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Administration of Acylated Ghrelin Reduces Insulin Sensitivity, Whereas the Combination of Acylated Plus Unacylated Ghrelin Strongly Improves Insulin Sensitivity

Department of Medicine (C.G., F.M.M., J.A.M.J.L.J., P.J.D.D., P.V.K., L.J.H., F.B., A.J.v.d.L.), Erasmus Medical Center, 3015 GE Rotterdam, The Netherlands; Theratechnologies Inc. (T.A.), Montréal, Québec, Canada H4S 2A4; and Section 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: C. Gauna, M.D., Section of Endocrinology, Department of Medicine, Room Ee542, Erasmus Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail: c.gauna{at}erasmusmc.nl.

We investigated the metabolic actions of ghrelin in humans by examining the effects of acute administration of acylated ghrelin, unacylated ghrelin, and the combination in eight adult-onset GH-deficient patients. We followed glucose, insulin, and free fatty acid concentrations before and after lunch and with or without the presence of GH in the circulation.

We found that acylated ghrelin, which is rapidly cleared from the circulation, induced a rapid rise in glucose and insulin levels. Unacylated ghrelin, however, prevented the acylated ghrelin-induced rise in insulin and glucose when it was coadministered with acylated ghrelin. Surprisingly, the injection of acylated ghrelin induced an acute increase in unacylated ghrelin and therefore total ghrelin levels. Finally, acylated ghrelin decreased insulin sensitivity up to the end of a period of 6 h after administration. This decrease in insulin sensitivity was prevented by coinjection of unacylated ghrelin. This combined administration of acylated and unacylated ghrelin even significantly improved insulin sensitivity, compared with placebo, for at least 6 h, which warrants studies to investigate the long-term efficacy of this combination in the treatment of disorders with disturbed insulin sensitivity.

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