Synchronizing Calpha2 + and cAMP oscillations in pancreatic beta-cells: a role for glucose metabolism and GLP-1 receptors? Focus on 'Regulation of cAMP dynamics by Ca~(2+) and G protein-coupled receptors in the pancreatic beta-cell: a computational a

摘要

the hormonal ACTrvATiON of cAMP production in pancreatic beta-cells is accompanied by an increase of cytosolic [cAMP] that can be measured in real time through the use of a cAMP sensor (Epacl-camps) that exhibits a decrease of fluorescence resonance energy transfer (FRET) when it binds to cAMP (9, 15, 18). When this cAMP sensor is paired with the fluorescent Ca~(2+) indicator fura-2, it is possible to perform simultaneous measurements of cytosolic [cAMP] and [Ca~(2+)] in single living beta-cells (9). Studies performed in this manner have revealed oscillations in the levels of both second messengers, a phenomenon that can be imaged to evaluate the spatial distribution and temporal dynamics of cAMP and Ca~(2+) (15). Fridlyand et al. (6) now report a new mathematical model that seeks to explain how oscillations of cAMP and Ca~(2+) are generated. A primary focus of the model is glucagon-like peptide-1 (GLP-1), a blood glucose-lowering hormone that stimulates beta-cell cAMP production and that also potentiates glucose-stimulated insulin secretion (4, 7, 12-14). An additional focus of the model concerns D-glucose, a metabolizable sugar that increases the cytosolic [Ca~(2+)] of beta-cells and that is generally considered to be the primary physiological stimulus regulating beta-cell insulin secretion (11). The computational approach devised by Fridlyand et al. is of interest because it may help resolve a long-standing debate within the field of endocrinology: specifically, how do GLP-1 and glucose metabolism interact to stimulate insulin secretion from beta-cells?