Fig. 6

(a) Model of the molecular mechanisms involved in GLP-1 secretion from intestinal L-cells and insulin secretion from pancreatic β-cells. A schematic summary of the results. We demonstrated the commonality that GLP-1 from intestinal L-cells and insulin from pancreatic β-cells are synergistically regulated by Gs signaling and glucose. We also highlighted that the main pathways of GLP-1 and insulin secretion are different; Gs signaling in L-cells and glucose in β-cells. In intestinal L-cells, bile acids (acting on GPBAR1) and L-glutamine (acting on TAS1R3) stimulate GLP-1 secretion via protein kinase A and EPAC1/2 (the main pathway). A glucose-induced signal amplifies GLP-1 secretion (the amplification pathway). Suppression of adenylyl cyclase (AC) activity via SSTR2,5-Gi activation by pasireotide drastically inhibits GLP-1 secretion by shutting down the main pathway. In pancreatic β-cells, high glucose stimulates insulin secretion (the main pathway). GLP-1-amplified insulin secretion via protein kinase A and EPAC1/2 (the amplification pathway). Suppression of adenylyl cyclase (AC) activity via SSTRs-Gi activation by pasireotide inhibits insulin secretion, which can be overcome by GLP-1 analogs (b) Synergy between glucose and Gs-coupled GPCR agonist for GLP-1 and insulin secretion. We demonstrated that the main pathway can independently stimulate hormone secretion, even if the amplification pathway is suppressed (Gs activation is suppressed by PAS or in a low glucose state). In contrast, the amplification pathway cannot stimulate hormone secretion when the main pathway is significantly suppressed (Gs activation is suppressed by PAS or in a low glucose state). However, it can potentiate hormone secretion induced by the main pathway. PAS: pasireotide. Intestinal L-cells (left , drawn in green) . Gs-coupled GPCR agonists, such as bile acids or L-glutamine, can independently stimulate GLP-1 secretion in the low-glucose (0.1 mM) state (+, upper-right column). A high glucose (25 mM) level can stimulate GLP-1 secretion under “basal” Gs activation, that is, Gs-coupled receptor activation without agonists; however, it cannot stimulate GLP-1 secretion when Gs activation is significantly suppressed by pasireotide (−, lower-left column). However, a high glucose level can potentiate Gs-coupled GPCR-stimulated GLP-1 secretion (++, lower-right column). Pancreatic β-cells (right , drawn in orange) . A high glucose (20 mM) level can independently stimulate insulin secretion even when Gs activation is significantly suppressed by pasireotide (+, lower-left column). In contrast, Gs-coupled GPCR agonists such as GLP-1 cannot independently stimulate insulin secretion in the low-glucose (2 mM) state (−, upper-right column), but they can potentiate insulin secretion stimulated by high glucose levels (++, lower-right column).