Mathematical Modeling of Human Pancreatic Alpha-Cells: Insight into the Role of SGLT2 in Glucagon Secretion

Abstract

Pancreatic alpha-cells, which secrete the glucose promoting hormone glucagon, have regained renewed interest as it has become evident that dysfunctional glucagon secretion contributes to the development of diabetes. In contrast to the well-studied insulin-secreting pancreatic beta-cells, the control of glucagon release is still poorly understood. Recently it was shown that inhibitors of the sodium glucose co-transporters SGLT2, which are used as anti-diabetic drugs, increase glucagon secretion and hepatic glucose production. Following studies showed that pancreatic alpha-cells express SGLT2 and their inhibition augments glucagon secretion in isolated human pancreatic islets, suggesting a direct effect of the SGLT2 inhibitors on the alpha-cells.The mechanisms by which SGLT2 contribute to control of alpha-cell function are far from clear. Besides transporting glucose into the cell, SGLT2 are electrogenic. Here we investigate the electrophysiological effects of SGLT2 by building the first mathematical model of electrical activity in human pancreatic alpha-cells. The model is of Hodgkin-Huxley type, and includes all major currents of human alpha-cells. Individual currents were carefully fitted to published data from human alpha-cells. A six-state model of SGLT2 sodium-glucose co-transport and the related currents was also inserted in the model.We show that the SGLT2 current lowers the height of simulated action potentials (APs), and consequently, that SGLT2 inhibition allows full APs to develop, which would augment glucagon secretion. The underlying mechanisms of SGLT2-mediated reduction of AP peaks are complex, and involve inactivation of Na+ and Ca2+ currents contributing to the upstroke of the AP. Calculations of SGLT2-dependent glucose influx suggests that the major part of glucose uptake in alpha-cells is due to GLUT1 glucose transporters, and hence that SGLT2 inhibition primarily stimulates glucagon secretion via electrophysiological mechanisms, and not simply because of a reduction of glucose uptake.