Reference
Gaisano, H., MacDonald, P. E., & Vranic, M. (2012). Glucagon secretion and signaling in the development of diabetes. Frontiers in Physiology, 3. https://doi.org/10.3389/fphys.2012.00349
Info
FirstAuthor:: Gaisano, Herbert
Author:: MacDonald, Patrick E.
Author:: Vranic, Mladen
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Title:: Glucagon secretion and signaling in the development of diabetes
Year:: 2012
Citekey:: GaisanoEtAl_2012_GlucagonSecretionSignaling
itemType:: journalArticle
Journal:: Frontiers in Physiology
Volume:: 3
DOI:: 10.3389/fphys.2012.00349
Link
Abstract
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.
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It is not surprising then that pancreatic α-cells are electrically excitable and, like β-cells, use their electrical activity to couple changes in glucose to the regulation of glucagon release (Rorsman and Hellman, 1988; Gromada et al., 1997; Yoshimoto et al., 1999; Barg et al., 2000). Looking at this excitatory and exocytotic machinery alone however, is becomes difficult to explain how glucose inhibits, rather than stimulates, α-cell glucagon secretion. Understanding how the glucagon secretory machinery is regulated by signals both intrinsic and extrinsic to the α-cell will be necessary to elucidate the exact mechanism of glucose-regulated glucagon secretion. Indeed, there are already hints that the excitatory machinery in α-cells is regulated in a manner opposite to that of β-cells: for example membrane depolarization is capable of turning off a number of the ion channels involved in α-cell electrical activity that are activated under similar conditions in β-cells (Ramracheya et al., 2010; Spigelman et al., 2010); and hormonal signals, notably GLP-1, activates Ca2+ currents in β-cells (Salapatek et al., 1999) but inhibits these in α-cells (De Marinis et al., 2010). Thus, elucidating not only the pieces of machinery that control glucagon secretion, but how these are regulated will provide novel insight into the physiological mechanism for glucose-regulated glucagon release.
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This question has been a matter of debate for many years. Based solely on studies of dispersed or purified α-cells (Pipeleers et al., 1985; Ishihara et al., 2003; Olsen et al., 2005; Le Marchand and Piston, 2010), the answer would seem to be no, since under these conditions glucose stimulates glucagon secretion. One must be quite careful in the interpretation of such studies however, since properties of both dispersed α- and β-cells are quite different than those in intact islets.
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