β细胞 KATP 通道的葡萄糖调节:是否需要一个新模型?

IF 6.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Diabetes Pub Date : 2024-04-19 DOI:10.2337/dbi23-0031
Guy A. Rutter, Ian R. Sweet
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引用次数: 0

摘要

葡萄糖诱导胰岛素分泌增加的典型模式包括葡萄糖通过糖酵解和柠檬酸循环进行新陈代谢,从而导致呼吸链合成 ATP 增加以及 ATP 敏感的 K+ (KATP) 通道关闭。由此产生的质膜去极化,随后 Ca2+ 通过 L 型 Ca2+ 通道流入,进而诱导胰岛素颗粒融合。梅林斯及其同事最近提出了另一种模式,即 KATP 通道受丙酮酸激酶控制,利用糖酵解和线粒体磷酸烯醇丙酮酸(PEP)产生紧邻 KATP 通道的高 ATP/ADP 微域。这种模式面临着几个挑战。首先,目前还不清楚线粒体产生的 PEP(而非线粒体 F1F0-ATP 合成酶产生的大量 ATP)如何进入拟议的微域。其次,质膜下的 ATP/ADP 波动与大量细胞质中的 ATP/ADP 波动非常相似。第三,在高糖条件下,呼吸链的 ADP 缺失被认为会驱动线粒体交替、分阶段锁定地产生 ATP 或 PEP,但这一点尚未得到直接证实。最后,用于探讨这些问题的方法可能会因脱靶效应而变得复杂。我们认为,众所周知会影响 ATP 生成和消耗的 Ca2+ 变化可能会驱动细胞膜 ATP/ADP 振荡,进而调节 KATP 通道和膜电位。因此,还需要证明需要一种新的模型来取代现有的基于线粒体生物能的模型。
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Glucose Regulation of β-Cell KATP Channels: Is a New Model Needed?
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.
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来源期刊
Diabetes
Diabetes 医学-内分泌学与代谢
CiteScore
12.50
自引率
2.60%
发文量
1968
审稿时长
1 months
期刊介绍: Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.
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