Metabolic reprogramming of cytotoxic T lymphocytes by high glucose enhances pancreatic beta cell apoptosis via TRAIL

Cytotoxic T lymphocytes (CTLs) are involved in development of diabetes. However, the impact of excessive glucose on CTL effector functions remains largely elusive. Here, we report that metabolic processes in CTLs are reprogrammed by high glucose (HG). TNF-related apoptosis inducing ligand (TRAIL) is substantially up-regulated in CTLs in environments with HG both in vitro and in vivo in a diabetic mouse model and in diabetic patients. The PI3K-Akt-NFκB axis and non-mitochondrial reactive oxygen species (ROS) are both involved in HG-induced TRAIL upregulation in CTLs. TRAILhigh CTLs induce apoptosis of insulin-producing beta cells. Metformin and Vitamin D synergistically reduce HG-enhanced expression of TRAIL in CTLs and coherently protect beta cells from TRAIL-mediated apoptosis. Our work not only reveals a novel mechanism of CTL involvement in progression of diabetes, but also establishes CTLs as a target for combined metformin and vitamin D therapy to protect pancreatic beta cells of diabetic patients.