Deletion of carboxypeptidase E in beta cells disrupts proinsulin processing and alters beta cell identity in mice

Chen, Y.-C.; Taylor, A. J.; Fulcher, J. M.; Swensen, A. C.; Dai, X.-Q.; Komba, M.; Wrightson, K. L. C.; Fok, K.; Patterson, A. E.; Klein-Geltink, R. I.; MacDonald, P. E.; Qian, W.-J.; Verchere, C. B.

doi:10.1101/2022.10.20.512925

bioRxiv · 10.1101/2022.10.20.512925

Deletion of carboxypeptidase E in beta cells disrupts proinsulin processing and alters beta cell identity in mice

Chen, Y.-C.·Taylor, A. J.·Fulcher, J. M.·Swensen, A. C.·Dai, X.-Q.·Komba, M.·Wrightson, K. L. C.·Fok, K.·Patterson, A. E.·Klein-Geltink, R. I.·MacDonald, P. E.·Qian, W.-J.·Verchere, C. B.

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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 beta cells disrupts proinsulin processing and accelerates development of diabetes and obesity in mice. Pancreatic beta cell-specific Cpe knockout mice ({beta}CpeKO; Cpefl/fl x Ins1Cre/+) lack mature insulin granules and have elevated proinsulin in plasma; however, glucose-and KCl-stimulated insulin secretion in {beta}CpeKO islets remained intact. High fat diet-fed {beta}CpeKO mice showed comparable weight gain and glucose tolerance compared to Wt littermates. Notably, beta-cell area was increased in chow-fed {beta}CpeKO mice and beta-cell replication was elevated in {beta}CpeKO islets. Transcriptomic analysis of {beta}CpeKO beta cells revealed elevated glycolysis and Hif1-target gene expression. Upon high glucose challenge, beta cells from {beta}CpeKO mice showed reduced mitochondrial membrane potential, increased reactive oxygen species, reduced MafA, and elevated Aldh1a3 transcript levels. Following multiple low-dose streptozotocin treatment, {beta}CpeKO 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 diabetes.

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Chen, Y.-C., Taylor, A. J., Fulcher, J. M., Swensen, A. C., Dai, X.-Q., Komba, M., Wrightson, K. L. C., Fok, K., Patterson, A. E., Klein-Geltink, R. I., MacDonald, P. E., Qian, W.-J., Verchere, C. B.. 2022-10-21. Deletion of carboxypeptidase E in beta cells disrupts proinsulin processing and alters beta cell identity in mice. https://doi.org/10.1101/2022.10.20.512925

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