Quantitative Analysis of Receptors and Second Messengers Interactions in Pancreatic Beta Cell

Abstract

The response of insulin secretion in pancreatic beta cell to nutrient stimuli and hormonal modulators is coordinated by the different receptors, messengers and signaling networks. We present an updated computational model of second messenger interactions in pancreatic beta cell that incorporate modern data on glucose metabolism, plasma membrane potential, G-protein-coupled-receptors (GPCRs), cytoplasmic and endoplasmic reticulum calcium dynamics, cAMP and phospholipase C pathways. Model includes glucagon like peptide 1 receptor, gastric inhibitory polypeptide receptor and adrenoreceptor for cAMP pathway regulation, and the muscarinic acetylcholine receptor and the fatty acid receptor (GPR40) for phospholipase C regulation. The values of most of the model parameters were inferred from available experimental data. Our analysis of the dynamic data provides evidence for a pivotal role for Ca2+-dependent adenylyl cyclase activation in the effect of glucagon-like peptide 1 on pancreatic β-cells. The regulatory properties of various adenylyl cyclase isoforms determine fluctuations in cytoplasmic cAMP concentration and reveal a synergistic action of glucose and glucagon-like peptide 1 on insulin secretion. On other hand, the regulatory properties of phospholipase C isoforms determine interaction of glucose, acetylcholine and fatty acids (that act through the receptor GPR40). We test the hypothesis that activation of specific key beta-cell GPCRs can be in some cases stimulate but in other combinations inhibit glucose-stimulated insulin secretion. The regulation of messenger's pathway interactions may be important pharmacological targets for improving insulin secretion in type 2 diabetes.