Cdk5-dependent regulation of glucose-stimulated insulin secretion

Abstract

Tight glycaemic control in patients with diabetes mellitus is essential to prevent or delay its complications. Present treatments to reduce hyperglycaemia mainly target ATP-sensitive K⁺ (K⁺_ATP) channel of pancreatic β-cells to increase insulin secretion. However, these current approaches are often associated with the side effect of hypoglycaemia. In the present study, we showed that inhibition of cyclin-dependent kinase 5 (Cdk5)/p35 activity enhanced insulin secretion under conditions of stimulation by high glucose but not in low glucose in MIN-6 cells and rat pancreatic islets. The role of Cdk5 in regulation of insulin secretion was also confirmed in pancreatic β-cells of p35-deficient mice. The kinase inhibition enhanced the inward whole-cell Ca²⁺ channel current and increased Ca²⁺ influx across the L-type voltage-dependent Ca²⁺ channel (L-VDCC) upon high glucose stimulation in β-cells, but had no effect on Ca²⁺ influx without glucose stimulation. The molecular mechanism of the Cdk5-dependent enhancement of insulin secretion was that Cdk5 phosphorylated loop II-III of L-VDCC at Ser783, and this phosphorylation reduced the binding to SNARE proteins, resulting in a decrease of the activity of L-VDCC. These results suggest that Cdk5/p35 may be a potential drug target for the control of hyperglycaemia without the side effect of hypoglycaemia. [Jpn J Physiol 55 Suppl:S208 (2005)]