Minireview: Meeting the Demand for Insulin: Molecular Mechanisms of Adaptive Postnatal β-Cell Mass Expansion

Type 2 diabetes results from pancreatic beta-cell failure in the setting of insulin resistance. This model of disease progression has received recent support from the results of genome-wide association studies that identify genes potentially regulating beta-cell growth and function as type 2 diabetes susceptibility loci. Normal beta-cell compensation for an increased insulin demand includes both enhanced insulin-secretory capacity and an expansion of morphological beta-cell mass, due largely to changes in the balance between beta-cell proliferation and apoptosis. Recent years have brought significant progress in the understanding of both extrinsic signals stimulating beta-cell growth as well as mediators intrinsic to the beta-cell that regulate the compensatory response. Here, we review the current knowledge of mechanisms underlying adaptive expansion of beta-cell mass, focusing on lessons learned from experimental models of physiologically occurring insulin-resistant states including diet-induced obesity and pregnancy, and highlighting the potential importance of interorgan cross talk. The identification of critical mediators of islet compensation may direct the development of future therapeutic strategies to enhance the response of beta-cells to insulin resistance. (Molecular Endocrinology 23: 747-758, 2009)