Genetic Reduction of Glucose Metabolism Preserves Functional β-Cell Mass in KATP-Induced Neonatal Diabetes

Beta-cell failure and loss of β-cell mass are key events in diabetes progression. Although insulin hypersecretion in early stages has been implicated in β-cell exhaustion/failure, loss of β-cell mass still occurs in KATP-gain-of-function (GOF) mouse models of human neonatal diabetes, in the absence of insulin secretion. Thus, we hypothesize that hyperglycemia-induced increased β-cell metabolism is responsible for β-cell failure, and that reducing glucose metabolism will prevent loss of β-cell mass. To test this, KATP-GOF mice were crossed with mice carrying β-cell specific glucokinase haploinsuficincy (GCK+/−), to genetically reduce glucose metabolism. As expected, both KATP-GOF and KATP-GOF/GCK+/− mice showed lack of glucose-stimulated insulin secretion. However, KATP-GOF/GCK+/− mice demonstrated markedly reduced blood glucose, delayed diabetes progression, and improved glucose tolerance compared to KATP-GOF mice. In addition, decreased plasma insulin and content, increased proinsulin and augmented plasma glucagon observed in KATP-GOF mice were normalized to control levels in KATP-GOF/GCK+/− mice. Strikingly, KATP-GOF/GCK+/− mice demonstrated preserved β-cell mass and identity, compared to the marked decrease in β-cell identity and increased dedifferentiation observed in KATP-GOF mice. Moreover KATP-GOF/GCK+/− mice demonstrated restoration of body-weight, and liver and brown/white adipose tissue mass and function, and normalization of physical activity and metabolic efficiency compared to KATP-GOF mice. These results demonstrate that decreasing β-cell glucose signaling can prevent glucotoxicity-induced loss of insulin content and β-cell failure independently of compensatory insulin hypersecretion and β-cell exhaustion.