PT - JOURNAL ARTICLE AU - Søs Skovsø AU - Evgeniy Panzhinskiy AU - Jelena Kolic AU - Haoning Howard Cen AU - Derek A. Dionne AU - Xiao-Qing Dai AU - Rohit B. Sharma AU - Lynda Elghazi AU - Cara E. Ellis AU - Katharine Faulkner AU - Stephanie A.M. Marcil AU - Peter Overby AU - Nilou Noursadeghi AU - Daria Hutchinson AU - Xiaoke Hu AU - Hong Li AU - Honey Modi AU - Jennifer S. Wildi AU - J. Diego Botezelli AU - Hye Lim Noh AU - Sujin Suk AU - Brian Gablaski AU - Austin Bautista AU - Ryekjang Kim AU - Corentin Cras-Méneur AU - Stephane Flibotte AU - Sunita Sinha AU - Dan S. Luciani AU - Corey Nislow AU - Elizabeth J. Rideout AU - Eric N. Cytrynbaum AU - Jason K. Kim AU - Ernesto Bernal-Mizrachi AU - Laura C. Alonso AU - Patrick E. MacDonald AU - James D. Johnson TI - Beta-cell specific <em>Insr</em> deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance AID - 10.1101/2020.10.15.338160 DP - 2021 Jan 01 TA - bioRxiv PG - 2020.10.15.338160 4099 - http://biorxiv.org/content/early/2021/07/19/2020.10.15.338160.short 4100 - http://biorxiv.org/content/early/2021/07/19/2020.10.15.338160.full AB - AbstractInsulin 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. Ins1cre allele was used to delete Insr specifically in β-cells of both female and male mice. Experimental mice were compared to Ins1cre-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 βInsrKO mice had reduced ATP-coupled oxygen consumption rate and reduced expression of genes involved in ATP synthesis. Female βInsrKO and βInsrHET 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 βInsrKO and βInsrHET 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.Competing Interest StatementThe authors have declared no competing interest.