{"doi":"10.1101/2020.10.15.338160","title":"Beta-cell specific <i>Insr</i> deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance","abstract":"Abstract Insulin receptor (Insr) protein can be found at higher levels in pancreatic β-cells than in most other tissues, but the consequences of β-cell insulin resistance remain enigmatic. Ins1 cre allele was used to delete Insr specifically in β-cells of both female and male mice. Experimental mice were compared to Ins1 cre -containing littermate controls at multiple ages and on multiple diets. RNA-seq of purified recombined β-cells revealed transcriptomic consequences of Insr loss, which differed between female and male mice. Action potential and calcium oscillation frequencies were increased in Insr knockout β- cells from female, but not male mice, whereas only male β Insr KO mice had reduced ATP-coupled oxygen consumption rate and reduced expression of genes involved in ATP synthesis. Female β Insr KO and β Insr HET mice exhibited elevated insulin release in perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr did not alter β-cell area up to 9 months of age, nor did it impair hyperglycemia-induced proliferation. Based on our data, we adapted a mathematical model to include β-cell insulin resistance, which predicted that β-cell Insr knockout would improve glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance was significantly improved in female β Insr KO and β Insr HET mice when compared to controls at 9, 21 and 39 weeks, and also in insulin-sensitive 4-week old males. We did not observe improved glucose tolerance in older male mice or in high fat diet-fed mice, corroborating the prediction that global insulin resistance obscures the effects of β-cell specific insulin resistance. The propensity for hyperinsulinemia was associated with mildly reduced fasting glucose and increased body weight. We further validated our main in vivo findings using the Ins1 -CreERT transgenic line and found that male mice had improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that loss of β-cell Insr contributes to glucose-induced hyperinsulinemia, thereby improving glucose homeostasis in otherwise insulin sensitive dietary and age contexts.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":125820,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9594,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":573246,"name":"Evgeniy Panzhinskiy","orcid":null,"position":1,"is_corresponding":false},{"id":573247,"name":"Jelena Kolic","orcid":null,"position":2,"is_corresponding":false},{"id":573248,"name":"Haoning Howard Cen","orcid":null,"position":3,"is_corresponding":false},{"id":573249,"name":"Derek A. 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Diego Botezelli","orcid":null,"position":18,"is_corresponding":false},{"id":210939,"name":"Hye Lim Noh","orcid":null,"position":19,"is_corresponding":false},{"id":210941,"name":"Sujin Suk","orcid":null,"position":20,"is_corresponding":false},{"id":573261,"name":"Brian Gablaski","orcid":null,"position":21,"is_corresponding":false},{"id":238645,"name":"Austin Bautista","orcid":null,"position":22,"is_corresponding":false},{"id":301222,"name":"Ryekjang Kim","orcid":"0000-0002-9786-1047","position":23,"is_corresponding":false},{"id":307437,"name":"Corentin Cras‐Méneur","orcid":"0000-0001-8921-8927","position":24,"is_corresponding":false},{"id":122859,"name":"Stephane Flibotte","orcid":null,"position":25,"is_corresponding":false},{"id":449455,"name":"Sunita Sinha","orcid":"0000-0002-6576-2407","position":26,"is_corresponding":false},{"id":573262,"name":"Dan S. 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