The role of insulin signaling in the development of β-cell dysfunction and diabetes.

The peptide hormone insulin not only regulates metabolic pathways, but also proliferative signaling pathways. Insulin regulates cell proliferation, protein synthesis and gene expression in most, if not all, mammalian tissues. Extensive recent studies have shown that insulin also plays an important role in the regulation of pancreatic islet β-cell function. In the development of peripheral insulin resistance leading to an increased demand for insulin production, increase in β-cell mass by compensatory hyperplasia and hypertrophy of β-cells and insulin output is a crucial mechanism to maintain euglycemia. Indeed, impaired insulin signaling in the β-cells and increased β-cell apoptosis are associated with the onset of diabetes in obese insulin resistant type 2 diabetes mellitus (T2DM). Studies using gene knockout approaches in mice have further demonstrated that the insulin signaling in the β-cells is critical for mediating insulin action on them to maintain appropriate mass and insulin production. It is conceivable that insulin resistance, which is usually associated with the compensatory mechanism of hyperinsulinemia, occurring in the β-cells could be a major contributor leading to increased rate of β-cell death and declined β-cell mass. It is hypothesized that a strategy to improve intra-islet insulin action via enhancing β-cell responsiveness could be a considerable benefit in the prevention and treatment of T2DM.