Genetic Reduction of Glucose Metabolism Preserves Functional β-Cell Mass in K(ATP)-Induced Neonatal Diabetes

β-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 K(ATP) 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, K(ATP)-GOF mice were crossed with mice carrying β-cell–specific glucokinase haploinsufficiency (GCK(+/−)), to genetically reduce glucose metabolism. As expected, both K(ATP)-GOF and K(ATP)-GOF/GCK(+/−) mice showed lack of glucose-stimulated insulin secretion. However, K(ATP)-GOF/GCK(+/−) mice demonstrated markedly reduced blood glucose, delayed diabetes progression, and improved glucose tolerance compared with K(ATP)-GOF mice. In addition, decreased plasma insulin and content, increased proinsulin, and augmented plasma glucagon observed in K(ATP)-GOF mice were normalized to control levels in K(ATP)-GOF/GCK(+/−) mice. Strikingly, K(ATP)-GOF/GCK(+/−) mice demonstrated preserved β-cell mass and identity compared with the marked decrease in β-cell identity and increased dedifferentiation observed in K(ATP)-GOF mice. Moreover K(ATP)-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 with K(ATP)-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.