Gaisano Herbert Y, Macdonald Patrick E, Vranic Mladen
Departments of Medicine and Physiology, University of Toronto Toronto, ON, Canada.
Front Physiol. 2012 Sep 4;3:349. doi: 10.3389/fphys.2012.00349. eCollection 2012.
Normal release of glucagon from pancreatic islet α-cells promotes glucose mobilization, which counteracts the hypoglycemic actions of insulin, thereby ensuring glucose homeostasis. In treatment of diabetes aimed at rigorously reducing hyperglycemia to avoid chronic complications, the resulting hypoglycemia triggering glucagon release from α-cells is frequently impaired, with ensuing hypoglycemic complications. This review integrates the physiology of glucagon secretion regulating glucose homeostasis in vivo to single α-cell signaling, and how both become perturbed in diabetes. α-cells within the social milieu of the islet micro-organ are regulated not only by intrinsic signaling events but also by paracrine regulation, particularly by adjacent insulin-secreting β-cells and somatostatin-secreting δ-cells. We discuss the intrinsic α-cell signaling events, including glucose sensing and ion channel regulation leading to glucagon secretion. We then discuss the complex crosstalk between the islet cells and the breakdown of this crosstalk in diabetes contributing to the dysregulated glucagon secretion. Whereas, there are many secretory products released by β- and δ-cells that become deficient or excess in diabetes, we discuss the major ones, including the better known insulin and lesser known somatostatin, which act as putative paracrine on/off switches that very finely regulate α-cell secretory responses in health and diabetes. Of note in several type 1 diabetes (T1D) rodent models, blockade of excess somatostatin actions on α-cell could normalize glucagon secretion sufficient to attain normoglycemia in response to hypoglycemic assaults. There has been slow progress in fully elucidating the pathophysiology of the α-cell in diabetes because of the small number of α-cells within an islet and the islet mass becomes severely reduced and inflamed in diabetes. These limitations are just now being surmounted by new approaches.
胰岛α细胞正常释放胰高血糖素可促进葡萄糖动员，抵消胰岛素的降血糖作用，从而确保葡萄糖稳态。在旨在严格降低高血糖以避免慢性并发症的糖尿病治疗中，由此引发的低血糖触发α细胞释放胰高血糖素的功能常常受损，进而导致低血糖并发症。本综述整合了胰高血糖素分泌在体内调节葡萄糖稳态的生理学知识，直至单个α细胞信号传导，以及两者在糖尿病中如何受到干扰。胰岛微环境中的α细胞不仅受内在信号事件调节，还受旁分泌调节，特别是受相邻分泌胰岛素的β细胞和分泌生长抑素的δ细胞调节。我们讨论了α细胞的内在信号事件，包括葡萄糖感知和导致胰高血糖素分泌的离子通道调节。然后，我们讨论了胰岛细胞之间复杂的相互作用以及这种相互作用在糖尿病中的破坏，这导致了胰高血糖素分泌失调。虽然β细胞和δ细胞释放的许多分泌产物在糖尿病中会变得不足或过量，但我们讨论了主要的产物，包括广为人知的胰岛素和鲜为人知的生长抑素，它们在健康和糖尿病状态下作为假定的旁分泌开/关开关，非常精细地调节α细胞的分泌反应。值得注意的是，在几种1型糖尿病（T1D）啮齿动物模型中，阻断生长抑素对α细胞的过量作用可使胰高血糖素分泌正常化，足以在低血糖攻击时实现血糖正常。由于胰岛内α细胞数量较少，且糖尿病时胰岛体积会严重缩小并发炎，因此在全面阐明糖尿病中α细胞的病理生理学方面进展缓慢。这些限制现在正被新方法克服。
