Abstract Increased circulating levels of incompletely processed insulin (i.e. proinsulin) are observed clinically in both type 1 and type 2 diabetes; however, the mechanisms underlying impaired proinsulin processing remain incompletely understood. Here, we identify the sarcoendoplasmic reticulum Ca 2+ ATPase-2 (SERCA2) pump and β cell ER Ca 2+ as key regulators of systemic glucose tolerance and proinsulin processing. We generated mice with a β cell-specific SERCA2 deletion (βS2KO) and SERCA2 deficient INS-1 cells to show that SERCA2 loss increases systemic and pancreatic levels of proinsulin protein and leads to aberrant localization of proinsulin within the proximal β cell secretory pathway. These defects in proinsulin processing were linked to reduced maturation of the proinsulin processing enzymes PC1/3 and PC2, suggesting a model whereby chronic ER Ca 2+ depletion in the β cell, which is observed in many pathological conditions, impairs the spatial regulation of prohormone trafficking, processing, and maturation within the β cell secretory pathway.

SERCA2 regulates proinsulin processing and processing enzyme maturation in the pancreatic β cell