| The physiological performance of an organ depends on a complex interplay between changes in cellular function and organ size, determined by cell growth, proliferation and death. Nowhere is this more evident than in the endocrine pancreas, where disturbances in function or mass result in severe disease. Recently, insulin/insulin-like growth factor 1 (IGF-1) signaling mediators have been accepted not only as regulators of pancreatic beta cell hormone secretion, but also as determinants of pancreatic beta cell mass. A prominent mediator of the actions of this pathway, which has yet to be characterized with regards to its role in beta cell regulation, is the serine/threonine kinase Akt. To elucidate its role in the endocrine pancreas, a transgenic mouse was created which expressed a constitutively active form of Akt1 predominantly in the pancreatic beta cells. Overexpression of active Akt1 in the mouse beta-cell substantially augmented the beta cell mass due in part to increased islet hyperplasia and hypertrophy, and in part to beta cell hypertrophy. Beta cell proliferative levels appeared normal, while basal apoptotic levels increased; thus, myr-Akt1 most likely exerted a neogenic effect. Although the transgenic animals suffered from slight metabolic anomalies, such as mild hypoglycemia, circulating hyperinsulinemia, and increased glucose tolerance, they retained their peripheral insulin sensitivity. Further, the Akt transgenic mice were able to completely prevent both a drug-induced (low-dose streptozotocin) and a genetic model (insulin receptor substrate 2 deficient mice) of experimental diabetes. These studies suggest that Akt may mediate not only the growth of the pancreatic beta cell, but also its function as well. |
