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.
Highlights
Reviewed by: Oksana Sorokina, The University of Edinburgh, UK Alexey Goltsov, University of Abertay Dundee, UK
This review integrates the physiology of glucagon secretion regulating glucose homeostasis in vivo to single αcell signaling, and how both become perturbed in diabetes. α-cells within the social milieu of the islet micro-organ are regulated by intrinsic signaling events and by paracrine regulation, by adjacent insulin-secreting β-cells and somatostatinsecreting δ-cells
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
Summary
Reviewed by: Oksana Sorokina, The University of Edinburgh, UK Alexey Goltsov, University of Abertay Dundee, UK. Low glucose levels trigger glucagon release from α-cells to abrogate the deleterious effects of insulin-induced acute hypoglycemia (Cryer, 2002; Dunning and Gerich, 2007; Quesada et al, 2008). Α-cells hypersecrete during meals (Butler and Rizza, 1991; Dunning and Gerich, 2007; Quesada et al, 2008) causing excessive release of glucose, resulting in hyperglycemia and eventually consequent chronic complications (blindness, kidney, heart failure, and neuropathy). In addition to increased α-cell sensitivity to insulin, chronic hyperglycemia plays an important role in dysregulation of α-cells (Shi et al, 1996) but no effective treatment has been developed to www.frontiersin.org α-cell in health and diabetes increase (or regulate) glucagon secretion to combat hypoglycemic attacks. How these coupling mechanisms become dysregulated in diabetes albeit recently postulated (switch on/off hypothesis), the precise underlying cellular basis is unknown
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