Glucose controls glucagon secretion by directly modulating cAMP in alpha cells

Abstract

Aims/hypothesis Glucagon is critical for normal glucose homeostasis and aberrant secretion of the hormone aggravates dysregulated glucose control in diabetes. However, the mechanisms by which glucose controls glucagon secretion from pancreatic alpha cells remain elusive. The aim of this study was to investigate the role of the intracellular messenger cAMP in alpha-cell-intrinsic glucose regulation of glucagon release. Methods Subplasmalemmal cAMP and Ca 2+ concentrations were recorded in isolated and islet-located alpha cells using fluorescent reporters and total internal reflection microscopy. Glucagon secretion from mouse islets was measured using ELISA. Results Glucose induced Ca 2+ -independent alterations of the subplasmalemmal cAMP concentration in alpha cells that correlated with changes in glucagon release. Glucose-lowering-induced stimulation of glucagon secretion thus corresponded to an elevation in cAMP that was independent of paracrine signalling from insulin or somatostatin. Imposed cAMP elevations stimulated glucagon secretion and abolished inhibition by glucose elevation, while protein kinase A inhibition mimicked glucose suppression of glucagon release. Conclusions/interpretation Glucose concentrations in the hypoglycaemic range control glucagon secretion by directly modulating the cAMP concentration in alpha cells independently of paracrine influences. These findings define a novel mechanism for glucose regulation of glucagon release that underlies recovery from hypoglycaemia and may be disturbed in diabetes. Electronic supplementary material The online version of this article (10.1007/s00125-019-4857-6) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Human pseudoislet system enables detection of differences in G-protein-coupled-receptor signaling pathways between α and β cells

“…Interestingly, direct KCl depolarization was not sufficient to overcome these inhibitory effects in either cell type, suggesting that reduced cAMP via the inhibition of adenylyl cyclase plays an important role in both insulin and glucagon secretion. These results align well with recent studies in β cells suggesting cAMP tone is crucial for insulin secretion and observations in α cells highlighting cAMP as a key mediator of glucagon secretion (Capozzi et al, 2019;Elliott et al, 2014;Tengholm and Gylfe, 2017;Yu et al, 2019).…”

“…This shift closes ATP-sensitive potassium channels, depolarizing the cell membrane and opening voltagedependent calcium channels where calcium influx is a trigger of insulin granule exocytosis (Tokarz et al, 2018). In α cells, the pathway of glucose inhibition of glucagon secretion is not clearly defined with both intrinsic and paracrine mechanisms proposed (Gylfe and Gilon, 2014;Hughes et al, 2018;Yu et al, 2019). Furthermore, gap junctional coupling and paracrine signaling between islet endocrine cells and within the 3D islet architecture are critical for islet function, as individual α or β cells do not show the same coordinated secretion pattern seen in intact islets (Capozzi et al, 2019;Elliott et al, 2014;Svendsen et al, 2018;Unger and Orci, 2010;Zhu et al, 2019).…”

GLP-1(9-36) mediates the glucagonostatic effect of GLP-1 by promiscuous activation of the glucagon receptor

“…This difference provides additional evidence that the two GLP-1 amides may act by distinct mechanisms/receptors. Notably, the PKA inhibitor had no effect on glucagon secretion at 1 mM glucose, at variance with recent reports (13).…”

Arginine-vasopressin mediates counter-regulatory glucagon release and is diminished in type 1 diabetes

“…The mechanism(s) by which glucagon secretion is controlled is a contentious topic (Gylfe, 2013;Lai et al, 2018). Based on observations in isolated (ex vivo) islets, islets have been shown to respond to hypoglycaemia (and adjust glucagon secretion accordingly) via intrinsic (Rorsman et al, 2014;Basco et al, 2018;Yu et al, 2019) and paracrine mechanisms (Briant et al, 2018;Vergari et al, 2019). While it is indisputable that the islet is a critical component of the body's glucostat (Rodriguez-Diaz et al, 2018) and has the ability to intrinsically modulate glucagon output, it is clear that such an 'islet-centric' viewpoint is overly simplistic (Schwartz et al, 2013).…”