Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania.
J Appl Physiol (1985). 2018 Aug 1;125(2):419-428. doi: 10.1152/japplphysiol.01077.2017. Epub 2018 Apr 12.
Regulation of insulin release and glucose homeostasis by pancreatic β-cells is dependent on the metabolism of glucose by glucokinase (GK) and the influence of that activity on oxidative phosphorylation. Genetic alterations that result in hyperactivity of mitochondrial glutamate dehydrogenase (GDH-1) can cause hypoglycemia-hyperammonemia following high protein meals, but the role of GDH-1 remains poorly understood. GDH-1 activity is strongly inhibited by GTP, to near zero in the absence of ADP, and cooperatively activated ( n = 2.3) by ADP. The dissociation constant for ADP is near 200 µM in vivo, but leucine and its nonmetabolized analog 2-amino-2-norbornane-carboxylic acid (BCH) can activate GDH-1 by increasing the affinity for ADP. Under physiological conditions, as [ADP] increases GDH-1 activity remains very low until ~35 µM (threshold) and then increases rapidly. A model for GDH-1 and its regulation has been combined with a previously published model for glucose sensing that coupled GK activity and oxidative phosphorylation. The combined model (GK-GDH-core) shows that GK activity determines the energy state ([ATP]/[ADP][Pi]) in β-cells for glucose concentrations > 5 mM ([ADP] < 35 µM). As glucose falls < 5 mM the [ADP]-dependent increase in GDH-1 activity prevents [ADP] from rising above ~70 µM. Thus, GDH-1 dynamically buffers β-cell energy metabolism during hypoglycemia, maintaining the energy state and the basal rate of insulin release. GDH-1 hyperactivity suppresses the normal increase in [ADP] in hypoglycemia. This leads to hypoglycemia following a high protein meal by increasing the basal rate of insulin release (β-cells) and decreasing glucagon release (α-cells). NEW & NOTEWORTHY A model of β-cell metabolism and regulation of insulin release is presented. The model integrates regulation of oxidative phosphorylation, glucokinase (GK), and glutamate dehydrogenase (GDH-1). GDH-1 is near equilibrium under physiological conditions, but the activity is inhibited by GTP. In hypoglycemia, however, GK activity is low and [ADP], a potent activator of GDH-1, increases. Reducing equivalents from GDH dynamically buffers the intramitochondrial [NADH]/[NAD], and thereby the energy state, preventing hypoglycemia-induced substrate deprivation.
胰腺β细胞中胰岛素的释放和葡萄糖稳态的调节依赖于葡萄糖通过葡萄糖激酶（GK）的代谢和该活性对氧化磷酸化的影响。导致线粒体谷氨酸脱氢酶（GDH-1）过度活跃的遗传改变可导致高蛋白餐后低血糖-高氨血症，但 GDH-1 的作用仍知之甚少。GDH-1 活性被 GTP 强烈抑制，在没有 ADP 的情况下接近零，并且被 ADP 协同激活（n = 2.3）。在体内，ADP 的解离常数接近 200µM，但亮氨酸及其非代谢类似物 2-氨基-2-降冰片烷羧酸（BCH）可通过增加对 ADP 的亲和力来激活 GDH-1。在生理条件下，随着[ADP]的增加，GDH-1 活性仍然非常低，直到约 35µM（阈值），然后迅速增加。已经将 GDH-1 及其调节的模型与先前发表的葡萄糖感应模型相结合，该模型将 GK 活性和氧化磷酸化偶联起来。组合模型（GK-GDH-core）表明，对于葡萄糖浓度>5mM（[ADP]<35µM），GK 活性决定了β细胞中的能量状态([ATP]/[ADP][Pi])。随着葡萄糖降至<5mM，GDH-1 活性的[ADP]依赖性增加可防止[ADP]升高至~70µM以上。因此，GDH-1 在低血糖期间动态缓冲β细胞能量代谢，维持能量状态和基础胰岛素释放率。GDH-1 过度活跃会抑制低血糖时[ADP]的正常增加。这通过增加基础胰岛素释放率（β细胞）和减少胰高血糖素释放（α细胞）来导致高蛋白餐后低血糖。新的和值得注意的是，提出了一种β细胞代谢和胰岛素释放调节的模型。该模型整合了氧化磷酸化、葡萄糖激酶（GK）和谷氨酸脱氢酶（GDH-1）的调节。在生理条件下，GDH-1 接近平衡，但活性受 GTP 抑制。然而，在低血糖期间，GK 活性较低，作为 GDH-1 的有效激活剂的 ADP 增加。来自 GDH 的还原当量动态缓冲线粒体中的[NADH]/[NAD]，从而防止低血糖诱导的底物剥夺，维持能量状态。
