Beta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance

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.

Development of Type 1 Diabetes may occur through a Type 2 Diabetes mechanism

“…We finally investigated the possibility that changes in beta cell insulin sensitivity could reduce the insulin secretion during diabetes development. We did see changes in insulin- and insulin-like growth factor 2-receptor expression in tissue from T1D patients (and not in tissue from T2D patients, as was also found by western blotting ( 39 )), but it is not currently clear what the implication of the finding is, since it has been found that a lack of insulin stimulation on beta cells can both decrease ( 40 ) and increase ( 41 ) insulin stimulation. Interestingly, we and others have found that overweight adolescents, predisposed to T2D, also have a higher risk of developing T1D ( 42 , 43 ).…”

Sex differences in islet stress responses support female β cell resilience

“…Plasma samples were analysed for insulin using Rodent Insulin Chemiluminescent ELISA (ALPCO: 80-INSMR). Glucose-stimulated insulin secretion from an independent large cohort of Ins r f/f : Ins1 Cre −/− :nTnG +/− mice reared in our facility was replotted from a published Johnson lab study [ 53 ]. Blood glucose was monitored using control and insulin-reduced mice.…”

Proteome mapping of the human pancreatic islet microenvironment reveals endocrine-exocrine signaling sphere of influence

“…Confirming the role of the islet cell in insulin signaling 60 , we see regulation of insulin secretion as one of the most enriched pathways in the islet cells. We also observed enrichment in RNA splicing 61,62 and pre mRNA capping as up-regulated. In the acinar tissue, we see up-regulation of immune signaling and the complement cascade, suggesting a role in immune machinery in the pancreas.…”