RT Journal Article SR Electronic T1 Beta-cell specific Insr deletion promotes glucose-stimulated insulin hypersecretion and improves glucose tolerance prior to global insulin resistance JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.10.15.338160 DO 10.1101/2020.10.15.338160 A1 Søs Skovsø A1 Evgeniy Panzhinskiy A1 Jelena Kolic A1 Haoning Howard Cen A1 Derek A. Dionne A1 Xiao-Qing Dai A1 Rohit B. Sharma A1 Lynda Elghazi A1 Cara E. Ellis A1 Katharine Faulkner A1 Stephanie A.M. Marcil A1 Peter Overby A1 Nilou Noursadeghi A1 Daria Hutchinson A1 Xiaoke Hu A1 Hong Li A1 Honey Modi A1 Jennifer S. Wildi A1 J. Diego Botezelli A1 Hye Lim Noh A1 Sujin Suk A1 Brian Gablaski A1 Austin Bautista A1 Ryekjang Kim A1 Corentin Cras-Méneur A1 Stephane Flibotte A1 Sunita Sinha A1 Dan S. Luciani A1 Corey Nislow A1 Elizabeth J. Rideout A1 Eric N. Cytrynbaum A1 Jason Kim A1 Ernesto Bernal-Mizrachi A1 Laura C. Alonso A1 Patrick E. MacDonald A1 James D. Johnson YR 2021 UL http://biorxiv.org/content/early/2021/04/05/2020.10.15.338160.abstract AB 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. Ins1cre allele was used to delete Insr specifically in β-cells of both female and male mice which 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, wherease 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 reduce 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 alone is sufficient to drive glucose-induced hyperinsulinemia, thereby improving glucose homeostasis in otherwise insulin sensitive dietary and age contexts.Competing Interest StatementThe authors have declared no competing interest.