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- Hamilton, A., et al.
(författare)
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Adrenaline stimulates glucagon secretion by Tpc2-Dependent ca2+ mobilization from acidic stores in pancreatic a-Cells
- 2018
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 67:6, s. 1128-1139
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Tidskriftsartikel (refereegranskat)abstract
- Adrenaline is a powerful stimulus of glucagon secretion. It acts by activation of b-adrenergic receptors, but the downstream mechanisms have only been partially elucidated. Here, we have examined the effects of adrenaline in mouse and human a-cells by a combination of electrophysiology, imaging of Ca2+ and PKA activity, and hormone release measurements. We found that stimulation of glucagon secretion correlated with a PKA- and EPAC2-dependent (inhibited by PKI and ESI-05, respectively) elevation of [Ca2+]i in a-cells, which occurred without stimulation of electrical activity and persisted in the absence of extracellular Ca2+ but was sensitive to ryanodine, bafilomycin, and thapsigargin. Adrenaline also increased [Ca2+]i in a-cells in human islets. Genetic or pharmacological inhibition of the Tpc2 channel (that mediates Ca2+ release from acidic intracellular stores) abolished the stimulatory effect of adrenaline on glucagon secretion and reduced the elevation of [Ca2+]i. Furthermore, in Tpc2-deficient islets, ryanodine exerted no additive inhibitory effect. These data suggest that b-adrenergic stimulation of glucagon secretion is controlled by a hierarchy of [Ca2+]i signaling in the a-cell that is initiated by cAMP-induced Tpc2-dependent Ca2+ release from the acidic stores and further amplified by Ca2+-induced Ca2+ release from the sarco/endoplasmic reticulum. © 2018 by the American Diabetes Association.
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| 2. |
- Shigeto, Makoto, et al.
(författare)
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GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation
- 2015
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Ingår i: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 125:12, s. 4714-4728
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Tidskriftsartikel (refereegranskat)abstract
- Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.4 pM. Moreover, we determined that GLP-1 activates PLC, which increases submembrane diacylglycerol and thereby activates PKC, resulting in membrane depolarization and increased action potential firing and subsequent stimulation of insulin secretion. The depolarizing effect of GLP-1 on electrical activity was mimicked by the PKC activator PMA, occurred without activation of PKA, and persisted in the presence of PKA inhibitors, the K-ATP channel blacker tolbutamide, and the L-type Ca2+ channel blacker isradipine; however, depolarization was abolished by lowering extracellular Na+. The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of NW-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca2+ from thapsigargin-sensitive Ca2+ stores. Concordantly, GLP-1 effects were negligible in Trpm4 or Trpm5 KO islets. These data provide important insight into the therapeutic action of GLP-1 and suggest that circulating levels of this hormone directly stimulate insulin secretion by beta cells.
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