{"doi":"10.2337/db20-1235","title":"β-Cell Knockout of SENP1 Reduces Responses to Incretins and Worsens Oral Glucose Tolerance in High-Fat Diet–Fed Mice","abstract":"SUMOylation reduces oxidative stress and preserves islet mass at the expense of robust insulin secretion. To investigate a role for the deSUMOylating enzyme sentrin-specific protease 1 (SENP1) following metabolic stress, we put pancreas/gut-specific SENP1 knockout (pSENP1-KO) mice on a high-fat diet (HFD). Male pSENP1-KO mice were more glucose intolerant following HFD than littermate controls but only in response to oral glucose. A similar phenotype was observed in females. Plasma glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) responses were identical in pSENP1-KO and wild-type littermates, including the HFD-induced upregulation of GIP responses. Islet mass was not different, but insulin secretion and β-cell exocytotic responses to the GLP-1 receptor agonist exendin-4 (Ex4) and GIP were impaired in islets lacking SENP1. Glucagon secretion from pSENP1-KO islets was also reduced, so we generated β-cell–specific SENP1 KO mice. These phenocopied the pSENP1-KO mice with selective impairment in oral glucose tolerance following HFD, preserved islet mass expansion, and impaired β-cell exocytosis and insulin secretion to Ex4 and GIP without changes in cAMP or Ca2+ levels. Thus, β-cell SENP1 limits oral glucose intolerance following HFD by ensuring robust insulin secretion at a point downstream of incretin signaling.","journal":"Diabetes","year":2021,"id":179703,"datarank":0.5371938708965183,"base_score":2.9444389791664403,"endowment":2.9444389791664403,"self_citation_contribution":0.44166584687496613,"citation_network_contribution":0.0955280240215521,"self_endowment_contribution":0.44166584687496613,"citer_contribution":0.0955280240215521,"corpus_percentile":null,"corpus_rank":null,"citation_count":18,"citer_count":6,"citers_with_citation_signal":5,"citers_with_endowment":5,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9498,"is_data_producer":true,"deposit_databanks":{"figshare":["10.2337/figshare.16435176"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":727424,"name":"Nancy Smith","orcid":"0000-0001-6317-7207","position":1,"is_corresponding":false},{"id":727425,"name":"Aliya F Spigelman","orcid":"0000-0001-6188-2041","position":2,"is_corresponding":false},{"id":235297,"name":"Kunimasa Suzuki","orcid":"0000-0003-0102-3493","position":3,"is_corresponding":false},{"id":727426,"name":"Mourad Ferdaoussi","orcid":"0000-0001-7636-0959","position":4,"is_corresponding":false},{"id":728012,"name":"Tamadher A. Alghamdi","orcid":null,"position":5,"is_corresponding":false},{"id":258182,"name":"Sophie L. Lewandowski","orcid":"0000-0002-2838-7054","position":6,"is_corresponding":false},{"id":728013,"name":"Yaxing Jin","orcid":null,"position":7,"is_corresponding":false},{"id":238645,"name":"Austin Bautista","orcid":null,"position":8,"is_corresponding":false},{"id":728014,"name":"Ying Wayne Wang","orcid":null,"position":9,"is_corresponding":false},{"id":255373,"name":"Jocelyn E. Manning Fox","orcid":"0000-0002-4157-2094","position":10,"is_corresponding":false},{"id":258194,"name":"Matthew J. Merrins","orcid":"0000-0003-1599-9227","position":11,"is_corresponding":false},{"id":728015,"name":"Jean Buteau","orcid":null,"position":12,"is_corresponding":false},{"id":7384,"name":"Patrick E. MacDonald","orcid":"0000-0002-5439-6288","position":13,"is_corresponding":false},{"id":553354,"name":"Haopeng Lin","orcid":null,"position":0,"is_corresponding":true}],"reference_count":54,"raw_metadata":null,"created_at":"2026-07-18T23:47:48.974996Z","pmid":"34462260","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":[]}