Diacylglycerol kinase δ functions as a proliferation suppressor in pancreatic β-cells.

Although an aberrant reduction in pancreatic β-cell mass contributes to the pathogenesis of diabetes, the mechanism underlying the regulation of β-cell mass is poorly understood. Here, we show that diacylglycerol kinase δ (DGKδ) is a key enzyme in the regulation of β-cell mass. DGKδ expression was detected in the nucleus of β-cells. We developed β-cell-specific DGKδ knockout (βDGKδ KO) mice, which showed lower blood glucose, higher plasma insulin levels, and better glucose tolerance compared to control mice. Moreover, an increased number of small islets and Ki-67-positive islet cells, as well as elevated cyclin B1 expression in the islets, were detected in the pancreas of βDGKδ KO mice. DGKδ knockdown in the β-cell line MIN6 induced significant increases in bromodeoxyuridine (BrdU) incorporation and cyclin B1 expression. Finally, we confirmed that streptozotocin-induced hyperglycemia and β-cell loss were alleviated in βDGKδ KO mice. Thus, suppressing the expression or enzymatic activity of DGKδ that functions as a suppressor of β-cell proliferation could be a novel therapeutic approach to increase β-cell mass for the treatment of diabetes.