title: A computational systems analysis of factors regulating α cell glucagon secretion.
abstract: Glucagon, a peptide hormone secreted from the α-cells of the pancreatic islets, is critical for blood glucose homeostasis. We reviewed the literature and employed a computational systems analysis of intracellular metabolic and electrical regulation of glucagon secretion to better understand these processes. The mathematical model of α-cell metabolic parameters is based on our previous model for pancreatic β-cells. We also formulated an ionic model for action potentials that incorporates Ca ( 2+) , K (+) , Na (+)  and Cl (-)  currents. Metabolic and ionic models are coupled to the equations describing Ca ( 2+)  homeostasis and glucagon secretion that depends on activation of specific voltage-gated Ca ( 2+)  channels. Paracrine and endocrine regulations were analyzed with an emphasis on their effects on a hyperpolarization of membrane potential. This general model simulates and gives insight into the mechanisms of regulation of glucagon secretion under a wide range of experimental conditions. We also reviewed and analyzed dysfunctional mechanisms in α-cells to determine key pharmacological targets for modulating glucagon secretion in type 1 and 2 diabetes.
authors.affiliation: The Kovler Diabetes Center, Departments of Medicine and Pediatrics, The University of Chicago, Chicago, IL, USA. lfridlia@medicine.bsd.uchicago.edu
authors.forename: Leonid E
authors.initials: LE
authors.lastname: Fridlyand
authors.forename: Louis H
authors.initials: LH
authors.lastname: Philipson
mesh_terms: D000818:Animals; D001692:Biological Transport; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000502:physiology; D018118:Chloride Channels / Q000502:physiology; D003198:Computer Simulation; D003920:Diabetes Mellitus / Q000378:metabolism / Q000503:physiopathology; D055724:Electrophysiological Phenomena; D005934:Glucagon / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism* / Q000502:physiology; D005947:Glucose / Q000378:metabolism* / Q000493:pharmacokinetics; D006728:Hormones / Q000378:metabolism; D006801:Humans; D008564:Membrane Potentials; D008954:Models, Biological; D019899:Paracrine Communication; D015221:Potassium Channels / Q000502:physiology; D049490:Systems Biology
chemical_list: D015220:Calcium Channels; D018118:Chloride Channels; D006728:Hormones; D015221:Potassium Channels; D005934:Glucagon; D005947:Glucose; D002118:Calcium