Inositol hexakisphosphate and sulfonylureas regulate beta-cell protein phosphatases

Area of Science:

• Endocrinology
• Cell Biology
• Metabolic Diseases

Background:

• Type 2 diabetes is characterized by impaired glucose-stimulated insulin exocytosis from pancreatic beta-cells.
• The precise molecular mechanisms governing insulin exocytosis remain incompletely understood.

Purpose of the Study:

• To investigate the role of inositol hexakisphosphate (InsP6) in regulating insulin exocytosis.
• To explore the effects of InsP6 on protein phosphatase activity in pancreatic beta-cells.

Main Methods:

• Measurement of InsP6 concentration in response to glucose stimulation.
• Assay of ser/thr protein phosphatase activities (PP1 and PP2A) in pancreatic beta-cells.
• Evaluation of hypoglycemic sulfonylurea effects on phosphatase activity.

Main Results:

• InsP6 concentration increases transiently upon glucose stimulation.
• InsP6 dose-dependently inhibits ser/thr protein phosphatase activities at physiologically relevant concentrations.
• Hypoglycemic sulfonylureas did not affect protein phosphatase-1 or -2A activity at clinically relevant concentrations.

Conclusions:

• InsP6 acts as a novel regulator of insulin exocytosis by inhibiting protein dephosphorylation.
• Increased cellular phosphorylation state, mediated by InsP6, may link glucose-stimulated polyphosphoinositide formation to insulin secretion.
• This provides a new perspective on the pathophysiology of type 2 diabetes.