A role of PLC/PKC-dependent pathway in GLP-1-stimulated insulin secretion

Glucagon-like peptide-1 (glp-1) is an endogenous glucose-lowering hormone and glp-1 receptor agonists are currently being used as antidiabetic drugs clinically. the canonical signalling pathway (including camp, epac2, protein kinase a (pka) and katp channels) is almost universally accepted as the main mechanism of glp-1-stimulated insulin secretion. this belief is based on in vitro studies that used nanomolar (1–100 nm) concentrations of glp-1. recently, it was found that the physiological concentrations (1–10 pm) of glp-1 also stimulate insulin secretion from isolated islets, induce membrane depolarization and increase of intracellular [ca2+] in isolated β cells/pancreatic islets. these responses were unaffected by pka inhibitors and occurred without detectable increases in intracellular camp and pka activity. these pka-independent actions of glp-1 depend on protein kinase c (pkc), involve activation of the standard glp-1 receptor (glp1r) and culminate in activation of phospholipase c (plc), leading to an elevation of diacylglycerol (dag), increased l-type ca2+ and trpm4/trpm5 channel activities. here, we review these recent data and contrast them against the effects of nanomolar concentrations of glp-1. the differential intracellular signalling activated by low and high concentrations of glp-1 could provide a clue to explain how glp-1 exerts different function in the central nervous system and peripheral organs.