An agreed-upon consensus model of glucose-stimulated insulin secretion from healthy β-cells is essential for understanding diabetes pathophysiology. Since the discovery of the KATP channel in 1984, an oxidative phosphorylation (OxPhos)–driven rise in ATP has been assumed to close KATP channels to initiate insulin secretion. This model lacks any evidence, genetic or otherwise, that mitochondria possess the bioenergetics to raise the ATP/ADP ratio to the triggering threshold, and conflicts with genetic evidence demonstrating that OxPhos is dispensable for insulin secretion. It also conflates the stoichiometric yield of OxPhos with thermodynamics, and overestimates OxPhos by failing to account for established features of β-cell metabolism, such as leak, anaplerosis, cataplerosis, and NADPH production that subtract from the efficiency of mitochondrial ATP production. We have proposed an alternative model, based on the spatial and bioenergetic specializations of β-cell metabolism, in which glycolysis initiates insulin secretion. The evidence for this model includes that 1) glycolysis has high control strength over insulin secretion; 2) glycolysis is active at the correct time to explain KATP channel closure; 3) plasma membrane–associated glycolytic enzymes control KATP channels; 4) pyruvate kinase has favorable bioenergetics, relative to OxPhos, for raising ATP/ADP; and 5) OxPhos stalls before membrane depolarization and increases after. Although several key experiments remain to evaluate this model, the 1984 model is based purely on circumstantial evidence and must be rescued by causal, mechanistic experiments if it is to endure.

中文翻译：

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β 细胞 KATP 通道的葡萄糖调节：是时候建立新模型了！

健康β细胞葡萄糖刺激胰岛素分泌的共识模型对于理解糖尿病病理生理学至关重要。自 1984 年发现 KATP 通道以来，氧化磷酸化 (OxPhos) 驱动的 ATP 升高被认为会关闭 KATP 通道以启动胰岛素分泌。该模型缺乏任何遗传或其他证据表明线粒体具有将 ATP/ADP 比率提高至触发阈值的生物能学，并且与证明 OxPhos 对于胰岛素分泌来说是可有可无的遗传证据相冲突。它还将 OxPhos 的化学计量产量与热力学混为一谈，并且由于未能考虑到 β 细胞代谢的既定特征，例如泄漏、回补、断裂和 NADPH 产生（这些特征会降低线粒体 ATP 产生的效率）而高估了 OxPhos。我们提出了一种基于 β 细胞代谢的空间和生物能专门化的替代模型，其中糖酵解启动胰岛素分泌。该模型的证据包括：1）糖酵解对胰岛素分泌具有高控制强度； 2）糖酵解在正确的时间活跃以解释KATP通道关闭； 3）质膜相关糖酵解酶控制KATP通道； 4) 相对于OxPhos，丙酮酸激酶对于提高ATP/ADP具有有利的生物能学； 5) OxPhos 在膜去极化之前停止并在膜去极化之后增加。尽管还需要进行几个关键实验来评估该模型，但 1984 年的模型纯粹基于间接证据，如果要持续下去，就必须通过因果、机械实验来挽救。