Reference
Wang, Q., Liang, X., & Wang, S. (2013). Intra-islet glucagon secretion and action in the regulation of glucose homeostasis. Frontiers in Physiology, 3. https://doi.org/10.3389/fphys.2012.00485
Info
FirstAuthor:: Wang, Qinghua
Author:: Liang, Xinyun
Author:: Wang, Susanne
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Title:: Intra-islet glucagon secretion and action in the regulation of glucose homeostasis
Year:: 2013
Citekey:: WangEtAl_2013_IntraisletGlucagonSecretion
itemType:: journalArticle
Journal:: Frontiers in Physiology
Volume:: 3
DOI:: 10.3389/fphys.2012.00485
Link
Abstract
Glucagon, a key hormone in the regulation of glucose homeostasis, acts as a counter-regulatory hormone to insulin by promoting hepatic glucose output. Under normal conditions, insulin and glucagon operate in concert to maintain the glucose level within a narrow physiological range. In diabetes, however, while insulin secretion or action is insufficient, the production and secretion of glucagon are excessive, contributing to the development of diabetic hyperglycemia. Within an islet, intra-islet insulin, in cooperation with intra-islet GABA, suppresses glucagon secretion via direct modulation of α-cell intracellular signaling pathways involving Akt activation, GABA receptor phosphorylation and the receptor plasma membrane translocation, while intra-islet glucagon plays an important role in modulating β-cell function and insulin secretion. Defects in the insulin-glucagon fine-tuning machinery may result in β-cell glucose incompetence, leading to unsuppressed glucagon secretion and subsequent hyperglycemia, which often occur under extreme conditions of glucose influx or efflux. Therefore, deciphering the precise molecular mechanisms underlying glucagon secretion and action will facilitate our understanding of glucagon physiology, in particular, its role in regulating islet β-cell function, and hence the mechanisms behind glucose homeostasis.
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Insulin, in cooperation with GABA, suppresses glucagon secretion via direct phosphorylation of GABAAR by protein kinase B (or Akt), a key molecule in insulin signaling that leads to the translocation of the receptors from intracellular pools to the cell surface and the subsequent membrane hyperpolarization and closure of voltage-dependent calcium channels
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The secretion of glucagon requires a full depolarization cascade involving the sequential activation of a number of ion channels. Particularly, the activation of T-type Ca2+ channels depolarizes the cell to an intermediate membrane potential which activates the tetrodotoxin (TTX)-sensitive Na+ channels; the influx of Na+ ions further depolarizes the α-cell, leading to the activation of the L- or N-type Ca2+ channels and the generation of sustained Ca2+ influx, triggering glucagon granule exocytosis. The hyperpolarization-activated cyclic nucleotidegated (HCN) channels, expressed in the α-cells, are presumably involved in initiating the depolarization cascades (Zhang et al., 2008). Maintenance of the ATP-sensitive K+ (KATP) channel activity in α-cells within an appropriate range is critical for allowing the operation of this machinery (Bansal and Wang, 2008). At high glucose concentrations, the closure of the KATP channels, as a consequence of increased intracellular ATP/ADP ratio, depolarizes the α-cell membrane potential beyond the narrow window, causing voltage inactivation of the depolarization cascade (Bansal and Wang, 2008). At low glucose concentrations, however, the opening of KATP channels only occurs in a subpopulation of these channels on the α-cell and sets the membrane potential to a very negative value, causing the activation of the T-type Ca2+ channels and/or the HCN channels to trigger the subsequent depolarization cascades (Gopel et al., 2000; MacDonald et al., 2007).
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The concept that insulin is a physiological suppressor of glucagon secretion is also supported by clinical studies.