The British Journal of Diabetes & Vascular Disease
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Thiazolidinedione-induced effects beyondglycaemic control
Effects of pioglitazone on selected target genes affecting
The thiazolidinediones exert their insulin sensitising effect by binding to the nuclear receptors (transcription factors) peroxisome proliferator activated receptor (PPAR) γ and, to varying Target gene degrees, to PPARα. Several different genes are activated by thiazolidinediones, many of which contribute to the increase in insulin sensitivity (eg. an increase in glucose uptake and utilisation, a decrease in gluconeogenesis and in insulin-antagonistic cytokines, such as tumour necrosis factor α). Activation of other genes indirectly reduces insulin resistance by, for example, increasing free fatty acid (FFA) uptake and oxidation resulting in lower circulating FFA levels. The action of thiazolidinediones at PPARγ is generally responsible for their insulin sensitising effects while action at PPARα contributes to their lipid lowering effects. Therefore, the relative affinities of the different thiazolidinediones for PPARγ and PPARα will also lead to a different spectrum of actions for each agent. Key words: diabetic dyslipidaemia, insulin resistance,
cerides and an increase in high-density lipoprotein (HDL) parti-
PPAR receptors, pioglitazone, thiazolidinedione.
cles.2 PPARβ/δ is ubiquitous but its role in insulin resistanceremains unclear.2
The peroxisome proliferator activated receptors
PPARγ exists in two isoforms: PPARγ1 and PPARγ2.2 A wide
variety of tissues express PPARγ1, while PPARγ2 is found pre-
The peroxisome proliferator activated receptor (PPARs; α, β/δ and
dominantly (and at high levels) in adipose tissue where it plays a
γ) are part of a subfamily of the nuclear hormone receptor super-
key role in adipogenesis.1,2 PPARγ also appears to modulate sev-
family. Other members of this family include 9-cis-retinoic acid
eral genes regulating energy storage and utilisation, in particular
receptor (RXR), thyroid receptor and vitamin D receptor.1 The
those affecting insulin sensitivity.1,2 However, the exact mecha-
three PPARs are distributed differently in different organs.1 PPARα
nisms by which PPARγ activation promotes insulin sensitivity are
is highly expressed in liver but is also found in skeletal and car-
still unknown. Some possible target genes are shown in table 1.
diac muscle. It regulates genes involved in fatty acid oxidation;
The natural ligands for PPARγ are also largely unknown. The
fatty acids below 20 carbons in length are oxidised in mitochon-
most likely candidates are eicosanoids.2 Nonetheless, several
dria while longer fatty acids are oxidised in peroxisomes.2 Insulin
high-affinity synthetic ligands have been generated, most impor-
reduces the expression of these genes while glucocorticoids
increase their expression.2 The fibrate class of lipid-lowering
After a PPAR binds with a ligand it becomes activated and
agents act via PPARα resulting in a reduction in serum trigly-
forms an activated complex with RXR which binds to specificperoxisome proliferator response elements (PPRE).3,4 These aredirect repeats of the nuclear receptor hexameric (AGGTCA)DNA core recognition motif separated by one or two
Correspondence to: Professor Ulf SmithThe Lundberg Laboratory for Diabetes Research, Department of Internal
nucleotides (DR1 and DR2). Formation of the complex triggers
Medicine, The Sahlgrenska Academy, S-413 45 Göteborg, Sweden.
recruitment of coactivator proteins. These coactivators are
Tel: +46 31 342 1104; Fax: +46 31 82 9138
required for transcriptional activation.1,2,4 This results in
increased transcription and protein synthesis, which in turn
Br J Diabetes Vasc Dis 2002;2(suppl 1):S24–S27
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
PPARγ polymorphism Figure 1. Development of the thiazolidinediones
PPARγ appears to be fundamental to the pathophysiology ofinsulin resistance and diabetes. Various polymorphisms inPPARγ are associated with increased or decreased degrees of
insulin resistance.1 For example, the Pro12Ala mutation in the
PPARγ2-specific exon B appears to be associated with improved
insulin sensitivity, lower body mass index and higher plasma
HDL concentrations.5 By contrast, Barroso et al.6 have described
two different mutations in the ligand-binding domain, which
result in severe insulin resistance, dyslipidaemia and hyperten-
Ciglitazone, Takeda Pioglitazone, Takeda Thiazolidinediones and insulin resistance AL-321, Takeda
The thiazolidinedione class was first discovered by Takeda
Chemical Industries in 1975 and the lead substance for all future
thiazolidinedione derivatives (ciglitazone) was synthesised in1980. Structural modification of this prototype molecule by dif-ferent pharmaceutical companies produced several agents withgreater glucose-lowering potential. In 1982, pioglitazone was
tor alpha (TNFα).20 These different effects probably explain the
synthesised and shown to be suitable for further development.
insulin sensitising and antihyperglycaemic effects of the thiazo-
Other agents in this new group of drugs are rosiglitazone and
troglitazone (now withdrawn) (figure 1).
The thiazolidinediones bind with varying affinities to PPARγ
and PPARα. For example, pioglitazone has a comparable activity
Several studies have indicated that pioglitazone increases expres-
at PPARγ to rosiglitazone, but appears to be a stronger activator
sion of glucose transporters (GLUT) 1 and 4,9-11 which in turn
of PPARα than rosiglitazone (figure 2).7
increases glucose uptake. Studies in people with type 2 diabetes
Insulin resistance is the prime defect in type 2 diabetes – in
using the euglycaemic-hyperinsulinaemic clamp have, indeed,
such individuals insulin production can no longer compensate for
shown an increase in insulin-stimulated glucose disposal with
the high level of insulin resistance resulting in hyperglycaemia
pioglitazone treatment.21,22 In addition, pioglitazone has been
and diabetes.8 Pioglitazone opposes insulin resistance in several
shown to improve the deficiency in insulin stimulation of PI-3-
ways, including increased expression of glucose transporters and
kinase and reduce hyperglycaemia and hyperinsulinaemia in a rat
uptake,9-11 enhancing insulin signalling,12,13 reducing hepatic glu-
model of insulin resistance.12 Further, pioglitazone has been found
cose production,14-17 increasing fatty acid uptake and lipogenesis
to target insulin receptor substrate 2 (IRS-2), a key molecule for
by adipocytes,18,19 decreasing cytokines like tumour necrosis fac-
insulin signalling and action.13 Pioglitazone also lowers blood glu-
Figure 2. Activation of PPARα and PPARγ1 by pioglitazone or rosiglitazone. Full-length hPPARγ1 and hRXRγ or hPPARα and hRXRα expression plasmids were
co-transfected into COS-1 cells with reporter plasmid contained PPRE, and cells were cultured in the presence of pioglitazone or rosiglitazone for 48 hours. The cell extracts were assayed for luciferase activity. The dotted lines indicate plasma C
at corresponding maximal clinical doses of
pioglitazone 45 mg and of rosiglitazone 8 mg7
Fold induction (PP Fold induction (PP Fold induction (PP Fold induction (PP Log (conc. [M]) Log (conc. [M])
Adapted with permission from Sakamoto et al.7 Copyright, Biochem Biophys Res Commun 2000. All rights reserved.
VOLUME 2 SUPPLEMENT 1 . JANUARY/FEBRUARY 2002
Figure 3. Pioglitazone: metabolic control in type 2 diabetes Key messages glucose uptake utilisation
● PPARγ is fundamental to the pathophysiology of
fat storage Improved glucose Thiazolidinediones lipolysis
Thiazolidinediones act on PPARγ to increase insulin
and lipid levels free fatty acids
● Pioglitazone opposes insulin resistance by increasing
glucose uptake, enhancing insulin signalling, reducing
gluconeogenesis, increasing fatty acid uptake anddecreasing cytokines
● Pioglitazone lowers plasma triglycerides and increases
HDL cholesterol production from the liver
● Pioglitazone appears to decrease visceral fat and may
cose by reducing hepatic glucose production via increased activity
of phosophoenolpyruvate carboxykinase (PEPCK), a key enzyme inglucose production.14 Lastly, pioglitazone reduces production ofinsulin-antagonistic cytokines like TNFα.20
Pioglitazone also indirectly lowers blood glucose by its effects
Pioglitazone also increases lipoprotein lipase in cultured
on FFA uptake and oxidation. When plasma-free fatty acids (FFA)
adipocytes.31 Decreased activity of this enzyme may be respon-
are elevated, insulin-stimulated glucose uptake can be impaired23
sible for the slowed clearance of triglyceride-rich lipoproteins in
and hepatic glucose output increased.24 The effects of pioglita-
insulin-resistant states. The three different thiazolidinediones
zone on metabolic control in type 2 diabetes are summarised in
studied so far have shown differences in their effects on plas-
ma lipids. Pioglitazone lowers triglycerides and raises HDL cho-
However, insulin resistance has consequences beyond hyper-
lesterol but does not affect low-density lipoprotein (LDL) cho-
glycaemia. Thus, it is likely that the actions of pioglitazone on
lesterol.8,27 Rosiglitazone, in contrast, appears to have no effect
insulin resistance result in effects beyond glycaemic control.
on triglycerides or on HDL cholesterol while significantlyincreasing LDL cholesterol.1,8,32 Troglitazone decreases trigly-
Effects on dyslipidaemia
cerides and FFA and also increases HDL cholesterol.1,8
Insulin resistance is linked, not only with disturbances of glu-
These varying effects of the thiazolidinediones on lipid pro-
cose metabolism, but also with lipid abnormalities – typically
files may also have clinical relevance. As high triglyceride and low
increased triglycerides and decreased high-density lipoprotein
HDL cholesterol levels typical of insulin resistance are known car-
(HDL) cholesterol.25 This occurs in part because insulin resis-
diovascular risk factors, an agent which can reverse these
tance in adipose tissue results in a reduced anti-lipolytic effect
changes, even in part, might bring benefits in terms of cardio-
of insulin, causing low glucose uptake and increased FFA and
vascular events. This requires further investigation like the ongo-
glycerol release. Increased FFAs passing into the liver result in
increased triglycerides, apolipoprotein B and very low-density
Another effect of pioglitazone that may be relevant to lipid
lipoprotein (VLDL) production, which in turn causes a decrease
metabolism is that it appears to affect visceral adiposity.27 Visceral
in HDL levels by affecting transfer of lipids between VLDL and
fat is also linked to insulin resistance25 and is important in lipid
HDL particles (described elsewhere in this supplement).26 It is of
metabolism because increased lipolysis in this fat depot (as
interest, therefore, that pioglitazone also has a beneficial effect
occurs in insulin resistance) directly increases the concentration
on this dyslipidaemia, lowering plasma triglycerides and raising
of FFAs in the portal circulation. This may have immediate effects
on VLDL and triglyceride production from the liver.26
The effects of pioglitazone on lipid metabolism appear to
occur in several ways. Insulin exerts its antilipolytic effect by
activating and phosphorylating the enzyme phosphodiesterase
The insulin sensitising effect of pioglitazone and other thiazo-
3B (PDE 3B), which in turn inactivates and dephosphorylates
lidinediones is mediated mainly through PPARγ activation,
hormone-sensitive lipase.28 Decreased PDE 3B has been found
whereas the lipid-lowering effect is in part mediated through
in adipocytes from people with type 2 diabetes.29 In a mouse
PPARα activation. Differential effects of different TZDs on the
model of obesity which shows reduced PDE 3B levels, pioglita-
lipid levels may be related to their affinity for PPARα receptors.
zone has been shown to restore PDE 3B mRNA and protein lev-
Whether these differences also affect the cardiovascular risk in
els and so decrease lipolysis and lower plasma FFA.30
type 2 diabetes patients remains to be established.
THE BRITISH JOURNAL OF DIABETES AND VASCULAR DISEASE
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VOLUME 2 SUPPLEMENT 1 . JANUARY/FEBRUARY 2002
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