Fasting hyperinsulinemia precedes the development of type 2 diabetes. However, it is unclear whether fasting insulin hypersecretion is a primary driver of insulin resistance or a consequence of the progressive increase in fasting glycemia induced by insulin resistance in the prediabetic state. Herein, we have discovered a mechanism that specifically regulates non–glucose-stimulated insulin secretion (NGSIS) in pancreatic islets that is activated by nonesterified free fatty acids, the major fuel used by β-cells during fasting. We show that the mitochondrial permeability transition pore regulator cyclophilin D (CypD) promotes NGSIS, but not glucose-stimulated insulin secretion, by increasing mitochondrial proton leak. Islets from prediabetic obese mice show significantly higher CypD-dependent proton leak and NGSIS compared with lean mice. Proton leak–mediated NGSIS is conserved in human islets and is stimulated by exposure to nonesterified free fatty acids at concentrations observed in obese subjects. Mechanistically, proton leak activates islet NGSIS independently of mitochondrial ATP synthesis but ultimately requires closure of the KATP channel. In summary, we have described a novel nonesterified free fatty acid–stimulated pathway that selectively drives pancreatic islet NGSIS, which may be therapeutically exploited as an alternative way to halt fasting hyperinsulinemia and the progression of type 2 diabetes.

中文翻译：

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由亲环蛋白 D 调节的线粒体质子泄漏在非刺激性葡萄糖水平下提高胰岛中的胰岛素分泌

空腹高胰岛素血症先于 2 型糖尿病的发展。然而，尚不清楚空腹胰岛素分泌过多是胰岛素抵抗的主要驱动因素，还是糖尿病前期状态下胰岛素抵抗诱导的空腹血糖逐渐升高的结果。在此，我们发现了一种机制，可以特异性调节胰岛中非葡萄糖刺激的胰岛素分泌 (NGSIS)，该分泌由非酯化游离脂肪酸激活，非酯化游离脂肪酸是禁食期间 β 细胞使用的主要燃料。我们表明线粒体通透性转换孔调节剂亲环蛋白 D (CypD) 通过增加线粒体质子泄漏促进 NGSIS，但不促进葡萄糖刺激的胰岛素分泌。与瘦小鼠相比，糖尿病前期肥胖小鼠的胰岛显示出显着更高的 CypD 依赖性质子泄漏和 NGSIS。质子泄漏介导的 NGSIS 在人类胰岛中是保守的，并且在暴露于肥胖受试者中观察到的浓度的非酯化游离脂肪酸时会受到刺激。从机制上讲，质子泄漏独立于线粒体 ATP 合成激活胰岛 NGSIS，但最终需要关闭 KATP 通道。总之，我们描述了一种新的非酯化游离脂肪酸刺激途径，它选择性地驱动胰岛 NGSIS，可作为一种替代方法在治疗上加以利用，以阻止空腹高胰岛素血症和 2 型糖尿病的进展。质子泄漏独立于线粒体 ATP 合成激活胰岛 NGSIS，但最终需要关闭 KATP 通道。总之，我们描述了一种新的非酯化游离脂肪酸刺激途径，它选择性地驱动胰岛 NGSIS，可作为一种替代方法在治疗上加以利用，以阻止空腹高胰岛素血症和 2 型糖尿病的进展。质子泄漏独立于线粒体 ATP 合成激活胰岛 NGSIS，但最终需要关闭 KATP 通道。总之，我们描述了一种新的非酯化游离脂肪酸刺激途径，它选择性地驱动胰岛 NGSIS，可作为一种替代方法在治疗上加以利用，以阻止空腹高胰岛素血症和 2 型糖尿病的进展。