The role of incretin peptides and ghrelin in upper gut motility and metabolic control

Metabolic control is essential for the individual and is strictly regulated via a wide range of factors. One important mechanism in maintaining an adequate blood sugar level is the regulation of insulin release and gastric emptying rate by gastrointestinal (GI) hormones. The aims of this study was to (1) investigate the effects of the two incretin hormones GIP and GLP-1 on insulin secretion and small bowel motility in a rat model of diabetes type 2 and (2) to investigate the effect of GIP and GLP-1 on gastric emptying, metabolic control and appetite after intake of a mixed meal in man. In addition, I (3) studied the effects of ghrelin on smooth muscle contractility in rat and (4) its effect on gastric emptying in humans after intake of a mixed meal. The effect of GIP and GLP-1 on insulin secretion was studied in isolated perfused pancreas in a rat model of diabetes type 2. Migrating motor complex (MMC) is a marker for small bowel motility recorded by electromyography. The effect of GIP and GLP-1 was studied in both diabetic and non-diabetic rats. In man, gastric emptying during GIP or GLP-1 infusion was investigated scintigraphically after intake of a 99Tc-labelled omelette. Simultaneously, appetite ratings were measured using visual analogue score (VAS) and blood samples collected for later analysis of GI hormones, e.g. insulin, glucagon, PYY, GLP-1, GIP and ghrelin by radioimmunoassay (RIA). GIP and GLP-1 stimulated insulin secretion in normal rats. The basal insulin level was higher in diabetic rats and insulin response to glucose stimulation was severely impaired. The potentiatory effect of both GIP and GLP-1 on glucose-induced insulin secretion was preserved in diabetic animals, being even more pronounced than in controls. In diabetic and non-diabetic animals GIP and GLP-1 showed a similar inhibition of small bowel motility. GIP induced a small acceleration of gastric emptying in man, whereas GLP-1 potently inhibited gastric emptying. Both peptides showed a trend towards increased insulinogenic index. GIP did not affect appetite, while GLP-1 decreased hunger and increased satiety. The effect of ghrelin was studied on isotonic contractions of smooth muscle strips of the gastric fundus and jejunum in an organ bath. MMC was studied during intravenous infusion of ghrelin in normal, atropinised and vagotomised rats. The effects of ghrelin on gastric emptying, VAS and GI hormones were studied in the same way as for GIP and GLP-1. Ghrelin caused dose-dependent contraction of the fundus and jejunum. Pre-treatment with atropine abolished the response. Ghrelin also dose-dependently shortened the MMC. In man, ghrelin accelerated gastric emptying followed by increased hunger and deceased satiety. The effect was independent of growth hormone (GH) secretion. In conclusion, there is an insulinotropic effect of GIP and GLP-1 in both normal and diabetic rat and in man. Novel finding is that GIP accelerates gastric emptying, whereas GLP-1 inhibits it. Ghrelin stimulates motility in vitro and in vivo in rat and accelerates gastric emptying in man. Moreover, both GLP-1 and ghrelin seems to have independent effects on appetite, which make them interesting tools for the study of diabetes type 2, diabetes type 1 as well as obesity. lisT of PublicaTions I Edholm T, Cejvan C, Efendic S, Holst JJ, Schmidt PT, Hellstrom PM. The incretin hormones GIP and GLP-1 in diabetic rats: Effects on motility and insulin secretion. (manuscript) II Edholm T, Gryback P, Lundberg S, Schmidt PT, Hellstrom PM. The incretin hormones GIP and GLP-1 in healthy volunteers: Effects on gastric emptying rate and insulin response. (manuscript) III Edholm T, Levin F, Hellstrom PM, Schmidt PT. Ghrelin stimulates motility in the small intestine of rats through intrinsic cholinergic neurons. Regul Pept. 2004, 121:25-30. IV Levin F, Edholm T, Schmidt PT, Gryback P, Jacobsson H, Degerblad M, Hoybye C, Holst JJ, Rehfeld JF, Hellstrom PM, Naslund E. Ghrelin stimulates gastric emptying and hunger in normal weight humans. J Clin Endocrinol Metab. 2006, 91:3296-3302. LisT of abbreviaTions Ach acethylcholine AUC area under the curve CCK cholecystokinin DD diabetic diarrhoea DFZ diabetic fatty zucker rat DPP IV dipeptidyl-peptidase IV ENS enteric nervous system GH growth hormone GHD growth hormone-deficient GHS-R growth hormone secretagogue receptor GI gastrointestinal GIP glucose-dependent insulinotropic polypeptide GK goto-kakizaki rat GLP-1 glucagon-like peptide-1 GPCR G-protein coupled receptor i.p. intraperitoneal i.v. intravenous MMC migrating myoelectric complex PI 3-K phosphoinositide-3-kinas PKA protein kinas A PKB protein kinas B PP pancreatic polypeptide