
receptors (50). Expression levels of the nuclear
receptor PPARg are highest in adipocytes, intestinal
cells and macrophages but very low in most other
tissues including muscle. Endogenous ligands of
PPARg include long-chain unsaturated fatty acids
and prostanoids such as 15-deoxy-delta12, 14-prosta-
glandin J2 (51). Upon activation, PPARg heterodi-
merizes with the retinoid X receptor (itself activated
by speci®c ligands) and the activated complex subse-
quently binds to speci®c DNA segments to induce
transcription of PPAR-responsive elements (PPRE)
(®g. 4). In various cell models (preadipocytes,
®broblasts, myoblasts) thiazolidinedione treatment
resulted in expression of a number of adipocyte
speci®c genes (lipoprotein lipase, fatty-acid binding
protein, glucose free fatty acids (GLUT4), acylco-
enzyme A (CoA) synthetase, etc.) so that PPARg
activation and/or overexpression has essentially been
associated with adipogenic differentiation (52±54).
The clinical observations that treatment with
thiazolidinediones improves insulin-stimulated (i.e.
muscle) glucose uptake while PPARg is mainly
# 2002 Taylor & Francis. ISSN 0785-3890
Figure 4. Cellular mechanism of action of thiazolidine-
diones. TZD = thiazolidinedione; Ins = Insulin; IR = insulin recep-
tor; RXR = retinoid X receptor; see text for details.
expressed in fat cells makes it somewhat dif®cult to
reconcile cellular and metabolic effects. In addition,
considering the well known connection between
obesity and insulin resistance it seems paradoxical
that an agent which promotes adipogenesis should
improve insulin sensitivity. A number of hypothetical
schemas to explain the available data have been put
forward. Firstly, PPARg is also expressed in skeletal
muscle (55) and the minute quantities may be
suf®cient to mediate the thiazolidinedione effect
directly. It is unclear what these muscle-speci®c
effects could be but in a fat-cell-free primary human
muscle cell culture system troglitazone enhanced
insulin-stimulated glycogen synthesis and phosphati-
dyl-inositol-3 kinase activity (16, 56). Direct effects in
muscle are also supported by in-vivo observations in a
lipoatrophic mouse model where thiazolidinedione
treatment improved insulin sensitivity in the absence
or near absence of adipose tissue (57).
Secondly, the effect of thiazolidinediones on insulin
stimulated glucose disposal may indeed be secondary
to changes in adipose tissue where PPARg is pre-
dominantly expressed and involve factors which alter
peripheral insulin sensitivity. Thiazolidinediones have
been shown to selectively stimulate lipogenic activities
in fat cells (58) resulting in greater insulin suppression
of lipolysis (59). This would leave less FFAs available
for other tissues (12). Thus, insulin desensitizing
effects of FFAs in muscle and liver (10) would be
reduced as a consequence of thiazolidinedione treat-
ment. This was originally proposed as `fatty-acid-steal
phenomenon’ (60) and recently con®rmed in humans
(61). Moreover, thiazolidinediones have been shown
to alter expression and release of adipocytokines.
Resistin, TNFa and leptin which have the potential to
decrease insulin sensitivity (see above) are reduced
following incubation with thiazolidinediones (22, 62±
Annals of Medicine 34
 GLITAZONES
Figure 5. Interference of thiazolidinediones with factors
released from adipose tissue. see text for details.
64). Conversely, expression and release of adiponectin
is increased upon thiazolidinedione treatment (58, 65).
Thus, all adipocytokines implicated in insulin sensi-
tivity are altered in a way that would ultimately
improve insulin sensitivity. Which of these mechan-
isms plays the most important role in vivo is unclear at
present but since they are not mutually exclusive all of
them may be involved (Fig. 5).
Side effects
In the early studies with troglitazone the thiazoli-
dinediones appeared to be well tolerated and main
adverse events included ¯uid retention and reversible
reductions in hemoglobin, hematocrit and neutro-
phil counts. The liver toxicity that resulted in
withdrawal of troglitazone from most markets does
not seem to be a problem with rosiglitazone or
pioglitazone (66) apart from anecdotal reports (67±
69). This difference is probably the result of different
metabolic degradation by the cytochrome P450
enzyme complex (70) and the vitamin E moiety of
troglitazone (71).
The adipogenic potential of thiazolidinediones in
preadipocytes in vitro and in therapeutic doses in
animals in vivo (72) has been of some concern.
Clinical use also demonstrated signi®cant weight
gain (73). The fact that an agent causes an increase in
body fat and at the same time improves insulin
sensitivity cannot easily be reconciled. 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 (53). It is also of note that thiazolidinediones
preferentially induce terminal differentiation of
preadipocytes of subcutaneous origin but not of
preadipocytes of visceral origin (74). This remodel-
# 2002 Taylor & Francis. ISSN 0785-3890
221
ing of fat depots away from metabolically unfavor-
able (i.e. visceral) to more innocent sites (i.e.
subcutaneous) has been con®rmed in humans by
computer tomography (75±78).
Nevertheless, novel concerns regarding the poten-
tial of these agents to affect cellular differentiation
originated from the observation that PPARg-activa-
tion causes fatty transformation of bone marrow
stromal cells (79). Furthermore, PPARg was recently
shown to be involved in differentiation of monocytes
into macrophages and uptake of oxidized LDL by
macrophages/monocytes, suggesting that PPARg is
an important regulator of gene expression during
athero-genesis (80). On the other hand, transcrip-
tional alterations with the potential to prevent
atherogenesis and in¯ammation have also been
reported (81). Moreover, in mice PPARg-agonists
were shown to promote carcinomatous growth in
colon epithelium (82, 83) while human colonic cancer
cells transplanted into mice showed a signi®cant
growth retardation following treatment with thiazo-
lidinediones (84). Conversely, PPARg-agonists have
been shown to inhibit growth of a human monocytic
leukemia cell line (85) setting the stage for a novel
treatment concept of malignant diseases. However, at
the present moment lack of clinical data makes it
impossible to determine the human relevance for any
of these mechanisms.
Conclusion
Thiazolidinediones represent a novel pharmacologi-
cal principle in the treatment of type 2 diabetes. With
respect to both mechanism of action and clinical
ef®cacy they are complementary or additive to
metformin and sulfonylureas. Evidently, thiazolidi-
nediones improve insulin sensitivity not only of type 2
diabetes but also of primarily non-diabetic conditions
such as: polycystic ovary syndrome (72), Werner
syndrome (genetic disease characterized by acceler-
ated aging) (86) and simple obesity (46). Theoreti-
cally, this opens up the possibility of pharmacological
prevention of type 2 diabetes and associated diseases.
The experimental veri®cation of this hypothesis on a
large scale by the American diabetes prevention trial
(87) had to be aborted following a fatal case of liver-
toxicity in the troglitazone arm.
The mechanism of action involves binding to the
peroxisome proliferator-activated receptor (PPAR)g,
a transcription factor with pleiotropic functions that
regulates the expression of speci®c genes especially in
fat cells but also in other tissues. It is likely that
thiazolidinediones primarily act in adipose tissue
where PPARg is predominantly expressed. Thiazoli-
dinediones have been shown to interfere with expres-
sion and release of mediators between adipose tissue
Annals of Medicine 34
222 STUMVOLL . HAÈRING
and insulin resistance (e.g. free fatty acids, adipocy-
tokines such as tumor necrosis factor a, resistin,
adiponectin) in a way that ultimately improves insulin
action. Nevertheless, a direct effect in skeletal muscle
cannot be completely excluded.
Interference with transcription contains a potential
risk for side effects, whose clinical relevance cannot
yet be de®nitively assessed. While the hepatotoxicity
observed with troglitazone does not seem to occur
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