Deletion of Carboxypeptidase E in b-Cells Disrupts Proinsulin Processing but Does Not Lead to Spontaneous Development of Diabetes in Mice

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Abstract

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 b-cells disrupts proinsulin processing and accelerates development of diabetes and obesity in mice. Pancreatic b-cell–specific Cpe knockout mice (bCpeKO; Cpefl/fl x Ins1Cre/+) lack mature insulin granules and have elevated proinsulin in plasma; however, glucose-and KCl-stimulated insulin secretion in bCpeKO islets remained intact. High-fat diet–fed bCpeKO mice showed weight gain and glucose tolerance comparable with those of Wt littermates. Notably, b-cell area was increased in chow-fed bCpeKO mice and b-cell replication was elevated in bCpeKO islets. Transcriptomic analysis of bCpeKO b-cells revealed elevated glycolysis and Hif1atarget gene expression. On high glucose challenge, b-cells from bCpeKO mice showed reduced mitochondrial membrane potential, increased reactive oxygen species, reduced MafA, and elevated Aldh1a3 transcript levels. Following multiple low-dose streptozotocin injections, bCpeKO mice had accelerated development of hyperglycemia with reduced b-cell insulin and Glut2 expression. These findings suggest that Cpe and proper proinsulin processing are critical in maintaining b-cell function during the development of hyperglycemia.

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Chen, Y. C., Taylor, A. J., Fulcher, J. M., Swensen, A. C., Dai, X. Q., Komba, M., … Verchere, C. B. (2023). Deletion of Carboxypeptidase E in b-Cells Disrupts Proinsulin Processing but Does Not Lead to Spontaneous Development of Diabetes in Mice. Diabetes, 72(9), 1277–1288. https://doi.org/10.2337/db22-0945

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