A KATP Channel-Dependent Pathway within α Cells Regulates Glucagon Release from Both Rodent and Human Islets of Langerhans
Open Access
- 15 May 2007
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Biology
- Vol. 5 (6), e143
- https://doi.org/10.1371/journal.pbio.0050143
Abstract
Glucagon, secreted from pancreatic islet α cells, stimulates gluconeogenesis and liver glycogen breakdown. The mechanism regulating glucagon release is debated, and variously attributed to neuronal control, paracrine control by neighbouring β cells, or to an intrinsic glucose sensing by the α cells themselves. We examined hormone secretion and Ca2+ responses of α and β cells within intact rodent and human islets. Glucose-dependent suppression of glucagon release persisted when paracrine GABA or Zn2+ signalling was blocked, but was reversed by low concentrations (1–20 μM) of the ATP-sensitive K+ (KATP) channel opener diazoxide, which had no effect on insulin release or β cell responses. This effect was prevented by the KATP channel blocker tolbutamide (100 μM). Higher diazoxide concentrations (≥30 μM) decreased glucagon and insulin secretion, and α- and β-cell Ca2+ responses, in parallel. In the absence of glucose, tolbutamide at low concentrations (10 μM) were inhibitory. In the presence of a maximally inhibitory concentration of tolbutamide (0.5 mM), glucose had no additional suppressive effect. Downstream of the KATP channel, inhibition of voltage-gated Na+ (TTX) and N-type Ca2+ channels (ω-conotoxin), but not L-type Ca2+ channels (nifedipine), prevented glucagon secretion. Both the N-type Ca2+ channels and α-cell exocytosis were inactivated at depolarised membrane potentials. Rodent and human glucagon secretion is regulated by an α-cell KATP channel-dependent mechanism. We propose that elevated glucose reduces electrical activity and exocytosis via depolarisation-induced inactivation of ion channels involved in action potential firing and secretion. Glucagon is a critical regulator of glucose homeostasis. Its major action is to mobilize glucose from the liver. Glucagon secretion from α cells of the pancreatic islets of Langerhans is suppressed by elevated blood sugar, a response that is often perturbed in diabetes. Much work has focused on the regulation of α-cell glucagon secretion by neuronal factors and by paracrine factors from neighbouring cells, including the important islet hormone insulin. In contrast, we provide evidence in support of a direct effect of glucose on α cells within intact rodent and human islets. Notably, our work implicates an α-cell glucose-sensing pathway similar to that found in insulin-secreting β cells, involving closure of ATP-dependent K+ channels in the presence of glucose. Furthermore, we find that membrane depolarisation results in inhibition of Na+ and Ca2+ channel activity and α-cell exocytosis. Thus, we propose that elevated blood glucose reduces α-cell electrical activity and glucagon secretion by inactivating the ion channels involved in action potential firing and secretion.Keywords
This publication has 56 references indexed in Scilit:
- Glucose-sensing mechanisms in pancreatic β-cellsPhilosophical Transactions Of The Royal Society B-Biological Sciences, 2005
- Glucose Stimulates Glucagon Release in Single Rat α-Cells by Mechanisms that Mirror the Stimulus-Secretion Coupling in β-CellsEndocrinology, 2005
- Serum Glucagon Counterregulatory Hormonal Response to Hypoglycemia Is Blunted in Congenital HyperinsulinismDiabetes, 2005
- Diverse Causes of Hypoglycemia-Associated Autonomic Failure in DiabetesNew England Journal of Medicine, 2004
- Capacitance measurements of exocytosis in mouse pancreatic α‐, β‐ and δ‐cells within intact islets of LangerhansThe Journal of Physiology, 2004
- Glucose Inhibition of Glucagon Secretion From Rat α-Cells Is Mediated by GABA Released From Neighboring β-CellsDiabetes, 2004
- Sulfonylurea-Binding Sites and ATP-Sensitive K+ Channels in α-TC Glucagonoma and β-TC Insulinoma CellsDiabetes, 1993
- The actions of arginine and glucose on glucagon secretion are mediated by opposite effects on cytoplasmic Ca2+Biochemical and Biophysical Research Communications, 1987
- Defective glucose counterregulation after subcutaneous insulin in noninsulin-dependent diabetes mellitus. Paradoxical suppression of glucose utilization and lack of compensatory increase in glucose production, roles of insulin resistance, abnormal neuroendocrine responses, and islet paracrine interactions.JCI Insight, 1984
- Calcium dependency of glucagon release: its modulation by nutritional factors.American Journal of Physiology-Endocrinology and Metabolism, 1979