Specific Deletion of CASK in Pancreatic β Cells Affects Glucose Homeostasis and Improves Insulin Sensitivity in Obese Mice by Reducing Hyperinsulinemia Running Title: β Cell CASK Deletion Reduces Hyperinsulinemia

Abstract

Calcium/calmodulin-dependent serine protein\nkinase (CASK) is involved in the secretion of insulin vesicles in pancreatic\nβ-cells. The present study revealed a new in\nvivo role of CASK in glucose homeostasis during the progression of type 2 diabetes mellitus (T2DM). A\nCre-loxP system was used to specifically delete the Cask gene in mouse\nβ-cells (βCASKKO), and the glucose metabolism was evaluated in βCASKKO mice fed a normal chow diet (ND) or a high-fat\ndiet (HFD). ND-fed mice exhibited impaired insulin secretion in response to\nglucose stimulation. Transmission electron microscopy showed significantly\nreduced numbers of insulin granules at or near the cell membrane in the islets\nof βCASKKO mice. By contrast, HFD-fed βCASKKO mice showed reduced blood glucose\nand a partial relief of hyperinsulinemia and insulin resistance when compared\nto HFD-fed wildtype mice. The IRS1/PI3K/AKT signaling pathway was upregulated\nin the adipose tissue of HFD-βCASKKO mice. These results indicated that\nknockout of the Cask gene in β cells had a diverse effect on glucose\nhomeostasis: reduced insulin secretion in ND-fed mice, but improves insulin\nsensitivity in HFD-fed mice. Therefore, CASK appears to function in the insulin\nsecretion and contributes to hyperinsulinemia and insulin resistance during the\ndevelopment of obesity-related T2DM.