Type 2 diabetes is a multifactorial disease. Collectively, our data show that ОІ-cell insulin resistance in the form of reduced ОІ-cell Insr contributes to hyperinsulinemia in the context of glucose stimulation, thereby improving glucose homeostasis in otherwise insulin sensitive sex, dietary and age contexts. 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. The propensity for hyperinsulinemia is associated with mildly reduced fasting glucose and increased body weight. 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 ОІ-cell specific insulin resistance. Indeed, glucose toleranceВ is significantly improved in female ОІ Insr KO and ОІ Insr HET mice compared to controls at 9, 21 and 39 weeks, and also in insulin-sensitive 4-week old males. Based on our data, we adapt a mathematical model to include ОІ-cell insulin resistance, which predicts that ОІ-cell Insr knockout improves glucose tolerance depending on the degree of whole-body insulin resistance. Deletion of Insr does not alter ОІ-cell area up to 9 months of age, nor does it impair hyperglycemia-induced proliferation. Female ОІ Insr KO and ОІ Insr HET mice exhibit elevated insulin release in ex vivoВ perifusion experiments, during hyperglycemic clamps, and following i.p. Action potential and calcium oscillation frequencies are increased in Insr knockout ОІ-cells from female, but not male mice, whereas only male ОІ Insr KO islets have reduced ATP-coupled oxygen consumption rate and reduced expression of genes involved in ATP synthesis. RNA-seq of purified recombined ОІ-cells reveals transcriptomic consequences of Insr loss, which differ between female and male mice. We compareВ experimental mice to Ins1 cre-containing littermate controls at multiple ages and on multiple diets.

Here, we use an Ins1 cre knock-in allele to delete Insr specifically in ОІ-cells of both female and male mice. Insulin receptor (Insr) protein is present at higher levels in pancreatic ОІ-cells than in most other tissues, but the consequences of ОІ-cell insulin resistance remain enigmatic.

Nature Communications volumeВ 13, ArticleВ number: 735 ( 2022) When a military installation or Government - related facility(whether or not specifically named) is located partially within more than one city or county boundary, the applicable per diem rate for the entire installation or facility is the higher of the rates which apply to the cities and / or counties, even though part(s) of such activities may be located outside the defined per diem locality.Beta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance Per diem localities with county definitions shall include 'all locations within, or entirely surrounded by, the corporate limits of the key city as well as the boundaries of the listed counties, including independent entities located within the boundaries of the key city and the listed counties (unless otherwise listed separately).' Unless otherwise specified, the per diem locality is defined as 'all locations within, or entirely surrounded by, the corporate limits of the key city, including independent entities located within those boundaries.'

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