b-Cell failure and loss of b-cell mass are key events in diabetes progression. Although insulin hypersecretion in early stages has been implicated in b-cell exhaus-tion/failure, loss of b-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 b-cell metabolism is responsible for b-cell failure and that reducing glucose metabolism will prevent loss of b-cell mass. To test this, KATP-GOF mice were crossed with mice carrying b-cell–specific glu-cokinase haploinsufficiency (GCK+/2), to genetically reduce glucose metabolism. As expected, both KATP-GOF and KATP-GOF/GCK+/2 mice showed lack of glucose-stimulated insulin secretion. However, KATP-GOF/GCK+/2 mice demonstrated markedly reduced blood glucose, delayed diabetes progression, and improved glucose tolerance compared with KATP-GOF mice. In addition, decreased plasma insulin and content, increased proinsu-lin, and augmented plasma glucagon observed in KATP-GOF mice were normalized to control levels in KATP-GOF/ GCK+/2 mice. Strikingly, KATP-GOF/GCK+/2 mice demonstrated preserved b-cell mass and identity compared with the marked decrease in b-cell identity and increased dedifferentiation observed in KATP-GOF mice. Moreover KATP-GOF/GCK+/2 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 KATP-GOF mice. These results demonstrate that decreasing b-cell glucose signaling can prevent glucotoxicity-induced loss of insulin content and b-cell failure independently of compensatory insulin hypersecretion and b-cell exhaustion.