2129-P: DAP-Related Apoptosis-Inducing Kinase-2 Negatively Regulate Islet Beta-Cell Function by Autophagy Repression

Islet apoptosis is a detrimental event causing or aggravating type 2 diabetes (T2D). The attenuation of islet β cells is always accompanied by the development of T2D. Current clinical antidiabetic drugs are shown to be effective, but they have not fundamentally solved the essence of islet cellular apoptosis and failure. Therefore, it is necessary to identify novel targets and potential therapeutics for hyperglycemic treatment with significant protection/delay islet function attenuation. DAP-related apoptosis-inducing kinase-2 (Drak2) is a member of death-associated protein kinase (DAPK) family. We found higher expression of Drak2 in pancreas of db/db mice compared with littermites. We demonstrated that Drak2 activity was negatively related with glucose-stimulated insulin secretion (GSIS) and the autophagic flux by knockdown or overexpression of Drak2 in primary islets. To further investigate the role of Drak2 in islet function, we generated β cell-specific Drak2 knockout mice (βKO) model. We found that the capacity of glucose tolerance was enhanced in βKO mice. And Drak2-deficient islets can resistant to palmitate-triggered apoptosis and GSIS impairment. On the other hand, Drak2 inhibitors were applied in the efficacy study, we demonstrated that these compounds effectively protected islets from apoptosis via autophagy promotion in vitro and ameliorated T2D in vivo in mouse models. Mechanistically, Drak2 may be involved in autophagy regulation through autophagy initiation complex, ULK1, to exerting its effects on the function and apoptosis of islet cells. Our preliminary work show that inhibition or deficiency of Drak2 protects β cell from apoptosis may due to autophagy promotion, and suggest that Drak2 might be a novel target for potential diabetic therapeutics development.