Abstract
Insulin secretory in pancreatic beta-cells responses to nutrient stimuli and hormonal modulators include multiple messengers and signaling pathways with complex interdependencies. Here we present a computational model that incorporates recent data on glucose metabolism, plasma membrane potential, G-protein-coupled-receptors (GPCR), cytoplasmic and endoplasmic reticulum calcium dynamics, cAMP and phospholipase C pathways that regulate interactions between second messengers in pancreatic beta-cells. The values of key model parameters were inferred from published experimental data. The model gives a reasonable fit to important aspects of experimentally measured metabolic and second messenger concentrations and provides a framework for analyzing the role of metabolic, hormones and neurotransmitters changes on insulin secretion. Our analysis of the dynamic data provides support for the hypothesis that activation of Ca2+-dependent adenylyl cyclases play a critical role in modulating the effects of glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP) and catecholamines. The regulatory properties of adenylyl cyclase isoforms determine fluctuations in cytoplasmic cAMP concentration and reveal a synergistic action of glucose, GLP-1 and GIP on insulin secretion. On the other hand, the regulatory properties of phospholipase C isoforms determine the interaction of glucose, acetylcholine and free fatty acids (FFA) (that act through the FFA receptors) on insulin secretion. We found that a combination of GPCR agonists activating different messenger pathways can stimulate insulin secretion more effectively than a combination of GPCR agonists for a single pathway. This analysis also suggests that the activators of GLP-1, GIP and FFA receptors may have a relatively low risk of hypoglycemia in fasting conditions whereas an activator of muscarinic receptors can increase this risk. This computational analysis demonstrates that study of second messenger pathway interactions will improve understanding of critical regulatory sites, how different GPCRs interact and pharmacological targets for modulating insulin secretion in type 2 diabetes.
Highlights
Insulin release from the pancreatic β-cells must respond acutely to meet the insulin demands of the organism
We have previously focused on applying this mathematical modeling approach to mechanisms of glucose sensing of insulin secretion, Ca2+ and cyclic AMP (cAMP) dynamics, electrophysiology events and exocytosis in pancreatic β-cells [23, 25, 29,30,31,32,33,34]
We modeled the processes of desensitization of glucagon-like peptide1 receptor (GLP-1R), G-protein-coupled receptor (GIPR) and adrenergic receptors (AdR) as a simplified mechanism that includes only one step for the active state pass off or recirculation of G protein coupled receptors (GPCRs), because these mechanisms are not well studied
Summary
Insulin release from the pancreatic β-cells must respond acutely to meet the insulin demands of the organism. We analyzed interactions of clinically relevant GPCR agonists We included those responding to the neurotransmitters acetylcholine and catecholamines with stimulation and inhibition of insulin secretion, respectively, to the incretin hormones GLP-1 and GIP with potentiation of GSIS, and the agonists for the free fatty acid (FFA) receptor (e.g., FFAR1/GPR40) and determined how combinations of different agonists affect second messenger dynamics in β-cell. Biochemical and structural studies have led to a model of class B1 GPCR activation by peptide hormones including GLP-1 and GIP, referred to as the “two-step” mechanism [72] This corresponds to collision coupling, where an agonist binds to the free receptor and the agonist-receptor complex ‘‘collides” with the free G-protein.
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