Molecular Mechanism of Insulin Resistance and Type2 Diabetes

Fatty acids (FA) are known to cause insulin resistance and type 2 diabetes. Underlying mechanism of this is still unclear. In general, consensus so far reached favors missing of insulin signals due to FA. We have observed down regulation of insulin receptor (IR) expression by FA in a major insulin target cell i.e. skeletal muscle cell. On searching the mechanism we have found that FA induced phosphorylation of Protein Kinase C epsilon (pPKC) plays a key role. It is pPKC that migrates to the nucleus whereas its non-phospho form can not. On entering the nucleus it is associated with an architectural transcription factor of IR gene i.e. high mobility group protein A1 (HMGA1) and causes its impairment that adversely affects IR gene expression. Decrease of insulin receptor (IR) copy number on cell surface considerably attenuated insulin signal transduction, this in turn significantly reduced insulin stimulated cellular glucose uptake. Details of the mechanism and possible therapeutic intervention will be discussed.