A Computational Systems Analysis of Factors Regulating α Cell Glucagon Secretion

Islets. Jul-Aug 2012;4(4):262-83. doi: 10.4161/isl.22193. Epub 2012 Jul 1.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Transport
  • Calcium / metabolism
  • Calcium Channels / physiology
  • Chloride Channels / physiology
  • Computer Simulation
  • Diabetes Mellitus / metabolism
  • Diabetes Mellitus / physiopathology
  • Electrophysiological Phenomena
  • Glucagon / antagonists & inhibitors
  • Glucagon / metabolism*
  • Glucagon-Secreting Cells / metabolism*
  • Glucagon-Secreting Cells / physiology
  • Glucose / metabolism*
  • Glucose / pharmacokinetics
  • Hormones / metabolism
  • Humans
  • Membrane Potentials
  • Models, Biological
  • Paracrine Communication
  • Potassium Channels / physiology
  • Systems Biology*

Substances

  • Calcium Channels
  • Chloride Channels
  • Hormones
  • Potassium Channels
  • Glucagon
  • Glucose
  • Calcium