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

Chen, Yi-Chun; Taylor, Austin J.; Fulcher, James M.; Swensen, Adam C.; Dai, Xiao-Qing; Komba, Mitsuhiro; Wrightson, Kenzie L.C.; Fok, Kenny; Patterson, Annette E.; Klein Geltink, Ramon I.; MacDonald, Patrick E.; Qian, Wei-Jun; Verchere, C. Bruce

doi:10.2337/db22-0945

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

Journal Article · Mon Jun 26 00:00:00 EDT 2023 · Diabetes

DOI:https://doi.org/10.2337/db22-0945· OSTI ID:2203041

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University of British Columbia, Vancouver, BC (Canada); BC Children’s Hospital Research Institute, Vancouver, BC (Canada)
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
University of Alberta, Edmonton, AB (Canada)
BC Children’s Hospital Research Institute, Vancouver, BC (Canada)

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 β-cells disrupts proinsulin processing and accelerates development of diabetes and obesity in mice. Pancreatic β-cell–specific Cpe knockout mice (βCpeKO; Cpe^fl/fl x Ins1^Cre/+) 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 weight gain and glucose tolerance comparable with those of Wt littermates. Notably, β-cell area was increased in chow-fed βCpeKO mice and β-cell replication was elevated in βCpeKO islets. Transcriptomic analysis of βCpeKO β-cells revealed elevated glycolysis and Hif1α-target gene expression. On high glucose challenge, β-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 injections, βCpeKO mice had accelerated development of hyperglycemia with reduced β-cell insulin and Glut2 expression. In conclusion, these findings suggest that Cpe and proper proinsulin processing are critical in maintaining β-cell function during the development of hyperglycemia.

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Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); Natural Sciences and Engineering Research Council of Canada (NSERC); Canadian Institutes of Health Research (CIHR); National Institutes of Health (NIH)

Grant/Contract Number:: AC05-76RL01830; RGPIN-2020-05390946; PJT-153156; R01DK122160; U01DK124020

OSTI ID:: 2203041

Report Number(s):: PNNL-SA-186901

Journal Information:: Diabetes, Vol. 72, Issue 9; ISSN 0012-1797

Publisher:: American Diabetes AssociationCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
Type 1 diabetes
carboxypeptidase
insulin
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prohormone
protein processing

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

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