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 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 haploinsufficiency (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 with 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 with 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 with 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.

中文翻译：

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葡萄糖代谢的遗传减少在 KATP 诱导的新生儿糖尿病中保持功能性 β 细胞质量

β 细胞衰竭和 β 细胞质量损失是糖尿病进展的关键事件。尽管早期阶段的胰岛素分泌过多与 β 细胞耗竭/衰竭有关，但在没有胰岛素分泌的情况下，人类新生儿糖尿病的 KATP 功能获得性 (GOF) 小鼠模型中仍会发生 β 细胞质量损失。因此，我们假设高血糖诱导的 β 细胞代谢增加是导致 β 细胞衰竭的原因，而减少葡萄糖代谢将防止 β 细胞质量的损失。为了测试这一点，将 KATP-GOF 小鼠与携带 β 细胞特异性葡萄糖激酶单倍剂量不足 (GCK+/-) 的小鼠杂交，以从基因上降低葡萄糖代谢。正如预期的那样，KATP-GOF 和 KATP-GOF/GCK+/- 小鼠均表现出缺乏葡萄糖刺激的胰岛素分泌。然而，KATP-GOF/GCK+/− 小鼠的血糖显着降低，与 KATP-GOF 小鼠相比，可延缓糖尿病进展并改善葡萄糖耐量。此外，在 KATP-GOF 小鼠中观察到的血浆胰岛素和含量降低、胰岛素原增加和血浆胰高血糖素增加被标准化为 KATP-GOF/GCK+/- 小鼠中的对照水平。引人注目的是，与 KATP-GOF 小鼠中观察到的 β 细胞特性显着降低和去分化增加相比，KATP-GOF/GCK+/− 小鼠表现出保留的 β 细胞质量和特性。此外，与 KATP-GOF 小鼠相比，KATP-GOF/GCK+/- 小鼠表现出体重和肝脏以及棕色/白色脂肪组织质量和功能的恢复以及身体活动和代谢效率的正常化。