Abstract
Glucagon secretion from pancreatic alpha-cells is dysregulated in diabetes. Despite decades of investigations of the control of glucagon release by glucose and hormones, the underlying mechanisms are still debated. Recently, mathematical models have been applied to investigate the modification of electrical activity in alpha-cells as a result of glucose application. However, recent studies have shown that paracrine effects such as inhibition of glucagon secretion by glucagon-like peptide 1 (GLP-1) or stimulation of release by adrenaline involve cAMP-mediated effects downstream of electrical activity. In particular, depending of the intracellular cAMP concentration, specific types of Ca(2+) channels are inhibited or activated, which interacts with mobilization of secretory granules. To investigate these aspects of alpha-cell function theoretically, we carefully developed a mathematical model of Ca(2+) levels near open or closed Ca(2+) channels of various types, which was linked to a description of Ca(2+) below the plasma membrane, in the bulk cytosol and in the endoplasmic reticulum. We investigated how the various subcellular Ca(2+) compartments contribute to control of glucagon-exocytosis in response to glucose, GLP-1 or adrenaline. Our studies refine previous modelling studies of alpha-cell function, and provide deeper insight into the control of glucagon secretion.