<strong>Deletion of carboxypeptidase E in beta cells disrupts proinsulin processing but does not lead to spontaneous development of diabetes in mice</strong>

<p>Carboxypeptidase E (CPE) facilitates the conversion of prohormones into mature hormones and is highly expressed in multiple neuroendocrine tissues. Carriers of <em>CPE</em> mutations have elevated plasma proinsulin and develop severe obesity and hyperglycemia. We aimed to determine whether loss of <em>Cpe</em> in pancreatic beta cells disrupts proinsulin processing and accelerates development of diabetes and obesity in mice. Pancreatic beta cell-specific Cpe knockout mice (β<em>Cpe</em>KO; <em>Cpe</em>fl/fl x <em>Ins1</em>Cre/+) lack mature insulin granules and have elevated proinsulin in plasma; however, glucose-and KCl-stimulated insulin secretion in β<em>Cpe</em>KO islets remained intact. High fat diet-fed β<em>Cpe</em>KO mice showed comparable weight gain and glucose tolerance compared to <em>Wt</em> littermates. Notably, beta-cell area was increased in chow-fed β<em>Cpe</em>KO mice and beta-cell replication was elevated in β<em>Cpe</em>KO islets. Transcriptomic analysis of β<em>Cpe</em>KO beta cells revealed elevated glycolysis and <em>Hif1α</em>-target gene expression. Upon high glucose challenge, beta cells from β<em>Cpe</em>KO mice showed reduced mitochondrial membrane potential, increased reactive oxygen species, reduced <em>MafA,</em> and elevated <em>Aldh1a3 </em>transcript levels. Following multiple low-dose streptozotocin treatment, β<em>Cpe</em>KO mice had accelerated hyperglycemia with reduced beta-cell insulin and Glut2 expression. These findings suggest that <em>Cpe</em> and proper proinsulin processing are critical in maintaining beta cell function during the development of hyperglycemia.</p>