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 Ca²⁺, K⁺, Na⁺ and Cl^- currents. Metabolic and ionic models are coupled to the equations describing Ca²⁺ homeostasis and glucagon secretion that depends on activation of specific voltage-gated Ca²⁺ 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.

Keywords: :

• diabetes
• calcium
• computational model
• ion channels
• insulin
• islets
• pancreas

Acknowledgments

Funding for this study was provided in part by the National Institute of Diabetes and Digestive and Kidney Diseases Grants DRTC P60DK020595, DK-48494, DK-063493, a Research Grant from the Keck foundation and the Blum-Kovler Foundation and the Kovler Diabetes Center.

Supplemental Materials

For the appendix and references 114–125, please see the supplemental materials, which may be found here: www.landesbioscience.com/journals/islets/article/22193