Cinnamtannin D1 Protects Pancreatic Beta-Cells From Glucolipotoxicity-Induced Apoptosis By Enhancement Of Autophagy In Vitro And In Vivo

In our previous study, cinnamtannin D1 (CD-1), one of the A-type procyanidin oligomers isolated from Cinnamomum tamala, was reported to have the activity of antiapoptosis in palmitic acid-treated pancreatic beta cells via alleviating oxidative stress in vitro. In this study, the aim was to further disclose its protective effect and underlying mechanisms against glucolipotoxicity-induced beta-cells apoptosis in vitro and in vivo. We found that CD-1 was able to dose-dependently and time-dependently activate autophagy in INS-1 pancreatic beta-cells. High glucose and palmitic acid (HG/PA)-induced apoptosis and autophagy impairment could be attenuated by CD-1 in INS-1 cells as well as primary cultured murine islets. We also demonstrated that CD-1-induced autophagy was through AMPK/mTOR/ULK1 pathway. Moreover, it was shown that the effects of CD-1 on activation of Keap1/Nrf2 antioxidant signaling pathway and the amelioration of inflammation, endoplasmic reticulum stress, and apoptosis were through autophagy induction in HG/PA-treated INS-1 cells. These protective effects in vivo and hypoglycemic activity of CD-1 were also observed in diabetic db/db mice. These findings have great significance in revealing the antidiabetic mechanisms of procyanidin oligomers and paving the way for their application in the treatment of diabetes.