Title:Molecular Remodeling of the Insulin Receptor Pathway by Thiazolidinediones in Type 2 Diabetes Mellitus: A Brief Review
Volume: 23
Issue: 9
Author(s): Nikhil S. Sahajpal and Subheet K. Jain
Affiliation:
Keywords:
Type 2 diabetes mellitus (T2DM), insulin receptor pathway, downstream signaling, downstream players, insulin
resistance, thiazolidinediones.
Abstract: Type 2 diabetes mellitus (T2DM) is characterized by abnormalities in
carbohydrate, lipoprotein and lipid metabolism, leading to hyperglycemia and
several other complications. Insulin is the major hormone regulating these facets
by eliciting various biological responses through its receptor. Insulin exerts diverse
effects on cells by targeting distinct functions such as gene expression, fatty
acid synthesis, glucose transport and receptor translocation. Insulin mediates these
effects through signaling pathways utilizing adapter molecules like small Gproteins,
lipid and tyrosine kinases. The anomalous cell response in diabetic condition
is due to altered expression/function of these molecules. Thiazolidinediones
(TZD’s), a class of oral hypoglycemic drugs, have shown to modify these responses,
leading to insulin sensitizing effect(s). The TZD’s are not only PPARγ agonists, but substantial
insulin sensitizing activity is observed through its direct and indirect targets of the insulin
receptor pathway, which contributes to its overall performance. TZD’s alter(s) cell response via
downstream players, primarily IRS, Akt/PKB, PKC, GLUT4, MEK, ERK and transcription factor
PGC1α. Thus, this review will focus on the alteration(s) of these molecules in various cell types in
diabetic condition and their regulation by TZD’s. The physiological changes that occur at the molecular
level in T2DM and their modulation by TZD’s will provide insights into the key players involved
and the potential drug targets for future drug development. The review further highlights the
key markers to be evaluated in screening of any potential anti-diabetic agent, and to standardize therapy
for T2DM based upon its modulation of the various signaling pathways.
