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.

ATP-regulated potassium channels and voltage-gated calcium channels in pancreatic alpha and beta cells: similar functions but reciprocal effects on secretion

“…The Orai1-dependent mechanism has recently been reviewed elsewhere [59]. It is noteworthy that the K ATP channel-and Orai1-dependent mechanisms for the intrinsic regulation of glucagon secretion predict opposite effects on the alpha cell membrane potential [60,61]. Our data showing that glucose depolarises rather than repolarises the alpha cell are not consistent with a major role of Orai1 in glucagon secretion, but this does not exclude a modulatory role.…”

“…This explains why glucagon secretion is stimulated rather than inhibited by glucose in type 2 diabetic islets. The electrophysiological and secretory responses shown here schematically have recently been substantiated by computational analyses [60].…”

Mathematical modelling of local calcium and regulated exocytosis during inhibition and stimulation of glucagon secretion from pancreatic alpha‐cells

“…). Although alpha‐cell electrical activity is well studied (Diderichsen & Göpel, ; Fridlyand & Philipson, ; Watts & Sherman, ), coupling to exocytosis is not. Therefore, our model couples the electrical activity and exocytosis to give a unified picture of the main mechanisms that control glucagon secretion; we characterize the complete Ca 2+ dynamics with particular attention to the modelling of microdomain Ca 2+ concentrations surrounding the P/Q‐ and L‐type Ca 2+ channels involved in glucagon release.…”

“…The devised mathematical model of electrical activity and exocytosis in mouse alpha-cells is an updated version of previous models (Diderichsen & Göpel, 2006;Watts & Sherman, 2014) based on recent experimental data (De Marinis et al 2010;Zhang et al 2013). Although alpha-cell electrical activity is well studied (Diderichsen & Göpel, 2006;Fridlyand & Philipson, 2012;Watts & Sherman, 2014), coupling to exocytosis is not. Therefore, our model couples the electrical activity and exocytosis to give a unified picture of the main mechanisms that control glucagon secretion; we characterize the complete Ca 2+ dynamics with particular attention to the modelling of microdomain Ca 2+ concentrations surrounding the P/Qand L-type Ca 2+ channels involved in glucagon release.…”

“…Very recently, Watts & Sherman (2014) presented an updated version of the model presented by Diderichsen & Göpel (2006), by including Ca 2+ dynamics and secretion. Similarly, Fridlyand & Philipson (2012) presented theoretical studies of electrical activity, Ca 2+ dynamics and secretion. In these studies, the main focus was on the regulation of alpha-cell electrical activity (Diderichsen & Göpel, 2006;Fridlyand & Philipson, 2012;Watts & Sherman, 2014), whereas exocytosis and secretion were mainly a read-out of electrical activity.…”