Trapα deficiency impairs the early events of insulin biosynthesis and glucose homeostasis.

Defects in the early events of insulin biosynthesis, including inefficient preproinsulin (PPI) translocation across the membrane of the ER and proinsulin (PI) misfolding in the ER, can cause diabetes. Cellular machineries involved in these events remain poorly defined. Genes encoding translocon-associated protein α (TRAPα) show linkage to glycemic control in humans, though their pathophysiological role remains unknown. Here, we found that β cell-specific TRAPα-KO mice fed a chow diet or a high-fat diet (HFD) had decreased levels of circulating insulin, with age- and diet-related glucose intolerance. Multiple independent approaches revealed that TRAPα-KO not only causes inefficient PPI translocation but also leads to PI misfolding and ER stress, selectively limiting PI ER export and β cell compensatory potential. Importantly, decreased TRAPα expression was evident in islets of wild-type mice fed the HFD and in patients with type 2 diabetes (T2D). Furthermore, TRAPα expression was positively correlated with insulin content in human islet β cells, and decreased TRAPα was associated with PI maturation defects in T2D islets. Together, these data demonstrate that TRAPα deficiency in pancreatic β cells impairs PPI translocation, PI folding, insulin production, and glucose homeostasis, contributing to its genetic linkage to T2D.