| First Author | Chen YC | Year | 2023 |
| Journal | Diabetes | Volume | 72 |
| Issue | 9 | Pages | 1277-1288 |
| PubMed ID | 37364047 | Mgi Jnum | J:339878 |
| Mgi Id | MGI:7524479 | Doi | 10.2337/db22-0945 |
| Citation | Chen YC, et al. (2023) Deletion of Carboxypeptidase E in beta-Cells Disrupts Proinsulin Processing but Does Not Lead to Spontaneous Development of Diabetes in Mice. Diabetes 72(9):1277-1288 |
| abstractText | 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 (betaCpeKO; Cpefl/fl x Ins1Cre/+) lack mature insulin granules and have elevated proinsulin in plasma; however, glucose-and KCl-stimulated insulin secretion in betaCpeKO islets remained intact. High-fat diet-fed betaCpeKO mice showed weight gain and glucose tolerance comparable with those of Wt littermates. Notably, beta-cell area was increased in chow-fed betaCpeKO mice and beta-cell replication was elevated in betaCpeKO islets. Transcriptomic analysis of betaCpeKO beta-cells revealed elevated glycolysis and Hif1alpha-target gene expression. On high glucose challenge, beta-cells from betaCpeKO mice showed reduced mitochondrial membrane potential, increased reactive oxygen species, reduced MafA, and elevated Aldh1a3 transcript levels. Following multiple low-dose streptozotocin injections, betaCpeKO mice had accelerated development of 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. ARTICLE HIGHLIGHTS: Carboxypeptidase E (Cpe) is an enzyme that removes the carboxy-terminal arginine and lysine residues from peptide precursors. Mutations in CPE lead to obesity and type 2 diabetes in humans, and whole-body Cpe knockout or mutant mice are obese and hyperglycemic and fail to convert proinsulin to insulin. We show that beta-cell-specific Cpe deletion in mice (betaCpeKO) does not lead to the development of obesity or hyperglycemia, even after prolonged high-fat diet treatment. However, beta-cell proliferation rate and beta-cell area are increased, and the development of hyperglycemia induced by multiple low-dose streptozotocin injections is accelerated in betaCpeKO mice. |
