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

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posted on 2023-06-26, 18:38 authored by Yi-Chun Chen, Austin J. Taylor, James M. Fulcher, Adam C. Swensen, Xiao-Qing Dai, Mitsuhiro Komba, Kenzie L.C. Wrightson, Kenny Fok, Annette E. Patterson, Ramon I. Klein-Geltink, Patrick E. MacDonald, Wei-Jun Qian, C. Bruce Verchere

Carboxypeptidase E (CPE) facilitates the conversion of prohormones into mature hormones and is highly expressed in multiple neuroendocrine tissues. Carriers of CPE mutations have elevated plasma proinsulin and develop severe obesity and hyperglycemia. We aimed to determine whether loss of Cpe in pancreatic beta cells disrupts proinsulin processing and accelerates development of diabetes and obesity in mice. Pancreatic beta cell-specific Cpe knockout mice (βCpeKO; Cpefl/fl x Ins1Cre/+) 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 to Wt littermates. 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 and Hif1α-target gene expression. Upon high glucose challenge, beta cells from βCpeKO mice showed reduced mitochondrial membrane potential, increased reactive oxygen species, reduced MafA, and elevated Aldh1a3 transcript levels. Following multiple low-dose streptozotocin treatment, βCpeKO mice had accelerated hyperglycemia with reduced beta-cell insulin and Glut2 expression. These findings suggest that Cpe and proper proinsulin processing are critical in maintaining beta cell function during the development of hyperglycemia.

Funding

This work is supported by Juvenile Diabetes Research Federation (advanced postdoctoral fellowship 3-APF-2022-1141-A-N to Y-C.C.), Canadian Institutes of Health and Research (grant PJT-153156 to C.B.V.), BC Children’s Hospital Foundation and BC Children’s Hospital Research Institute (Canucks for Kids Fund Childhood Diabetes Laboratories Summer Studentship to K.W.), and National Institutes of Health grants R01DK122160 and U01DK124020 to W-J. Q.

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