Beta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance
Skovsø, Søs ; Panzhinskiy, Evgeniy ; Kolic, Jelena ; Cen, Haoning Howard ; Dionne, Derek A ; Dai, Xiao-Qing ; Sharma, Rohit B ; Elghazi, Lynda ; Ellis, Cara E ; Faulkner, Katharine ... show 10 more
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Panzhinskiy, Evgeniy
Kolic, Jelena
Cen, Haoning Howard
Dionne, Derek A
Dai, Xiao-Qing
Sharma, Rohit B
Elghazi, Lynda
Ellis, Cara E
Faulkner, Katharine
Marcil, Stephanie A M
Overby, Peter
Noursadeghi, Nilou
Hutchinson, Daria
Hu, Xiaoke
Li, Hong
Modi, Honey
Wildi, Jennifer S
Botezelli, J Diego
Noh, Hye Lim
Suk, Sujin
Gablaski, Brian
Bautista, Austin
Kim, Ryekjang
Cras-Méneur, Corentin
Flibotte, Stephane
Sinha, Sunita
Luciani, Dan S
Nislow, Corey
Rideout, Elizabeth J
Cytrynbaum, Eric N
Kim, Jason K
Bernal-Mizrachi, Ernesto
Alonso, Laura C
MacDonald, Patrick E
Johnson, James D
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UMass Chan Affiliations
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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.
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Skovsø S, Panzhinskiy E, Kolic J, Cen HH, Dionne DA, Dai XQ, Sharma RB, Elghazi L, Ellis CE, Faulkner K, Marcil SAM, Overby P, Noursadeghi N, Hutchinson D, Hu X, Li H, Modi H, Wildi JS, Botezelli JD, Noh HL, Suk S, Gablaski B, Bautista A, Kim R, Cras-Méneur C, Flibotte S, Sinha S, Luciani DS, Nislow C, Rideout EJ, Cytrynbaum EN, Kim JK, Bernal-Mizrachi E, Alonso LC, MacDonald PE, Johnson JD. Beta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance. Nat Commun. 2022 Feb 8;13(1):735. doi: 10.1038/s41467-022-28039-8. PMID: 35136059; PMCID: PMC8826929.