Taguchi N, Aizawa T, Sato Y, Ishihara F, Hashizume K
Department of Geriatrics, Endocrinology and Metabolism, Shinshu University School of Medicine, Nagano-ken, Japan.
Endocrinology. 1995 Sep;136(9):3942-8. doi: 10.1210/endo.136.9.7649103.
The mechanism of glucose-induced biphasic insulin release by the B cell was investigated using isolated rat pancreatic islets. In perifusion experiments, 16.7 mM glucose in combination with 25 mM K+ transformed the high K(+)-induced monophasic insulin release into a biphasic one in the presence of diazoxide (Dz), an ATP-sensitive K+ channel opener. Inclusion of Dz during the initial 6 min of glucose stimulation abolished the first phase, but was without effect on the second phase. In batch incubation experiments, fuels, including 16.7 mM glucose, 6 mM D-glyceraldehyde, and 10 mM 2-ketoisocaproate, but not sulfonylurea, caused time-dependent potentiation of the B cell so that the response to 25 mM K+, applied later, was increased in the fuel-primed islets. Inclusion of Dz or lowering extracellular Ca2+ (to micromolar range) during the priming, which eliminates the initiation of insulin release, did not eradicate the potentiation. We conclude that high glucose closes ATP-sensitive K+ channels, leading to membrane depolarization, Ca2+ influx, and initiation of insulin release (first phase), and subsequently self-augments insulin release in an ATP-sensitive K+ channel-independent manner (second phase), acting at steps distal to cytosolic Ca2+ elevation. The biphasic insulin release is thus generated by an interaction of ATP-sensitive K+ channel-dependent and -independent glucose actions.
利用分离的大鼠胰岛研究了B细胞葡萄糖诱导的双相胰岛素释放机制。在灌流实验中，16.7 mM葡萄糖与25 mM K⁺联合使用，在ATP敏感性钾通道开放剂二氮嗪（Dz）存在的情况下，将高钾诱导的单相胰岛素释放转变为双相释放。在葡萄糖刺激的最初6分钟内加入Dz消除了第一相，但对第二相没有影响。在批量孵育实验中，包括16.7 mM葡萄糖、6 mM D-甘油醛和10 mM 2-酮异己酸在内的燃料，但不包括磺酰脲类药物，引起B细胞的时间依赖性增强，因此在预先用燃料处理的胰岛中，随后施加的25 mM K⁺引起的反应增强。在引发过程中加入Dz或降低细胞外Ca²⁺（至微摩尔范围），这消除了胰岛素释放的起始，但并没有消除这种增强作用。我们得出结论，高葡萄糖关闭ATP敏感性钾通道，导致膜去极化、Ca²⁺内流和胰岛素释放的起始（第一相），随后以一种不依赖于ATP敏感性钾通道的方式自我增强胰岛素释放（第二相），作用于胞质Ca²⁺升高的远端步骤。因此，双相胰岛素释放是由ATP敏感性钾通道依赖性和非依赖性葡萄糖作用的相互作用产生的。
