Liver-Expressed Antimicrobial Peptide 2 antagonizes the insulinostatic effect of ghrelin in rat isolated pancreatic islets.

The hormone ghrelin is the endogenous agonist of the G protein-coupled receptor (GPCR) termed growth hormone secretagogue receptor (GHSR). Ghrelin inhibits glucose-stimulated insulin secretion by activating pancreatic GHSR. Recently, Liver-Expressed Antimicrobial Peptide 2 (LEAP2) was recognized as an endogenous GHSR ligand that blocks ghrelin-induced actions. Nonetheless, the effect of LEAP2 on glucose-stimulated insulin secretion from pancreatic islets is unknown. We aimed at exploring the activity of LEAP2 on glucose-stimulated insulin secretion. Islets of Langerhans isolated from rat pancreas were exposed to glucose in the presence or in the absence of LEAP2 and ghrelin and then insulin secretion was assayed. LEAP2 did not modulate glucose-stimulated insulin secretion. However, LEAP2 blocked the insulinostatic action of ghrelin. Our data show that LEAP2 behaves as an antagonist of pancreatic GHSR.

The ellagitannin metabolite urolithin C is a glucose-dependent regulator of insulin secretion through activation of L-type calcium channels.

BACKGROUND AND PURPOSE: The pharmacology of polyphenol metabolites on beta-cell function is largely undetermined. We sought to identify polyphenol metabolites that enhance the insulin-secreting function of beta-cells and to explore the underlying mechanisms. EXPERIMENTAL APPROACH: INS-1 beta-cells and rat isolated islets of Langerhans or perfused pancreas preparations were used for insulin secretion experiments. Molecular modelling, intracellular Ca2+ monitoring, and whole-cell patch-clamp recordings were used for mechanistic studies. KEY RESULTS: Among a set of polyphenol metabolites, we found that exposure of INS-1 beta-cells to urolithins A and C enhanced glucose-stimulated insulin secretion. We further characterized the activity of urolithin C and its pharmacological mechanism. Urolithin C glucose-dependently enhanced insulin secretion in isolated islets of Langerhans and perfused pancreas preparations. In the latter, enhancement was reversible when glucose was lowered from a stimulating to a non-stimulating concentration. Molecular modelling suggested that urolithin C could dock into the Cav 1.2 L-type Ca2+ channel. Calcium monitoring indicated that urolithin C had no effect on basal intracellular Ca2+ but enhanced depolarization-induced increase in intracellular Ca2+ in INS-1 cells and dispersed cells isolated from islets. Electrophysiology studies indicated that urolithin C dose-dependently enhanced the L-type Ca2+ current for levels of depolarization above threshold and shifted its voltage-dependent activation towards more negative potentials in INS-1 cells. CONCLUSION AND IMPLICATIONS: Urolithin C is a glucose-dependent activator of insulin secretion acting by facilitating L-type Ca2+ channel opening and Ca2+ influx into pancreatic beta-cells. Our work paves the way for the design of polyphenol metabolite-inspired compounds aimed at ameliorating beta-cell function.