The canonical model of glucose-induced increase in insulin secretion involves the metabolism of glucose via glycolysis and the citrate cycle, resulting in increased ATP synthesis by the respiratory chain and the closure of ATP-sensitive K+ (KATP) channels. The resulting plasma membrane depolarization, followed by Ca2+ influx through L-type Ca2+ channels, then induces insulin granule fusion. Merrins and colleagues have recently proposed an alternative model whereby KATP channels are controlled by pyruvate kinase, using glycolytic and mitochondrial phosphoenolpyruvate (PEP) to generate microdomains of high ATP/ADP immediately adjacent to KATP channels. This model presents several challenges. First, how mitochondrially generated PEP, but not ATP produced abundantly by the mitochondrial F1F0-ATP synthase, can gain access to the proposed microdomains is unclear. Second, ATP/ADP fluctuations imaged immediately beneath the plasma membrane closely resemble those in the bulk cytosol. Third, ADP privation of the respiratory chain at high glucose, suggested to drive alternating, phased-locked generation by mitochondria of ATP or PEP, has yet to be directly demonstrated. Finally, the approaches used to explore these questions may be complicated by off-target effects. We suggest instead that Ca2+ changes, well known to affect both ATP generation and consumption, likely drive cytosolic ATP/ADP oscillations that in turn regulate KATP channels and membrane potential. Thus, it remains to be demonstrated that a new model is required to replace the existing, mitochondrial bioenergetics–based model.

中文翻译：

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β 细胞 KATP 通道的葡萄糖调节：需要新模型吗？

葡萄糖诱导的胰岛素分泌增加的经典模型涉及通过糖酵解和柠檬酸循环进行的葡萄糖代谢，导致呼吸链的 ATP 合成增加以及 ATP 敏感的 K+ (KATP) 通道的关闭。由此产生的质膜去极化，随后 Ca2+ 通过 L 型 Ca2+ 通道流入，然后诱导胰岛素颗粒融合。 Merrins 及其同事最近提出了一种替代模型，其中 KATP 通道由丙酮酸激酶控制，使用糖酵解和线粒体磷酸烯醇丙酮酸 (PEP) 来生成紧邻 KATP 通道的高 ATP/ADP 微域。该模型提出了一些挑战。首先，线粒体生成的 PEP（而非线粒体 F1F0-ATP 合酶大量生成的 ATP）如何能够进入所提出的微结构域尚不清楚。其次，在质膜正下方成像的 ATP/ADP 波动与大量细胞质中的波动非常相似。第三，ADP 在高葡萄糖条件下剥夺呼吸链，这被认为可以驱动线粒体 ATP 或 PEP 的交替、锁相生成，但尚未得到直接证明。最后，用于探索这些问题的方法可能会因脱靶效应而变得复杂。相反，我们认为 Ca2+ 的变化（众所周知会影响 ATP 的生成和消耗）可能会驱动胞质 ATP/ADP 振荡，进而调节 KATP 通道和膜电位。因此，仍有待证明是否需要一种新模型来取代现有的基于线粒体生物能学的模型。