Smoking is widely regarded as a risk factor for type 2 diabetes, as nicotine contributes to insulin resistance by desensitizing the insulin receptors in muscle, liver, or fat. Little is known, however, about the immediate regulation of islet hormonal output by nicotine, an agonist of ionotropic cholinergic receptors. We investigated this by imaging cytosolic Ca2+ dynamics in mouse and human islets using confocal microscopy and measuring glucagon secretion in response to the alkaloid from isolated mouse islets. Nicotine acutely stimulated cytosolic Ca2+ in glucagon-secreting α-cells but not in insulin-secreting β-cells. The 2.8±0.5-fold (p<0.05) increase in the Ca2+, observed in >70% of α-cells, correlated well with a 2.5±0.3-fold stimulation of glucagon secretion. Nicotine-induced elevation of cytosolic Ca2+ relied on the influx from the extracellular compartment rather than the release of the cation from intracellular depots. Metabotropic cholinergic signaling, monitored at the level of intracellular diacylglycerol, was limited to 69% of α-cells vs 94% of β-cells. We conclude that parasympathetic regulation of pancreatic islet hormone release utilizes different signaling pathways in β- (metabotropic) and α-cells (metabotropic and ionotropic), resulting in the finetuning of the ACh-induced glucagon exocytosis. Sustained nicotinic stimulation is, therefore, likely to attenuate insulin sensitivity by increasing glucagon release.

中文翻译：

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烟碱信号传导刺激小鼠和人胰腺 α 细胞中的胰高血糖素分泌


吸烟被广泛认为是 2 型糖尿病的危险因素，因为尼古丁通过使肌肉、肝脏或脂肪中的胰岛素受体脱敏而导致胰岛素抵抗。然而，人们对尼古丁（一种离子型胆碱能受体的激动剂）对胰岛荷尔蒙输出的直接调节知之甚少。我们通过使用共聚焦显微镜对小鼠和人胰岛中的胞质 Ca 2 + 动力学进行成像，并测量胰高血糖素分泌对离体小鼠胰岛生物碱的响应来研究这一点。尼古丁急性刺激分泌胰高血糖素的 α 细胞中的胞质 Ca2+，但不刺激分泌胰岛素的 β 细胞中的胞质 Ca2+。在 >70% 的 α 细胞中观察到的 Ca2+ 增加 2.8±0.5 倍 （p<0.05） 与胰高血糖素分泌的 2.5±0.3 倍刺激密切相关。尼古丁诱导的胞质 Ca2 + 升高依赖于细胞外区室的流入，而不是从细胞内贮库释放阳离子。在细胞内甘油二酯水平监测的代谢性胆碱能信号传导仅限于 α 细胞的 69%，而 β 细胞的 94%。我们得出结论，胰岛激素释放的副交感神经调节利用 β 细胞（代谢性）和 α 细胞（代谢性和离子型）中的不同信号通路，导致 ACh 诱导的胰高血糖素胞吐作用的微调。因此，持续的烟碱刺激可能通过增加胰高血糖素的释放来减轻胰岛素敏感性。