The K+-ATP channel-independent pathway of regulation of insulin secretion by glucose -: In search of the underlying mechanism
The K+-ATP channel-independent pathway of regulation of insulin secretion by glucose -: In search of the underlying mechanism
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DOI：
10.2337/diabetes.47.11.1713
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发表时间：
1998-11-01
期刊：
影响因子：
7.7
通讯作者：
Henquin, JC
中科院分区：
文献类型：
--
作者：
Sato, Y;Henquin, JC
通过关闭ATP敏感性K+（K+-ATP）通道，葡萄糖促进β细胞中去极化依赖性Ca 2+内流和细胞质游离Ca 2+浓度（[Ca 2 +]（i））升高。胰岛素颗粒的Ca 2+依赖性胞吐作用随后被葡萄糖的K+-ATP通道非依赖性作用增强。第二种途径的潜在机制尚不清楚。通过在二氮嗪存在下孵育正常小鼠胰岛以打开K+-ATP通道和30 mmol/l K+以恢复Ca 2+内流来研究它们。葡萄糖的作用不需要在高葡萄糖存在下通过预孵育引发β细胞，并且不能归因于糖与“葡萄糖受体”的相互作用。“没有证据表明蛋白激酶A和C参与K+-ATP通道非依赖性途径，因为激酶的抑制剂不会改变葡萄糖的作用。在3 mmol/l葡萄糖，脂肪酸并没有影响K+诱导的胰岛素分泌，即使在存在溴棕榈酸酯，脂肪酸氧化的抑制剂。溴棕榈酸单独没有影响，但它降低了脂肪酸在20 mmol/l葡萄糖中产生的增强作用。因此，长链酰基辅酶A不太可能介导葡萄糖的作用。葡萄糖的作用与胰岛花生四烯酸释放的增加无关，也不被外源性花生四烯酸模仿。磷脂酶A抑制剂拮抗葡萄糖的作用，但其作用不被花生四烯酸或棕榈酸逆转，并与胰岛ATP的下降。没有证据表明NO、cGMP、Mg、磷酸盐、磷脂酰肌醇3-激酶或百日咳毒素敏感性G蛋白的干预作用。福霉素A是一种腺苷类似物，在胰岛中转化为福霉素A-三磷酸，在无葡萄糖和有葡萄糖的情况下增加胰岛素分泌。总之，目前和我们以前的研究结果强烈表明，在所有已知的潜在的第二信使，腺嘌呤核苷酸是最好的候选人作为调节胰岛素分泌通过K+-ATP通道的非依赖性途径。
By closing ATP-sensitive K+ (K+-ATP) channels, glucose promotes depolarization-dependent Ca2+ entry and cytoplasmic free Ca2+ concentration ([Ca2+](i)) rise in beta-cells. Ca2+-dependent exocytosis of insulin granules is then potentiated by a K+-ATP channel-independent action of glucose. The underlying mechanisms of this second pathway are still unclear. They were studied by incubating normal mouse islets in the presence of diazoxide to open K+-ATP channels and 30 mmol/l K+ to restore Ca2+ entry. The effect of glucose did not require priming of beta-cells by preincubation in the presence of high glucose and could not be attributed to interaction of the sugar with a "glucoreceptor." There is no evidence that protein kinases A and C are involved in the K+-ATP channel-independent pathway, because inhibitors of the kinases did not alter the effect of glucose. In 3 mmol/l glucose, fatty acids did not influence K+-induced insulin secretion, even in the presence of bromopalmitate, an inhibitor of fatty acid oxidation. Bromopalmitate alone had no effect, but it decreased the potentiation that the fatty acids produce in 20 mmol/l glucose. It is thus unlikely that long-chain acyl CoAs mediate the effect of glucose. The action of glucose was not associated with an increase in arachidonic acid release from the islets and was not mimicked by exogenous arachidonic acid. Phospholipase A, inhibitors antagonized the effect of glucose, but their action was not reversed by arachidonic acid or palmitate and was associated with a fall in islet ATP. No evidence could be found for the intervention of NO, cGMP, Mg, phosphate, phosphatidylinositol 3-kinase, or pertussis toxin-sensitive G-proteins. Formycin A, an adenosine analog that is converted to formycin A-triphosphate in islets, increased insulin secretion in the absence and presence of glucose. In conclusion, the present and our previous results strongly suggest that among all known potential second messengers, adenine nucleotides are the best candidates as regulators of insulin secretion through the K+-ATP channel-independent pathway.