Ghrelin and des‐acyl ghrelin stimulate glucose output in mouse primary hepatocytes (1114.2)

Abstract

In humans, i.v. administration of ghrelin elicits an increase in glucose levels. In pig, ghrelin stimulates whereas des‐acyl ghrelin inhibits glucose output from hepatocytes. The aims of the current study were to pharmacolgically characterise the receptor responsible for the changes in glucose release from mouse hepatocytes in response to ghrelin family ligands and compare this profile to the profile of the known ghrelin receptor expressed in HEK293 cells. Ghrelin activated GHSR1a in transfected HEK293 cells causing a release of intracellular calcium with an EC50 of 2.5 nM. Des acyl ghrelin had an EC50 > 2 µM. Hepatocytes were cultured overnight and incubated with 100 nM ghrelin, 100 nM des‐acyl ghrelin, 1 µM glucagon or vehicle for 20 minutes. Ghrelin, des‐acyl ghrelin and glucagon all significantly increased glucose output above basal levels. When glycogen stores were depleted no significant changes were seen in glucose output in response to ghrelin and des acyl ghrelin. In mouse hepatocytes ghrelin and des acyl ghrelin both stimulate glucose release. The released glucose is a product of glycogenolysis. It is likely that the actions of ghrelin and des acyl ghrelin in mouse hepatocytes are via a novel receptor as ghrelin and des acyl ghrelin are equipotent at stimulating glucose release whereas at GHSR1a des acyl ghrelin is 1000 fold less potent than ghrelin, and GHSR1a is absent or barely detectable in liver.