Beta-cell specific insulin resistance promotes glucose-stimulated insulin hypersecretion

Insulin receptor (Insr) protein can be found at higher levels in pancreatic {beta}-cells than in most other cell types, but the consequences of {beta}-cell insulin resistance remain enigmatic. Ins1cre allele was used to delete Insr specifically in {beta}-cells of both female and male mice which were compared to Ins1cre-containing littermate controls at multiple ages and on multiple diets. RNA-seq of recombined {beta}-cells revealed significant differences in multiple pathways previously implicated in insulin secretion and cellular fate, including rewired Ras and NF{kappa}B signaling. Male, but not female, {beta}InsrKO mice had reduced oxygen consumption rate, while action potential and calcium oscillation frequencies were increased in Insr knockout {beta}-cells from female, but not male mice. Female {beta}InsrKO and {beta}InsrHET mice exhibited elevated insulin release in perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr did not reduce {beta}-cell mass up to 9 months of age, nor did it impair hyperglycemia-induced proliferation. Based on our data, we adapted a mathematical model to include {beta}-cell insulin resistance, which predicted that {beta}-cell Insr knockout would improve glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance was significantly improved in female {beta}InsrKO and {beta}InsrHET mice when compared to controls at 9, 21 and 39 weeks. We did not observe improved glucose tolerance in adult 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. We further validated our in vivo findings using the Ins1-CreERT transgenic line and found improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that loss of {beta}-cell Insr alone is sufficient to drive glucose-induced hyperinsulinemia, thereby improving glucose homeostasis in otherwise insulin sensitive dietary and age contexts.