Glucolipotoxicity-induced PKCdelta dependent pancreatic beta cell death

2016 Fiscal Year Final Research Report

• Project/Area Number: 25461366
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Jikei University School of Medicine
• Principal Investigator: Fujimoto Kei 東京慈恵会医科大学, 医学部, 准教授 (40372974)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Keywords: Beta cell death / Glucolipotoxicity / Beta cell mass / Diabetes

Outline of Final Research Achievements

Glucolipotoxicity, a combination of high glucose and elevated free fatty acids (FFA), induces β cell dysfunction and death. High glucose and FFA both activate novel protein kinase c (Pkc), including Pkcδ. However, the role of Pkcδ in diabetes remains unclear. Wild-type mice on neonate streptozotocin plus high-fat diet showed impaired glucose tolerance and reduced insulin secretion. Prkcd deficiency in β cells improved glucose tolerance and insulin secretion. Prkcd deficiency in β cells ameliorated β cell mass via reduced β cell death. To confirm the mechanisms of PKCδ in β cells, we used MIN6 cells. High glucose and palmitate activated PKCδ and induced MIN6 cell death. Palmitate reduced Pdx1 protein expression and phosphorylated Pdx1 at T11. PKCδ deficiency prevented palmitate-induced MIN6 cell death and inhibited Pdx1 protein reduction and phosphorylation. These results suggest that glucolipotoxicity induces β cell death via PKCδ-Pdx1 pathway.

Free Research Field

糖尿病