Figure 1.

Modulation of insulin secretion by FFA2 and FFA3.

Glucose once internalized in β cells is metabolized which results in elevation of ATP:ADP ratio, closure of K_ATP channels, cell membrane depolarization, opening of voltage dependent calcium channels (Ca²⁺ channels) causing calcium influx triggering insulin vesicle exocytosis. SCFAs (acetate and propionate) can bind to FFA2 and FFA3 either amplifying (in blue) or diminishing (in golden) glucose stimulated insulin secretion. Upon ligand activation of FFA2, Gα_q/11 subunits activate PLC which hydrolyses PIP₂ to DAG and IP₃ which in turn activates PKC and releases calcium from ER stores, respectively, amplifying the insulin release. FFA2, like FFA3, can also couple with Gα_i/o subunits and inhibit AC, which decreases the concentration of cAMP, inhibiting PKA and EPAC mediated insulin release.

Abbreviations: AC, adenylate cyclase; cAMP, cyclic AMP; DAG, diacylglycerol; EPAC, exchange protein directly activated by cAMP; ER, endoplasmic reticulum; FFA2, free fatty acid receptor 2; FFA3, free fatty acid receptor 3; IP₃, inositol triphosphate; K_ATP channels, ATP sensitive potassium channels; PLC, phospholipase C; PIP₂, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase C; PKA, protein kinase A; SCFAs, short chain fatty acids. Green circle for acetate and yellow triangle for propionate.