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 (<1 μM) stimulated glucagon secretion, whereas high 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.
Highlights
Blood glucose levels are under the control of two hormones released from the pancreatic islets of Langerhans
We show that glucose retained the ability to suppress glucagon release from isolated islets during blockade of the Zn2þ and c-aminobutyric acid (GABA) paracrine pathways, and in the absence of stimulated insulin secretion or b-cell Ca2þ responses
Glucose Can Regulate Glucagon Secretion Directly To examine a role for GABA and Zn2þ as paracrine mediators of glucagon secretion, we examined the ability of the GABAA receptor antagonist SR-95531 and Zn2þ chelation with Ca2þ-EDTA to prevent the glucose-dependent suppression of glucagon release
Summary
Blood glucose levels are under the control of two hormones released from the pancreatic islets of Langerhans. Islet b cells secrete insulin when glucose is high, decreasing glucose production by the liver and increasing glucose storage in multiple tissues. Islet a cells secrete glucagon in response to decreased blood glucose, whereas elevated glucose levels suppress glucagon release. Glucagon is the principal factor stimulating glucose production by the liver. Baseline glucagon release is elevated, and glucagon secretion in the low-glucose condition is blunted [2,3,4]. These effects contribute to chronic hyperglycaemia and to an increased risk for acute hypoglycaemic events
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
