Insulin resistance in glomerular podocytes: Potential mechanisms of induction.

Glomerular podocytes are a target for the actions of insulin. Accumulating evidence indicates that exposure to nutrient overload induces insulin resistance in these cells, manifested by abolition of the stimulatory effect of insulin on glucose uptake. Numerous recent studies have investigated potential mechanisms of the induction of insulin resistance in podocytes. High glucose concentrations stimulated reactive oxygen species production through NADPH oxidase activation, decreased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, and reduced deacetylase sirtuin 1 (SIRT1) protein levels and activity. Calcium signaling involving transient receptor potential cation channel C, member 6 (TRPC6) also was demonstrated to play an essential role in the regulation of insulin-dependent signaling and glucose uptake in podocytes. Furthermore, podocytes exposed to diabetic environment, with elevated insulin levels become insulin resistant as a result of degradation of insulin receptor (IR), resulting in attenuation of insulin signaling responsiveness. Also elevated levels of palmitic acid appear to be an important factor and contributor to podocytes insulin resistance. This review summarizes cellular and molecular alterations that contribute to the development of insulin resistance in glomerular podocytes.