PT  - JOURNAL ARTICLE
AU  - Søs Skovsø
AU  - Evgeniy Panzhinskiy
AU  - Jelena Kolic
AU  - Derek A. Dionne
AU  - Xiao-Qing Dai
AU  - Rohit B. Sharma
AU  - Lynda Elghazi
AU  - Haoning Howard Cen
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  - Jen 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 Kim
AU  - Ernesto Bernal-Mizrachi
AU  - Laura C. Alonso
AU  - Patrick E. MacDonald
AU  - James D. Johnson
TI  - Beta-cell specific insulin resistance promotes glucose-stimulated insulin hypersecretion
AID  - 10.1101/2020.10.15.338160
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.10.15.338160
4099  - http://biorxiv.org/content/early/2020/10/15/2020.10.15.338160.short
4100  - http://biorxiv.org/content/early/2020/10/15/2020.10.15.338160.full
AB  - Insulin receptor (Insr) protein can be found at higher levels in pancreatic β-cells than in most other cell types, 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 recombined β-cells revealed significant differences in multiple pathways previously implicated in insulin secretion and cellular fate, including rewired Ras and NFκB signaling. Male, but not female, βInsrKO mice had reduced oxygen consumption rate, while action potential and calcium oscillation frequencies were increased in Insr knockout β-cells from female, but not male mice. 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 mass 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. We did not observe improved glucose tolerance in adult 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. We further validated our in vivo findings using the Ins1-CreERT transgenic line and found 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.