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Beta-cell specific Insr deletion promotes insulin hypersecretion and improves
glucose tolerance prior to global insulin resistance.
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
Submitted Externally on 3/9/2022
Volume : Pages
13 : 735
Insulin receptor (Insr) protein is present at higher levels in pancreatic
ß-cells than in most other tissues, but the consequences of ß-cell insulin
resistance remain enigmatic. Here, we use an Ins1cre knock-in allele to delete
Insr specifically in ß-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 ß-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 ß-cells from female, but not male mice, whereas only male ßInsrKO
islets have reduced ATP-coupled oxygen consumption rate and reduced expression
of genes involved in ATP synthesis. Female ßInsrKO and ßInsrHET 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
ß-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
ß-cell insulin resistance, which predicts that ß-cell Insr knockout improves
glucose tolerance depending on the degree of whole-body insulin resistance.
Indeed, glucose tolerance is significantly improved in female ßInsrKO and
ßInsrHET 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 ß-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 ß-cell insulin resistance in the form of
reduced ß-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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Financial support for this work was provided by the NIDDK Mouse Metabolic Phenotyping Centers (National MMPC, RRID:SCR_008997,
) under the MICROMouse Program, grants DK076169.
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