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These drugs
reduce insulin resistance and improve insulin sensitivity, resulting in a
reduction of fasting plasma glucose, insulin, and free fatty acids.
All the drugs in this class exhibit a characteristic delay from 4-12 weeks
in the onset of their therapeutic benefits. This is likely related to their
mode of action, which involves the regulation of gene expression.
Pioglitazone and rosiglitazone are selective agonists for the peroxisome
proliferator-activated receptor
g
(PPARg),
a member of the superfamily of nuclear hormone receptors that function as
ligand-activated transcription factors. It does not appear that
rosiglitazone and pioglitazone improve insulin sensitivity and glucose
disposal by direct effects on either liver or muscle. PPARg
is expressed chiefly in adipose tissue, and its expression in liver and
skeletal muscle is low. Thus, it is more likely that the primary effects of
these drugs are on adipose tissue, followed by secondary benefits on other
target tissues of insulin. |
In the study shown below, a "glucose clamp" was used
to determine the effects of metformin and troglitazone on endogenous glucose
production (hepatic gluconeogenesis) and peripheral glucose disposal
(basically glucose uptake into skeletal muscle).
The take-home message here is that metformin
predominantly reduces glucose production and troglitazone mainly increased
glucose uptake in the periphery.
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