1. Metabolic GI peptide hormones Ghrelin Insulin Glucagon Insulin Glucagon GIP GLP-1 Insulin Leptin Insulin Adiposity tissue insulin Insulin

2. Historik 1988 Glucagon-like peptide-1 Holst et al 1978. 1999 Ghrelin Kojima et al. 1999

3. Fontaine KR et al 2003 Obesity: Years of Life Lost

4. The incretin concept Moore et al 1966

5. GLUKAGON-LIKE PEPTIDE-1 GLP-1

6. Gastric feed-back loop Slow/rapid gastric emptying rate ± Intestinal inhibition ”Ileal brake”

7. GLP-1 and gastric emptying GLP-1 0.75 pmol/kg min IV Control

8. GLP-1 in obese men GLP-1 Saline Näslund et al 1998 GLP-1 Gastric emptying No difference in food intake

9. GLP-1 in obese men Saline GLP-1 0.7 pmol/kg*min Näslund 1998

10. GLP-1 and decreased food intake: Study design for GLP-1 infusion 8 h Fixed breakfast 500 kcal Lunch ad libitum + gastric emptying test Dinner ad libitum + gastric emptying test Infusion of GLP-1 0.75 pmol/kg/min IV (pump) Every hour: VAS scales for satiety hunger every hour Blood samples for glucose, insulin, glucagon, GLP-1

11. Appetite during GLP-1 infusion 8 hours Saline GLP-1 Saline GLP-1 Saline GLP-1 Saline Näslund et al 1999 **

12. GLP-1 and weight loss: Gastric emptying Gastric emptying (%) Näslund et al 2003 GLP-1 injections 30 min before a meal

13. Food intake with GLP-1 BN-GLP-SEOB-1 p < 0.02 Total intake p <0.017 n.s. Näslund et al 2003

14. GLP-1 and weight loss 5 days with GLP-1 -1,0 -0,5 0,0 0,5 1,0 1,5 Weight change (kg) Placebo GLP-1 Prandial injections Continuous infusion p <0,02 Näslund et al 2003

15. GHRELIN

16. Cummings et al 2002

17. Cummings et al 2001 Peripheral signalling: Ghrelin Insulin Leptin

18. Gastric emptying: Ghrelin and GLP-1

19. Segments of the stomach, removed and placed in cold modified Krebs-Ringer buffer. Muscle strips, 1.5 cm long, mounted in 5 ml organ bath chambers containing Krebs-Ringer buffer, bubbled with 95/5% O 2 /CO 2. Temperature maintained at 37º C. Organ bath Isometric tension continuously recorded using a Powerlab ® instrument and analysed with Chart 4.2 software.

20. Rat gastric fundus

21. 13/06/2016per.hellstrom@ki.se21

22. 13/06/2016per.hellstrom@ki.se22 Plasma glucose

23. 13/06/2016 Hunger, satiety, nausea P <0.01

24. SURGERY GASTRIC BY-PASS

25. 25 Background  Gastric bypass (GBP) surgery ameliorates diabetes early after surgery even before a significant weight loss  Proposed mechanism is increased incretin response (GLP-1)  Few studies of postprandial glucose and incretin response early (<1 week) after GBP

26. Glucose and insulin

27. GLP-1 and ghrelin

28. GHRELIN ANALOGUE TZP-101, TZP-102, ULIMORELIN

29. TZP-101: A macrocyclic peptidomimetic Agonist at the cloned, human ghrelin receptor characterized as: –Highly potent –Reversible –Selective –With a low propensity for desensitizing

30. TZP-101: Gastric Emptying in Rats Presented at Digestive Disease Week 2006 Naive (Rats were treated with morphine) TZP-101 30

31. TZP-101: Ghrelin analog in man Gastric emptying at 4 h Gastroparesis cardinal symptoms index Ejskjaer 2010 Indications or use: Diabetic gastroparesis Postinfectious gastroparesis Functional dyspepsia?

32. Pathways in the action of ghrelin and GLP-1 Gut-derived GLP-1