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Division of Endocrinology (C.G., P.J.D.D., L.J.H., J.A.M.J.L.J., F.B., A.J.v.d.L.), Department of Internal Medicine, Erasmus MC, 3015 GE Rotterdam, The Netherlands; Division of Endocrinology (R.J.M.R.), Sheffield University, Clinical Sciences, Northern General Hospital, Sheffield S5 7AU, United Kingdom; and Division of Endocrinology and Metabolism (F.B., E.G.), Department of Internal Medicine, University of Turin, 10126 Turin, Italy
Address all correspondence and requests for reprints to: Carlotta Gauna, M.D., Department of Internal Medicine, Section of Endocrinology, Room Ee542, Erasmus MC, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail: c.gauna{at}erasmusmc.nl.
Ghrelin exerts various metabolic activities, including regulation of glucose levels in humans. To verify whether the glucose response to ghrelin reflects a modulation of an insulin-independent hepatic phenomenon, we studied glucose output by primary porcine hepatocytes in suspension culture, after incubation with acylated ghrelin (AG), unacylated ghrelin (UAG), and hexarelin (HEX). AG induced glucose output dose dependently after 20 min of incubation (P < 0.001), whereas HEX, a GH secretagogue receptor type 1a (GHS-R1a) agonist, had no effect. UAG inhibited glucose release also dose dependently and after 20 min (P < 0.001). Moreover, UAG completely reversed AG-induced glucose output (P < 0.01). Using real-time PCR, GHS-R1a gene expression was undetectable in all the hepatocyte preparations studied. The lack of efficacy of HEX, the efficacy of UAG, and the absence of GHS-R1a expression indicate the involvement of a yet uncharacterized ghrelin receptor type.
In conclusion, glucose output by primary hepatocytes is time- and dose-dependently stimulated by AG and inhibited by UAG. Moreover, UAG counteracts the stimulatory effect of AG on glucose release. These actions might be mediated by a different receptor than GHS-R1a, and apparently, we must consider AG and UAG as separate hormones that can modify each other’s actions on glucose handling, at least in the liver.
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