Differential incretin effects of GIP and GLP-1 on gastric emptying, appetite, and insulin-glucose homeostasis T. EDHOLM,* M. DEGERBLAD,  P. GRYBA ¨ CK, à L. HILSTED,§ J. J. HOLST, – H. JACOBSSON, à S. EFENDIC,   P. T. SCHMIDT* & P. M. HELLSTRO ¨ M** *Department of Medicine, Karolinska Institutet Solna, Stockholm, Sweden  Department of Molecular Medicine and Surgery, Karolinska Institutet Solna, Stockholm, Sweden àDepartment of Nuclear Medicine, Karolinska Institutet Solna, Stockholm, Sweden §University Department of Clinical Chemistry, Rigshospitalet, Copenhagen, Denmark –Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark **Gastroenterology Unit, Department of Medical Sciences, Uppsala University, Uppsala, Sweden Abstract Background Glucose-dependent insulinotropic poly- peptide (GIP) and glucagon-like peptide-1 (GLP-1) are major incretins with important effects on gluco- regulatory functions. The aim of this study was to investigate effects of GIP and GLP-1 on gastric emp- tying and appetite after a mixed meal, and effects on insulin secretion and glucose disposal in humans. Methods Randomized crossover single-blind study in 17 healthy volunteers receiving GIP (2 or 5 pmol kg )1 min )1 , n = 8), GLP-1 (0.75 pmol kg )1 min )1 , n = 9) or NaCl for 180 min with a radionuclide-labeled ome- lette and fruit punch (370 kcal). Outcome measures were gastric emptying rate, insulinogenic index, hun- ger, satiety, desire to eat, and prospective food consumption. Blood was analyzed for GIP, GLP-1, glucagon, C-peptide, peptide YY (PYY) and ghrelin. Key Results Glucose-dependent insulinotropic poly- peptide 2 and 5 pmol kg )1 min )1 decreased gastric half-emptying time from 128.5 ± 34.0 min in controls to 93.3 ± 6.3 and 85.2 ± 11.0 min (P < 0.05). Glucose- dependent insulinotropic polypeptide 5 pmol kg )1 min )1 decreased postprandial glucose (P < 0.001) and insulin (P < 0.05) with increased insulinogenic index. Glucose-dependent insulinotropic polypeptide had no effects on hunger, desire to eat, satiety or prospective consumption. Glucagon-like peptide-1 0.75 pmol kg )1 min )1 increased half-emptying time from 76.6 ± 7.6 min to 329.4 ± 71.6 (P < 0.01). Glucagon-like peptide-1 decreased plasma glucose and insulin (both P < 0.05– 0.001), and increased insulinogenic index markedly. Hunger, desire to eat and prospective consumption were decreased (P < 0.05), and satiety borderline increased (P < 0.06). Conclusions & Inferences The incretin effect of GIP and GLP-1 differs as GLP-1 exerts a strong glucoregulatory incretin through inhi- bition of gastric emptying, which GIP does not. Thus, GLP-1 as incretin mimetic may offer unique benefits in terms of weight loss in treatment of type 2 diabetes. Keywords appetite, gastrointestinal hormones, glucagon-like peptide, glucose metabolism, insulin signaling. INTRODUCTION After a meal several gut hormones are released into the circulation from enteroendocrine cells. Some of these hormones have the capability to enhance insulin secretion beyond the release caused by an equal amount of energy (glucose) given intravenously (i.v.). This so-called the incretin effect contributes to 50–70% of the total postprandial insulin secretion. 1–3 The most important incretin hormones are glucose- dependent insulinotropic polypeptide (GIP) 4,5 and glu- cagon-like peptide-1 (GLP-1). 6 Glucose-dependent insulinotropic polypeptide is released from endocrine K-cells in the duodenum after ingestion of carbohydrates and fat 4,5 and was first identified due to its ability to decrease gastric acid secretion in dog. 7 Glucose-dependent insulinotropic Address for Correspondence Per M. Hellstro ¨ m, MD, PhD, Gastroenterology Unit, Depart- ment of Medical Sciences, Uppsala University Hospital, bldg 40, SE-751 85, Uppsala, Sweden. Tel: +46 18 6114285; fax: +46 18 5643693; e-mail: per.hellstrom@medsci.uu.se Received: 4 March 2010 Accepted for publication: 1 June 2010 Neurogastroenterol Motil (2010) 22, 1191–e315 doi: 10.1111/j.1365-2982.2010.01554.x Ó 2010 Blackwell Publishing Ltd 1191