1. A brief report Zeynep Oşar Istanbul Univ. Cerrahpaşa Medical Faculty Division for Endocrinology, Metabolism and Diabetes

2. Topics summarized Incretin biology Their role of in the treatment of type 2 diabetes mellitus

3. GLP1 and incretin biology The role of GIP in glucose, lipid and calcium homeostasis Y. Yamada (Japan) Incretin action and the neural control of glucose homeostasis R. Burcelin (France) The islet beta cell: a critical target for acute and chronic incretin action D. Drucker (Canada) Incretin action in type 2 diabetes: mechanisms and clinical implications M.A. Nauck (Germany)

4. Type 2 diabetes-advances in therapy GLP1 agonists and DPP4 inhibitors B.Gallwitz (Germany) Exendins and related compounds MA.Nauck (Germany) PPAR agonists, glitazones and beyond U. Smith (Sweden) Endocannabinoid blockade L:Van Gaal (Belgium)

5. Incretins The hormonal factors implicated as transmitters of signals from the gut to pancreatic beta-cells Secondary control system of glucose homeostasis after meal intake GIP & GLP1 members of the glucagon peptide superfamily and share considerable aminoacid identity.

6. Incretins 42 amino acid peptide Released from duodenal and proximal jejunal K cells NH2 terminal inactivation by DPP-4 30/31 aminoacid peptide Released from L cells in distal small bowel and colon NH2 terminal inactivation by DPP-4 GIPGLP1 Drucker DJ. Diabetes Care 2003.

7. Incretin receptor: A G-protein coupled receptor GIPR  Islet ß-cells  Adipose tissue  Osteoblasts  CNS GLP1-R  Islet  - and ß-cells  CNS  Periperal NS  Heart  Kidney  Lung  Gastrointestinal tract

8. Postreceptor pathways GIP secreted from gut after nutrient stimulus Stimuli other than nutrients (neural or endocrine) in GLP-1 secretion?  Receptor interaction  Activated beta cell signalling pathways: cAMP (MAP kinase, PI3-kinase/protein kinase B?)  Increase in ic. Ca  Stimulation of insulin secretion Visboll T et al. Diabetologia 2004;47:357–366.

9. Actions Stimulates insulin secretion Promotes expansion of beta cell mass Minimal effect on gastric emptying No effect on glucagon secretion Normal GIP secretion in diabetic subjects Defective GIP reponse in type 2 DM Stimulates insulin secretion Expansion of B cell mass Inhibits gastric emptying Inhibits glucagon secretion Inhibits food intake and weight gain Reduced GLP-1 secretion in T2DM Preserved GLP-1 reponse in type 2 DM GIPGLP1

10. Effects on insulin secretion

11. * * Time (min) Plasma insulin (pg/ml)) Miyavaki K et al. Proc Natl Acad Sci 1999; 96:14843–14847. Insulin levels after glucose challenge in GIPR deficient mice

12. Plasma glucose excursions after glucose chalenge in GIPR deficient mice Blood glucose (mg/dl) Time (min) * * Miyavaki K et al. Proc Natl Acad Sci 1999; 96:14843–14847.

13. Additive effects of GLP-1 and GIP on insulin secretion Basal and peak plasma insulin levels after oral glucose load in male WT, Glp-1R–/–,Gipr–/–, and double-KO mice Time (min) Plasma İnsulin (ng/ml) Preitner F et al. J Clin Invest 2004; 113:635–645. ## § §§ ##p<0.01 vs double KO § p< 0.005 vs. double KO §§ p < 5 × 10–4 vs. WT controls

14. Effects on beta cell mass

15. GLP-1 improves beta cell survival and mass Modulation of ER stress Increased levels of cAMP, Akt, and IRS Reduced expression and reduced activation of effector caspases Decreased glucolipotoxicity Adaptation to metabolic and cellular stress Prevention of beta cell apoptosis & proliferation Upregulation of expression of genes (glucokinase, GLUT 2) Increased mitotic activity Promotes differentiation of duct progenitor cells Drucker D et al. C Met 2006;4:391–406.

16. Effects beyond incretin

17. GIPR on adipocytes  Stimulation of LPL  Fat accumulation (Role in obesity?) GIPR on osteoblasts  Ca accumulation  Inhibition of apoptosis in osteoblast  Increased osteoblastic activity  Increased bone mineral density Yamada Y et al. Diabetes 2006;55 (Suppl. 2):S86–S91. Miyawaki K et al. Proc Natl Acad Sci 1999; 96:14843–14847.

18. Acronym GIP = Gastric inhibitory polypeptide Glucose dependent insulinotropic polypeptide Gut derived nutrient intake polypeptide Yamada Y et al. Diabetes 2006;55 (Suppl. 2):S86–S91.

19. Targets of GLP-1 Hepatoportal sensors Nervous system

20. The effects GLP-1 on hepatoportal sensors L cells Beta cells & GLPR Beta cells & GLPR GLP1 Peripheral circulation Peripheral circulation Portal circulation Sensor+GLUT2 & GLP1-R Portal circulation Sensor+GLUT2 & GLP1-R Burcelin R et al. Diabetes 50:1720–1728, 2001 Stimulation of glucose utilization

21. Brain GLP-1 and its effects GLP1 secretion from cerebral cells in nucleus tractus solitarius and area postrema Activation of cerebral GLP1-R Sympatethic stimulation and increase in BP and HR Regulation of food and water intake Extrapancreatic regulation of glucose metabolism  Inhibited muscle glucose utilization  Increased insulin secretion and increased insulin resistance to favor hepatic glycogen storage Knauf C et al. J Clin Invest 2005; 115:3554–3563.

22. Incretins as therapeutic agents

23. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin- dependent) diabetic patients. Nauck MA et al. Diabetologia 1993. 36:741-744.

24. GLP1 agonists Exenatide Liraglutide Exenatide LAR

25. DPP4 Inhibitors (DPP4 is a serine protease, bound to endothelial membranes or in the soluble form) Vildagliptin Sitagliptin Saxagliptin Denagliptin (Non-selectivity for actions on the related enzymes DPP-8, DPP-9) Lankas G et al. Diabetes 2004; 54: 2988 –94. Nauck M et al. Diabetologia 2005; 48: 608–11.

27. Exenatide - 1 Naturally occurring GLP1-related peptide isolated from the venom of the lizard Heloderma suspectum 50% homology with mammalian GLP1 Potent degradationresistant agonist of GLP1 Circulating half life of 60-90 min Duration of action lasts 4-6 h Drucker D. J Clin Invest 2007; 117: 24-31

28. Exenatide - 2 5-10  g sc injections twice daily Postprandial glucose control HbA1c reductions of 0.8-1.0% in combination with OAD Prevention of weight gain or weight loss of 1-3 kg Adverse events:Nausea, vomiting, diarrhoea, hypoglycemia,antibody formation DeFronzo RA et al. Diabetes Care 2005; 28: 1092–00. Kendall DM et al. Diabetes Care 2005; 28: 1083–91.

29. Liraglutide A DPP-4-resistant GLP-1 analogue Non-covalent binding to albumin Half-life 10–14 h A once daily sc. Injection up to 0.75 mg-2 g daily Reduces fasting and postprandial glucose Reduction in HbA1c by up to 1.75 % Weight neutral or modest weight loss Nausea, vomiting, and diarrhoea Drucker D. J Clin Invest 2007; 117: 24-31

30. DPP4 Inhibitors Reduced DPP4 activity by more than 80% maintained for 24 h with once daily treatment Vildagliptin 100mg od and Sitagliptin 100mg od as effective as rosiglitazone in monotherapy, significant reductions in HbA1c combination with metformin Adverse effects: No significant hypoglycaemia or weight gain Inhibition of lymphocyte proliferation ? Fewer data for saxagliptin and denagliptin Raz I et al. Diabetologia 2006; 49: 2564–71. Garber A et al. Diabetes 2006; 55 (suppl 1): 29.

31. Contrasting actions of GLP1-R agonsits and DPP4 inhibitors Administration GLP1 concentrations Mechanisms of action Activ. of portal gluc. sensor Increased insulin secretion Reduced glucagon secretion Gastric emptying Weight loss Expansion of beta cell mass Nausea/vomitting Potential immunogenicity GLP1R agonists Injection Pharmacological GLP1 No Yes Inhibited Yes DPP4 Inhibitors Orally available Physiological GLP1 plus GIP Yes No effect No Yes No Drucker D. J Clin Invest 2007; 117: 24-31

32. Summary The incretins are hormonal factors regulating postprandial glucose metabolism. They increase beta cell mass. GIP is an obesity promoting factor and increases bone mass. Brain GLP-1 has a role in controlling whole-body and tissue-specific glucose metabolism in hyperglycemic conditions. The available evidence strongly suggests that drugs having incretinomimetic actions are promising alternatives for the treatment of type 2 diabetes mellitus.

33. Campain for the Promotion of Physical Activity