title: Glucagon secretion from pancreatic α-cells.
abstract: Type 2 diabetes involves a ménage à trois of impaired glucose regulation of pancreatic hormone release: in addition to impaired glucose-induced insulin secretion, the release of the hyperglycaemic hormone glucagon becomes dysregulated; these last-mentioned defects exacerbate the metabolic consequences of hypoinsulinaemia and are compounded further by hypersecretion of somatostatin (which inhibits both insulin and glucagon secretion). Glucagon secretion has been proposed to be regulated by either intrinsic or paracrine mechanisms, but their relative significance and the conditions under which they operate are debated. Importantly, the paracrine and intrinsic modes of regulation are not mutually exclusive; they could operate in parallel to control glucagon secretion. Here we have applied mathematical modelling of α-cell electrical activity as a novel means of dissecting the processes that underlie metabolic regulation of glucagon secretion. Our analyses indicate that basal hypersecretion of somatostatin and/or increased activity of somatostatin receptors may explain the loss of adequate counter-regulation under hypoglycaemic conditions, as well as the physiologically inappropriate stimulation of glucagon secretion during hyperglycaemia seen in diabetic patients. We therefore advocate studying the interaction of the paracrine and intrinsic mechanisms; unifying these processes may give a more complete picture of the regulation of glucagon secretion from α-cells than studying the individual parts.
authors.affiliation: a Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine , University of Oxford , Oxford , UK ;
authors.forename: Linford
authors.initials: L
authors.lastname: Briant
authors.affiliation: b Metabolic Research, Department of Physiology , Institute of Neuroscience and Physiology, University of Göteborg , Göteborg , Sweden.
authors.forename: Albert
authors.initials: A
authors.lastname: Salehi
authors.affiliation: a Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine , University of Oxford , Oxford , UK ;
authors.forename: Elisa
authors.initials: E
authors.lastname: Vergari
authors.affiliation: a Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine , University of Oxford , Oxford , UK ;
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: a Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine , University of Oxford , Oxford , UK ;|b Metabolic Research, Department of Physiology , Institute of Neuroscience and Physiology, University of Göteborg , Göteborg , Sweden.
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000378:metabolism*; D004594:Electrophysiology; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D008962:Models, Theoretical; D051381:Rats; D017481:Receptors, Somatostatin / Q000378:metabolism; D015398:Signal Transduction; D013004:Somatostatin / Q000378:metabolism
chemical_list: D007328:Insulin; D017481:Receptors, Somatostatin; D013004:Somatostatin; D005934:Glucagon; D005947:Glucose
keywords: diabetes; electrophysiology; experimental diabetes; glucagon; intrinsic mechanisms; pancreatic alpha-cells; paracrine