A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm
A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm
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DOI：
10.2337/diabetes.45.2.223
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发表时间：
1996-02-01
期刊：
影响因子：
7.7
通讯作者：
Matschinsky, FM
中科院分区：
文献类型：
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作者：
Matschinsky, FM
胰腺β细胞中葡萄糖代谢的特殊特征对于理解这些细胞在葡萄糖稳态中的生理作用至关重要。强调了这些特征中的几个：用于葡萄糖转运的高容量系统;由高K-m葡萄糖激酶（GK）进行的葡萄糖磷酸化，其是葡萄糖代谢的速率限制，并且在生理学上决定β细胞中介和能量代谢以及胰岛素释放中的许多过程的葡萄糖依赖性曲线，因此被视为葡萄糖传感器;乳酸脱氢酶的活性非常低，并且存在有效的氢穿梭以允许糖酵解NADH的几乎定量氧化;几乎不存在糖原和脂肪酸合成以及糖原异生，使得中间代谢主要是分解代谢;线粒体过程的关键作用，包括柠檬酸循环、电子传递和FoF 1 ATP酶的氧化磷酸化，控制ATP质量作用比的葡萄糖依赖性增加; Ca 2+非依赖性葡萄糖诱导的呼吸爆发和β细胞中ATP产量的增加是关键线粒体反应的显着表现;通过ATP和电压依赖性Ca 2+内流的质量作用比控制膜电位，作为胰岛素释放的信号;积累丙二酰辅酶A、酰基辅酶A和二酰基甘油作为必需或辅助代谢偶联因子;以及腺嘌呤核苷酸、脂质相关和Ca 2+信号的放大，以募集许多辅助过程来最大化胰岛素生物合成和释放，生化设计还表明某些与燃料代谢相关的候选糖尿病基因：低活性和低稳定性GK突变体，部分解释了人类中的年轻人成熟型糖尿病（MODY）表型和FoF 1 ATP酶组分的线粒体DNA突变，这些突变被认为会导致BHE（cdb）大鼠迟发性糖尿病。选择这两个例子是为了说明参与β细胞能量代谢并产生偶联因子和细胞内信号的具有高控制强度的代谢反应是对遗传、环境和药理学影响非常敏感的步骤。除了胰岛素分泌和胰岛素生物合成之外，β细胞的葡萄糖代谢还控制对过度燃料负荷的适应性反应，并且可以通过肥大、增生和新生来增加β细胞质量。很可能这种适应性反应在糖尿病中受到损害，因为GK或ATP酶突变体在这里突出显示。因此，对β细胞中介和能量代谢的全面了解是理解这些细胞在燃料稳态中的作用以及在最普遍的代谢疾病糖尿病的发病机制中的基础。
Special features of glucose metabolism in pancreatic beta-cells are central to an understanding of the physiological role of these cells in glucose homeostasis. Several of these characteristics are emphasized: a high-capacity system for glucose transport; glucose phosphorylation by the high-K-m glucokinase (GK), which is rate-limiting for glucose metabolism and determines physiologically the glucose dependency curves of many processes in beta-cell intermediary and energy metabolism and of insulin release and is therefore viewed as glucose sensor; remarkably low activity of lactate dehydrogenase and the presence of effective hydrogen shuttles to allow virtually quantitative oxidation of glycolytic NADH; the near absence of glycogen and fatty acid synthesis and of gluconeogenesis, such that intermediary metabolism is primarily catabolic; a crucial role of mitochondrial processes, including the citric acid cycle, electron transport, and oxidative phosphorylation with FoF1 ATPase governing the glucose-dependent increase of the ATP mass-action ratio; a Ca2+-independent glucose-induced respiratory burst and increased ATP production in beta-cells as striking manifestations of crucial mitochondrial reactions; control of the membrane potential by the mass-action ratio of ATP and voltage-dependent Ca2+ influx as signal for insulin release; accumulation of malonyl-CoA, acyl-CoA, and diacylglycerol as essential or auxiliary metabolic coupling factors; and amplification of the adenine nucleotide, lipid-related, and Ca2+ signals to recruit many auxiliary processes to maximize insulin biosynthesis and release, The biochemical design also suggests certain candidate diabetes genes related to fuel metabolism: low-activity and low-stability GK mutants that explain in part the maturity-onset diabetes of the young (MODY) phenotype in humans and mitochondrial DNA mutations of FoF1 ATPase components thought to cause late-onset diabetes in BHE(cdb) rats. These two examples are chosen to illustrate that metabolic reactions with high control strength participating in beta-cell energy metabolism and generating coupling factors and intracellular signals are steps with great susceptibility to genetic, environmental, and pharmacological influences. Glucose metabolism of beta-cells also controls, in addition to insulin secretion and insulin biosynthesis, an adaptive response to excessive fuel loads and may increase the beta-cell mass by hypertrophy, hyperplasia, and neogenesis. It is probable that this adaptive response is compromised in diabetes because of the GK or ATPase mutants that are highlighted here. A comprehensive knowledge of beta-cell intermediary and energy metabolism is therefore the foundation for understanding the role of these cells in fuel homeostasis and in the pathogenesis of the most prevalent metabolic disease, diabetes.