Sphingosine kinase 1-interacting protein is a novel regulator of glucose-stimulated insulin secretion

Glucose-stimulated insulin secretion (GSIS) is essential in keeping blood glucose levels within normal range. GSIS is impaired in type 2 diabetes, and its recovery is crucial in treatment of the disease. We find here that sphingosine kinase 1-interacting protein (SKIP, also called Sphkap) is highly expressed in pancreatic β-cells but not in α-cells. Intraperitoneal glucose tolerance test showed that plasma glucose levels were decreased and insulin levels were increased in SKIP^-/- mice compared to SKIP^+/+ mice, but exendin-4-enhanced insulin secretion was masked. GSIS was amplified more in SKIP^-/- but exendin-4-enhanced insulin secretion was masked compared to that in SKIP^+/+ islets. The ATP and cAMP content were similarly increased in SKIP^+/+ and SKIP^-/- islets; depolarization-evoked, PKA and cAMP-mediated insulin secretion were not affected. Inhibition of PDE activity equally augmented GSIS in SKIP^+/+ and SKIP^-/- islets. These results indicate that SKIP modulates GSIS by a pathway distinct from that of cAMP-, PDE- and sphingosine kinase-dependent pathways.