葡萄糖对β细胞KATP通道的调控:是建立新模型的时候了

IF 6.2 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Diabetes Pub Date : 2024-04-19 DOI:10.2337/dbi23-0032
Matthew J. Merrins, Richard G. Kibbey
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引用次数: 0

摘要

要了解糖尿病的病理生理学,就必须就葡萄糖刺激健康β细胞分泌胰岛素的模式达成共识。自 1984 年发现 KATP 通道以来,人们一直认为氧化磷酸化(OxPhos)驱动的 ATP 上升会关闭 KATP 通道,从而启动胰岛素分泌。这一模型缺乏任何遗传或其他方面的证据,证明线粒体具有将 ATP/ADP 比率提高到触发阈值的生物能,并且与遗传学证据相冲突,遗传学证据表明 OxPhos 对于胰岛素分泌是不可或缺的。该模型还将 OxPhos 的化学计量产量与热力学混为一谈,没有考虑β细胞新陈代谢的既定特征,如泄漏、无凋亡、催凋亡和 NADPH 的产生等减损线粒体 ATP 生产效率的因素,从而高估了 OxPhos。我们根据β细胞代谢的空间和生物能特异性提出了另一种模式,即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有很高的控制强度;2)糖酵解在正确的时间活跃,以解释 KATP 通道的关闭;3)质膜相关的糖酵解酶控制 KATP 通道;4)相对于 OxPhos,丙酮酸激酶具有提高 ATP/ADP 的有利生物能;5)OxPhos 在膜去极化前停滞,在膜去极化后增加。尽管仍有一些关键实验需要对这一模型进行评估,但 1984 模型纯粹是建立在间接证据的基础上,如果要使其继续存在,就必须通过因果关系和机理实验来拯救它。
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Glucose Regulation of β-Cell KATP Channels: It Is Time for a New Model!
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.
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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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