{"doi":"10.1101/2022.10.20.512925","title":"Deletion of carboxypeptidase E in beta cells disrupts proinsulin processing and alters beta cell identity in mice","abstract":"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 (β Cpe KO; Cpe fl/fl x Ins1 Cre/+ ) lack mature insulin granules and have elevated proinsulin in plasma; however, glucose-and KCl-stimulated insulin secretion in β Cpe KO islets remained intact. High fat diet-fed β Cpe KO mice showed comparable weight gain and glucose tolerance compared to Wt littermates. Notably, beta-cell area was increased in chow-fed β Cpe KO mice and beta-cell replication was elevated in β Cpe KO islets. Transcriptomic analysis of β Cpe KO beta cells revealed elevated glycolysis and Hif1α -target gene expression. Upon high glucose challenge, beta cells from β Cpe KO mice showed reduced mitochondrial membrane potential, increased reactive oxygen species, reduced MafA , and elevated Aldh1a3 transcript levels. Following multiple low-dose streptozotocin treatment, β Cpe KO 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":312527,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9581,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":656865,"name":"Austin J. Taylor","orcid":"0000-0001-8167-1209","position":1,"is_corresponding":false},{"id":990688,"name":"James Fulcher","orcid":"0000-0001-9033-3623","position":2,"is_corresponding":false},{"id":775955,"name":"Adam Swensen","orcid":"0000-0001-8135-1766","position":3,"is_corresponding":false},{"id":238644,"name":"Xiao-Qing Dai","orcid":null,"position":4,"is_corresponding":false},{"id":1009961,"name":"Mitsuhiro Komba","orcid":"0000-0001-7485-1746","position":5,"is_corresponding":false},{"id":1009962,"name":"Kenzie L.C. Wrightson","orcid":"0000-0001-8914-530X","position":6,"is_corresponding":false},{"id":1010435,"name":"Kenny Fok","orcid":null,"position":7,"is_corresponding":false},{"id":264913,"name":"Annette E. Patterson","orcid":null,"position":8,"is_corresponding":false},{"id":235582,"name":"Ramon I. Klein Geltink","orcid":"0000-0003-4610-3059","position":9,"is_corresponding":false},{"id":7384,"name":"Patrick E. MacDonald","orcid":"0000-0002-5439-6288","position":10,"is_corresponding":false},{"id":269960,"name":"Weijun Qian","orcid":"0000-0002-5393-2827","position":11,"is_corresponding":false},{"id":7338,"name":"C. Bruce Verchere","orcid":"0000-0002-9262-0586","position":12,"is_corresponding":false},{"id":397533,"name":"Yi‐Chun Chen","orcid":"0000-0003-4328-0383","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T00:33:36.072096Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}