Role Of Class IA PI 3-Kinase In Pancreatic β Cells.

Recent studies using several knockout models have shown that autocrine insulin (and/or IGF-1) regulates growth and some functions of pancreatic β cells through activation of insulin receptor (IR)→insulin receptor substrate (IRS) proteins→Class IA phosphoinositide 3-kinase (PI3K). Class IA PI3K is composed of a catalytic subunit (p110) and a regulatory subunit (p85), which occurs in multiple isoforms. Among them, p85α and β are two major isoforms. P85α is derived from the Pik3rl gene that also encodes two shorter isoforms, p55α and p50α, while p85β is derived from the Pik3r2. To identify the role of Class IA P13K in β cells, we have generated β cell specific Pik3rl gene knockout (βPik3rlKO) mice using Cre-LoxP system, since the whole body Pik3rl KO mice die within 1 week after birth. To gain more insight in the PI3K pathway of β cells, we ablated the genes of two major regulatory subunits, p85α and p85β, of PI3K by crossing mice lacking Pik3rl in β cells with Pik3r2 null mice, for creating β cells-specific double knockout mice (βDKO mice). βPik3r1KO mice grew normally and were indistinguishable from control RIP-Cre transgenic mice. There was an 80% reduction of the regulatory subunits in isolated islets from βPik3rlKO mice, while p85β still remained. βPik3rlKO mice displayed modestly elevated fed glucose concentrations at 4 months of age and older, whereas fasting glucose levels were normal and they never developed diabetes during entire life. However, βPik3rlKO mice exhibited glucose intolerance and markedly suppressed glucose stimulated insulin secretion (GSIS) in vivo at 2 months and older. GSIS was also impaired using isolated islets from βPik3rlKO mice especially at lower concentrations of glucose, suggesting the existence of a defect in glucose sensing. Moreover, islet size of βPik3rlKO mouse was decreased by 30% compared to that of RIP-Cre mouse. Until a few months of age that we have observed for, βDKO mice also grew normally. However, βDKO mice showed more prominent glucose intolerance than βPik3rlKO mice due to a declined insulin secretion. Despite this, βDKO mice did not develop diabetes at this stage presumably because Pik3r2 null background is more sensitive to insulin than wild-type, as we have previously shown. These data suggest that Class IA PI3K is required for age-dependent islet growth and normal insulin secretion, and that decreased Class IA PI3K activity causes postprandial hyperglycemia. This may also provide a novel therapeutic approach for diabetes. [ABSTRACT FROM AUTHOR]