Glucose regulation of glutaminolysis and its role in insulin secretion
Glucose regulation of glutaminolysis and its role in insulin secretion
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DOI：
10.2337/diabetes.48.8.1535
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发表时间：
1999-08-01
期刊：
影响因子：
7.7
通讯作者：
Matschinsky, FM
中科院分区：
文献类型：
--
作者：
Gao, Z;Li, GZ;Matschinsky, FM
亮氨酸或非代谢亮氨酸类似物 +/- 2-氨基-2-降冰片烷-羧酸 (BCH)（均为 10 mmol/l）在 2 mmol/l 谷氨酰胺 (Q2) 存在的情况下，在没有葡萄糖但存在 Q2 的情况下预处理培养的小鼠胰岛 40 分钟时诱导双相胰岛素分泌。 β 细胞反应由高于基础值 20 至 25 倍的初始峰值和不太明显的第二阶段组成。然而，当用 25 mmol/l 葡萄糖加 Q2 预处理胰岛时，BCH 仅产生延迟反应，而亮氨酸完全无效。对于 Q2，在用 0、5 或 15 mmol/l 葡萄糖预处理 40 分钟的胰岛中，10 mmol/l BCH 或亮氨酸分别引起近三倍增加、两倍增加或没有影响。因此，用高葡萄糖预处理胰岛可抑制 BCH 和亮氨酸诱导的胞质 Ca2+ 变化和胰岛素释放。当 BCH 浓度为 10 mmol/l 时，葡萄糖会降低培养的大鼠胰岛中的谷氨酰胺氧化，但在不存在 BCH 时则不会，最低有效水平约为 0.1 mmol/l，最高为 18-30 mmol/l，抑制浓度为 50%，约为 3 mmol/l。这些数据与葡萄糖以浓度依赖性方式抑制胰腺β细胞中的谷氨酰胺分解并因此阻断亮氨酸刺激的胰岛素分泌的假设一致。我们假设，在基础餐间状态下，β 细胞的谷氨酰胺分解部分开启，因为谷氨酸脱氢酶 (GDH) 被部分燃料耗尽和对内源性激活剂（如亮氨酸）敏感而降低的 β 电位激活。此外，它可能对基础胰岛素释放有显着贡献，已知基础胰岛素约占每日释放的胰岛素的一半。这些数据解释了低血糖期间3-细胞的“亮氨酸过敏”，并有助于阐明与血清氨水平升高相关的高胰岛素血症的GDH相关综合征。因此，了解β细胞谷氨酰胺分解的精确调节和作用可能是我们正常血糖控制概念的核心。
Leucine or the nonmetabolized leucine analog +/- 2-amino-2-norbornane-carboxylic acid (BCH) (both at 10 mmol/l) induced biphasic insulin secretion in the presence of 2 mmol/l glutamine (Q2) in cultured mouse islets pretreated for 40 min without glucose but with Q2 present. The beta-cell response consisted of an initial peak of 20- to 25-fold above basal and a less marked secondary phase. However, BCH produced only a delayed response, while leucine was totally ineffective when islets were pretreated with 25 mmol/l glucose plus Q2. With Q2, 10 mmol/l BCH or leucine caused a nearly threefold increase, a twofold increase, or had no effect on cytosolic Ca2+ levels in islets pretreated for 40 min with 0, 5, or 15 mmol/l glucose, respectively. Thus, pretreatment of islets with high glucose inhibited BCH- and leucine-induced cytosolic Ca2+ changes and insulin release. Glucose decreased glutamine oxidation in cultured rat islets when BCH was present at 10 mmol/l, but not in its absence, with a lowest effective level of similar to 0.1 mmol/l, a maximum of 18-30 mmol/l, and an inhibitory concentration, 50%, of similar to 3 mmol/l. The data are consistent with the hypothesis that glucose inhibits glutaminolysis in pancreatic beta-cells in a concentration-dependent manner and hence blocks leucine-stimulated insulin secretion. We postulate that in the basal inter-prandial state, glutaminolysis of beta-cells is partly turned on because glutamate dehydrogenase (GDH) is activated by a decreased beta-potential due to partial fuel depletion and sensitization to endogenous activators such as leucine. Additionally, it may contribute significantly to basal insulin release, which is known to be responsible for about half of the insulin released daily. The data explain "leucine-hypersensitivity" of 3-cells during hypoglycemia and contribute to the elucidation of the GDH-linked syndrome of hyperinsulinism associated with elevated serum ammonia levels. Thus, understanding the precise regulation and role of beta-cell glutaminolysis is probably central to our concept of normal blood glucose control.