Deletion of carboxypeptidase E in beta cells disrupts proinsulin processing and alters beta cell identity in mice

Abstract

AbstractCarboxypeptidase E (CPE) facilitates the conversion of prohormones into mature hormones and is highly expressed in multiple neuroendocrine tissues. Carriers ofCPEmutations have elevated plasma proinsulin and develop severe obesity and hyperglycemia. We aimed to determine whether loss ofCpein pancreatic beta cells disrupts proinsulin processing and accelerates development of diabetes and obesity in mice. Pancreatic beta cell-specific Cpe knockout mice (βCpeKO;Cpefl/flxIns1Cre/+) lack mature insulin granules and have elevated proinsulin in plasma; however, glucose-and KCl-stimulated insulin secretion in βCpeKO islets remained intact. High fat diet-fed βCpeKO mice showed comparable weight gain and glucose tolerance compared toWtlittermates. Notably, beta-cell area was increased in chow-fed βCpeKO mice and beta-cell replication was elevated in βCpeKO islets. Transcriptomic analysis of βCpeKO beta cells revealed elevated glycolysis andHif1α-target gene expression. Upon high glucose challenge, beta cells from βCpeKO mice showed reduced mitochondrial membrane potential, increased reactive oxygen species, reducedMafA, and elevatedAldh1a3transcript levels. Following multiple low-dose streptozotocin treatment, βCpeKO mice had accelerated hyperglycemia with reduced beta-cell insulin and Glut2 expression. These findings suggest thatCpeand proper proinsulin processing are critical in maintaining beta cell function during the development of diabetes.