Requirement of inositol pyrophosphates for full exocytotic capacity in pancreatic β cells

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 (InsP₇ or IP ₇). Inositol hexakisphosphate kinases (IP6Ks) that can generate IP₇ were overexpressed. This overexpression stimulated exocytosis of insulin-containing granules from the readily releasable pool. Exogenously applied IP₇ 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 IP₇ in the pancreatic β cell may enhance the immediate exocytotic capacity and consequently allow rapid adjustment of insulin secretion in response to increased demand.