title: Systems analysis of GLP-1 receptor signaling in pancreatic β-cells.
abstract: Glucagon-like peptide-1 (GLP-1) elevates intracellular concentration of cAMP ([cAMP]) and facilitates glucose-dependent insulin secretion in pancreatic β-cells. There has been much evidence to suggest that multiple key players such as the GLP-1 receptor, G(s) protein, adenylate cyclase (AC), phosphodiesterase (PDE), and intracellular Ca(2+) concentration ([Ca(2+)]) are involved in the regulation of [cAMP]. However, because of complex interactions among these signaling factors, the kinetics of the reaction cascade as well as the activities of ACs and PDEs have not been determined in pancreatic β-cells. We have constructed a minimal mathematical model of GLP-1 receptor signal transduction based on experimental findings obtained mostly in β-cells and insulinoma cell lines. By fitting this theoretical reaction scheme to key experimental records of the GLP-1 response, the parameters determining individual reaction steps were estimated. The model reconstructed satisfactorily the dynamic changes in [cAMP] and predicted the activities of cAMP effectors, protein kinase A (PKA), and cAMP-regulated guanine nucleotide exchange factor [cAMP-GEF or exchange protein directly activated by cAMP (Epac)] during GLP-1 stimulation. The simulations also predicted the presence of two sequential desensitization steps of the GLP1 receptor that occur with fast and very slow reaction rates. The cross talk between glucose- and GLP-1-dependent signal cascades for cAMP synthesis was well reconstructed by integrating the direct regulation of AC and PDE by [Ca(2+)]. To examine robustness of the signaling system in controlling [cAMP], magnitudes of AC and PDE activities were compared in the presence or absence of GLP-1 and/or the PDE inhibitor IBMX.(1).
authors: Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Japan.
authors: Yukari
authors: Y
authors: Takeda
authors: Akira
authors: A
authors: Amano
authors: Akinori
authors: A
authors: Noma
authors: Yasuhiko
authors: Y
authors: Nakamura
authors: Shimpei
authors: S
authors: Fujimoto
authors: Nobuya
authors: N
authors: Inagaki
mesh_terms: D000818:Animals; D019295:Computational Biology / Q000379:methods*; D000067757:Glucagon-Like Peptide-1 Receptor; D050417:Insulin-Secreting Cells / Q000502:physiology*; D008954:Models, Biological; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013597:Systems Analysis
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D018027:Receptors, Glucagon