Requirement of Inositol Pyrophosphates for Full Exocytotic Capacity in Pancreatic β Cells

Abstract

Inositol pyrophosphates are recognized components of cellular processes that regulate vesicle trafficking, telomere length, and apoptosis. We observed that pancreatic β cells maintain high basal concentrations of the pyrophosphate diphosphoinositol pentakisphosphate (Ins P 7 or IP 7 ). Inositol hexakisphosphate kinases (IP6Ks) that can generate IP 7 were overexpressed. This overexpression stimulated exocytosis of insulin-containing granules from the readily releasable pool. Exogenously applied IP 7 dose-dependently enhanced exocytosis at physiological concentrations. We determined that IP6K1 and IP6K2 were present in β cells. RNA silencing of IP6K1, but not IP6K2, inhibited exocytosis, which suggests that IP6K1 is the critical endogenous kinase. Maintenance of high concentrations of IP 7 in the pancreatic β cell may enhance the immediate exocytotic capacity and consequently allow rapid adjustment of insulin secretion in response to increased demand.