Oral Antidiabetic Agents - Luzimar Teixeira

404 Krentz & Bailey
ed metformin has been challenged by some authorities,
but dialysis may nonetheless be helpful in optimising
fluid and electrolyte balance during treatment
with high-dose intravenous bicarbonates. [54]
3.2 Thiazolidinediones
3.2.2 Pharmacokinetics
Rosiglitazone and pioglitazone are rapidly, and
nearly completely absorbed (1–2 hours to peak con-
centration), although absorption is slightly delayed
when taken with food. Both agents are extensively
metabolised by the liver. Rosiglitazone is metabol-
ised mainly to very weakly active metabolites with
lesser activity that are excreted predominantly in the
urine. The metabolites of pioglitazone are more
active and excreted mainly in the bile. Metabolism
of rosiglitazone is undertaken mainly by cyto-
3.2.1 Mode of Action
Stimulation of PPARγ is regarded as the principal
mechanism through which thiazolidinediones enhance
insulin sensitivity. PPARγ is expressed at
highest levels in adipose tissue, and less so in
muscle and liver. PPARγ operates in association
with the retinoid X receptor. The resulting heterodimer
binds to nuclear response elements, thereby
modulating transcription of a range of insulin-sensitive
genes, in the presence of necessary cofactors
(figure 4). [55,57] Many of the genes activated or suppressed
by thiazolidinediones are involved in lipid
and carbohydrate metabolism (table VI). Stimulation
of PPARγ by a thiazolidinedione promotes
differentiation of pre-adipocytes with accompanying
lipogenesis, effects that promote or enhance the
local effects of insulin. Thiazolidinediones increase
Table VI. Metabolic effects of thiazolidinediones [55]
Adipose tissue Muscle Liver
↑ Glucose uptake ↑ Glucose uptake ↓ Gluconeogenesis
↑ Fatty acid uptake ↑ Glycolysis ↓ Glycogenolysis
↑ Lipogenesis ↑ Glucose oxidation ↑ Lipogenesis
↑ Pre-adipocyte ↑ Glycogenesis a ↑ Glucose uptake a
differentiation
a Inconsistent findings.
↑ indicates increase; ↓ indicates decrease.
Thiazolidinediones improve whole-body insulin
sensitivity via multiple actions on gene regulation.
These effects result from stimulation of a nuclear
receptor peroxisome proliferator-activated receptorγ
(PPARγ), for which thiazolidinediones are potent
synthetic agonists. [55] The antidiabetic activity of
thiazolidinediones was described in the early 1980s,
troglitazone being the first of the class to become
available for clinical use. Troglitazone was introduced
in the US in 1997, only to be withdrawn in
2000 because of cases of idiosyncratic hepato-
toxicity resulting in fatalities. Troglitazone was
available in the UK for only for a few weeks in 1997
before being withdrawn by its distributor as reports
of hepatotoxicity accumulated in other countries. To
date, two other thiazolidinediones, rosiglitazone and
pioglitazone, have not shown the hepatotoxicity that
led to the demise of troglitazone. Rosiglitazone and
pioglitazone were introduced in the US in 1999 and
in Europe in 2000. [56] Combination preparations
(e.g. thiazolidinedione plus metformin) are also
available.
glucose uptake via glucose transporter-4 in skeletal
muscle, and some reports indicate that rates of glu-
coneogenesis in the liver are reduced. Stimulation of
lipogenesis via PPARγ reduces circulating non-es-
terified fatty acid (NEFA) concentrations through
cellular uptake and triglyceride synthesis (figure 5).
The reduction in plasma NEFA concentrations is
associated with increased glucose utilisation and
reducing gluconeogenesis by reducing operation of
the glucose-fatty acid cycle; reductions in ectopic
lipid deposition in muscle and liver may contribute
to the improvements on glucose metabolism. Thia-
zolidinediones also reduce the production and ac-
tivity of the adipocyte-derived cytokine tumour ne-
crosis factor (TNF)-α. [55] The latter has been impli-
cated in the development of impaired insulin action
in muscle, [58] although the precise role of TNFα in
human states of insulin resistance remains unclear.
Reductions in plasma insulin concentrations and
lowering of circulating triglycerides are additional
indirect mechanisms that may help to improve
whole-body insulin sensitivity. Thiazolidinediones,
like metformin, are anti-hyperglycaemic agents and
require the presence of sufficient insulin to generate
a significant blood glucose-lowering effect.
© 2005 Adis Data Information BV. All rights reserved. Drugs 2005; 65 (3)