Beta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance

Søs Skovsø, Evgeniy Panzhinskiy, Jelena Kolic, Haoning Howard Cen, Derek A. Dionne, Xiao-Qing Dai, Rohit B. Sharma, Lynda Elghazi, Cara E. Ellis, Katharine Faulkner, Stephanie A. M. Marcil, Peter Overby, Nilou Noursadeghi, Daria Hutchinson, Xiaoke Hu, Hong Li, Honey Modi, Jennifer S. Wildi, J. Diego Botezelli, Hye Lim Noh, Sujin Suk, Brian Gablaski, Austin Bautista, Ryekjang Kim, Corentin Cras-Méneur, Stephane Flibotte, Sunita Sinha, Dan S. Luciani, Corey Nislow, Elizabeth J. Rideout, Eric N. Cytrynbaum, Jason K. Kim, Ernesto Bernal-Mizrachi, Laura C. Alonso, Patrick E. MacDonald and James D. Johnson ()
Additional contact information
Søs Skovsø: University of British Columbia
Evgeniy Panzhinskiy: University of British Columbia
Jelena Kolic: University of British Columbia
Haoning Howard Cen: University of British Columbia
Derek A. Dionne: University of British Columbia
Xiao-Qing Dai: University of Alberta
Rohit B. Sharma: Weill Cornell Medicine
Lynda Elghazi: University of Michigan Kellogg Eye Center
Cara E. Ellis: University of British Columbia
Katharine Faulkner: University of British Columbia
Stephanie A. M. Marcil: University of British Columbia
Peter Overby: University of British Columbia
Nilou Noursadeghi: University of British Columbia
Daria Hutchinson: University of British Columbia
Xiaoke Hu: University of British Columbia
Hong Li: University of British Columbia
Honey Modi: University of British Columbia
Jennifer S. Wildi: University of British Columbia
J. Diego Botezelli: University of British Columbia
Hye Lim Noh: Program in Molecular Medicine University of Massachusetts Medical School
Sujin Suk: Program in Molecular Medicine University of Massachusetts Medical School
Brian Gablaski: University of Massachusetts Medical School
Austin Bautista: University of Alberta
Ryekjang Kim: University of Alberta
Corentin Cras-Méneur: University of Michigan
Stephane Flibotte: University of British Columbia
Sunita Sinha: University of British Columbia
Dan S. Luciani: University of British Columbia
Corey Nislow: University of British Columbia
Elizabeth J. Rideout: University of British Columbia
Eric N. Cytrynbaum: University of British Columbia
Jason K. Kim: Program in Molecular Medicine University of Massachusetts Medical School
Ernesto Bernal-Mizrachi: University of Miami Miller School of Medicine and Miami VA Health Care System
Laura C. Alonso: Weill Cornell Medicine
Patrick E. MacDonald: University of Alberta
James D. Johnson: University of British Columbia

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: Abstract Insulin receptor (Insr) protein is present at higher levels in pancreatic β-cells than in most other tissues, but the consequences of β-cell insulin resistance remain enigmatic. Here, we use an Ins1cre knock-in allele to delete Insr specifically in β-cells of both female and male mice. We compare experimental mice to Ins1cre-containing littermate controls at multiple ages and on multiple diets. RNA-seq of purified recombined β-cells reveals transcriptomic consequences of Insr loss, which differ between female and male mice. Action potential and calcium oscillation frequencies are increased in Insr knockout β-cells from female, but not male mice, whereas only male βInsrKO islets have reduced ATP-coupled oxygen consumption rate and reduced expression of genes involved in ATP synthesis. Female βInsrKO and βInsrHET mice exhibit elevated insulin release in ex vivo perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr does not alter β-cell area up to 9 months of age, nor does it impair hyperglycemia-induced proliferation. Based on our data, we adapt a mathematical model to include β-cell insulin resistance, which predicts that β-cell Insr knockout improves glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance is significantly improved in female βInsrKO and βInsrHET mice compared to controls at 9, 21 and 39 weeks, and also in insulin-sensitive 4-week old males. We observe no 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 is associated with mildly reduced fasting glucose and increased body weight. We further validate our main in vivo findings using an Ins1-CreERT transgenic line and find that male mice have improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that β-cell insulin resistance in the form of reduced β-cell Insr contributes to hyperinsulinemia in the context of glucose stimulation, thereby improving glucose homeostasis in otherwise insulin sensitive sex, dietary and age contexts.

Date: 2022
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DOI: 10.1038/s41467-022-28039-8

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