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A brief report

A brief report. Zeynep Oşar Istanbul Univ. Cerrahpaşa Medical Faculty Division for Endocrinology, Metabolism and Diabetes. Topics summarized. I ncretin biology Their role of in the treatment of type 2 diabetes mellitus . GLP1 and incretin biology. Type 2 diabetes-advances in therapy.

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A brief report

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  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

  4. Type 2 diabetes-advances in therapy

  5. Incretins • The hormonal factorsimplicated as transmitters of signalsfrom the gut to pancreatic beta-cells • Secondary control system of glucose homeostasis after meal intake • GIP & GLP1 members of the glucagon peptide superfamilyand share considerable aminoacid identity.

  6. 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 Incretins GIP GLP1 Drucker DJ. Diabetes Care 2003.

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

  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. 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 Actions GIP GLP1

  10. Effects on insulin secretion

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

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

  14. Effects on beta cell mass

  15. 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 GLP-1 improves beta cell survival and mass Drucker D et al. C Met 2006;4:391–406.

  16. Effects beyond incretin

  17. Effects beyond incretin • 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 GLP1 Peripheral circulation Portal circulation Sensor+GLUT2 & GLP1-R Beta cells & GLPR Stimulation of glucose utilization Burcelin R et al. Diabetes 50:1720–1728, 2001

  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.

  26. 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. JClin Invest 2007; 117: 24-31

  27. 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. DiabetesCare 2005; 28: 1092–00. Kendall DM et al. Diabetes Care2005; 28: 1083–91.

  28. 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 andpostprandial glucose • Reduction in HbA1c by up to 1.75 % • Weight neutral or modest weight loss • Nausea, vomiting,and diarrhoea Drucker D. JClin Invest 2007; 117: 24-31

  29. DPP4 Inhibitors • Reduced DPP4 activity by more than 80% maintained for 24 h withonce daily treatment • Vildagliptin 100mg od and Sitagliptin 100mg od as effective as rosiglitazone inmonotherapy, significant reductions in HbA1c combinationwith metformin • Adverse effects: No significant hypoglycaemia or weight gain • Inhibition of lymphocyte proliferation ? • Fewer data for saxagliptin and denagliptin Raz I et al. Diabetologia2006; 49: 2564–71. Garber A et al. Diabetes 2006;55 (suppl 1): 29.

  30. Contrasting actions of GLP1-R agonsits and DPP4 inhibitors Drucker D. JClin Invest 2007; 117: 24-31

  31. 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-specificglucose 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.

  32. Campain for the Promotion of Physical Activity

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