| First Author | Skovsø S | Year | 2022 |
| Journal | Nat Commun | Volume | 13 |
| Issue | 1 | Pages | 735 |
| PubMed ID | 35136059 | Mgi Jnum | J:354833 |
| Mgi Id | MGI:6876533 | Doi | 10.1038/s41467-022-28039-8 |
| Citation | Skovso S, et al. (2022) Beta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance. Nat Commun 13(1):735 |
| abstractText | Insulin receptor (Insr) protein is present at higher levels in pancreatic beta-cells than in most other tissues, but the consequences of beta-cell insulin resistance remain enigmatic. Here, we use an Ins1(cre) knock-in allele to delete Insr specifically in beta-cells of both female and male mice. We compare experimental mice to Ins1(cre)-containing littermate controls at multiple ages and on multiple diets. RNA-seq of purified recombined beta-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 beta-cells from female, but not male mice, whereas only male betaInsr(KO) islets have reduced ATP-coupled oxygen consumption rate and reduced expression of genes involved in ATP synthesis. Female betaInsr(KO) and betaInsr(HET) 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 beta-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 beta-cell insulin resistance, which predicts that beta-cell Insr knockout improves glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance is significantly improved in female betaInsr(KO) and betaInsr(HET) 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 beta-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 beta-cell insulin resistance in the form of reduced beta-cell Insr contributes to hyperinsulinemia in the context of glucose stimulation, thereby improving glucose homeostasis in otherwise insulin sensitive sex, dietary and age contexts. |
