Class IA Phosphatidylinositol 3-Kinase in Pancreatic β Cells Controls Insulin Secretion by Multiple Mechanisms

Type 2 diabetes is characterized by insulin resistance and pancreatic beta cell dysfunction, the latter possibly caused by a defect in insulin signaling in beta cells. Inhibition of class IA phosphatidylinositol 3-kinase (PI3K), using a mouse model lacking the pik3r1 gene specifically in beta cells and the pik3r2 gene systemically (beta DKO mouse), results in glucose intolerance and reduced insulin secretion in response to glucose. beta cells of beta DKO mice had defective exocytosis machinery due to decreased expression of soluble N-ethylmaleimide attachment protein receptor (SNARE) complex proteins and loss of cell-cell synchronization in terms of Ca2+ influx. These defects were normalized by expression of a constitutively active form of Akt in the islets of beta DKO mice, preserving insulin secretion in response to glucose. The class IA PI3K pathway in beta cells in vivo is important in the regulation of insulin secretion and may be a therapeutic target for type 2 diabetes.