Phosphatidylinositol-4-Phosphate-5-Kinase α Deficiency Alters Dynamics of Glucose-Stimulated Insulin Release to Improve Glucohomeostasis and Decrease Obesity in Mice

OBJECTIVE: Phosphatidylinositol-4-phosphate-5-kinase (PI4P5K) has been proposed to facilitate regulated exocytosis and specifically insulin secretion by generating phosphatidylinositol-4,5-bisphosphate (PIP(2)). We sought to examine the role of the α isoform of PI4P5K in glucohomeostasis and insulin secretion. RESEARCH DESIGN AND METHODS: The response of PI4P5Kα(−/−) mice to glucose challenge and a type 2-like diabetes-inducing high-fat diet was examined in vivo. Glucose-stimulated responses and PI4P5Kα(−/−) pancreatic islets and β-cells were characterized in culture. RESULTS: We show that PI4P5Kα(−/−) mice exhibit increased first-phase insulin release and improved glucose clearance, and resist high-fat diet-induced development of type 2-like diabetes and obesity. PI4P5Kα(−/−) pancreatic islets cultured in vitro exhibited decreased numbers of insulin granules docked at the plasma membrane and released less insulin under quiescent conditions, but then secreted similar amounts of insulin on glucose stimulation. Stimulation-dependent PIP(2) depletion occurred on the plasma membrane of the PI4P5Kα(−/−) pancreatic β-cells, accompanied by a near-total loss of cortical F-actin, which was already decreased in the PI4P5Kα(−/−) β-cells under resting conditions. CONCLUSIONS: Our findings suggest that PI4P5Kα plays a complex role in restricting insulin release from pancreatic β-cells through helping to maintain plasma membrane PIP(2) levels and integrity of the actin cytoskeleton under both basal and stimulatory conditions. The increased first-phase glucose-stimulated release of insulin observed on the normal diet may underlie the partial protection against the elevated serum glucose and obesity seen in type 2 diabetes-like model systems.