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A brief report Zeynep Oşar Istanbul Univ. Cerrahpaşa Medical Faculty Division for Endocrinology, Metabolism and Diabetes Topics summarized Incretin biology Their role of in the treatment of type 2 diabetes mellitus 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) 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) 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. Incretins GIP 42 amino acid peptide Released from duodenal and proximal jejunal K cells NH2 terminal inactivation by DPP-4 GLP1 30/31 aminoacid peptide Released from L cells in distal small bowel and colon NH2 terminal inactivation by DPP-4 Drucker DJ. Diabetes Care 2003. Incretin receptor: A G-protein coupled receptor GIPR Islet ß-cells Adipose tissue GLP1-R Islet - and ß-cells CNS Osteoblasts Periperal CNS Heart NS Kidney Lung Gastrointestinal tract 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. GIP 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 GLP1 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 Effects on insulin secretion Insulin levels after glucose challenge in GIPR deficient mice Plasma insulin (pg/ml)) 1200 1000 800 GIPR-/Wild 600 * 400 * 200 0 0 10 20 30 Time (min) Miyavaki K et al. Proc Natl Acad Sci 1999; 96:14843–14847. Plasma glucose excursions after glucose chalenge in GIPR deficient mice 450 Blood glucose (mg/dl) 400 * 350 300 * 250 GIPR-/- 200 Wild 150 100 50 0 0 10 20 30 60 90 120 Time (min) Miyavaki K et al. Proc Natl Acad Sci 1999; 96:14843–14847. 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 Plasma İnsulin (ng/ml) 2,5 ## 2 § 1,5 §§ 1 WT GLP-1R-/GIPR-/DoubleKO 0,5 0 0 ##p<0.01 vs double KO § p< 0.005 vs. double KO §§ p < 5 × 10–4 vs. WT controls Time (min) 15 Preitner F et al. J Clin Invest 2004; 113:635–645. Effects on beta cell mass GLP-1 improves beta cell survival and mass Modulation of ER stress Increased levels of cAMP, Akt, and IRS Adaptation to metabolic and cellular stress Prevention of beta cell apoptosis & proliferation Reduced expression and reduced activation of Upregulation of expression of genes (glucokinase, GLUT 2) Increased mitotic activity Promotes differentiation of duct progenitor cells effector caspases Decreased glucolipotoxicity Drucker D et al. C Met 2006;4:391–406. Effects beyond incretin Effects beyond incretin GIPR on adipocytes Stimulation Fat of LPL 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. 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. Targets of GLP-1 Hepatoportal sensors Nervous system The effects GLP-1 on hepatoportal sensors L cells GLP1 Portal circulation Sensor+GLUT2 & GLP1-R Stimulation of glucose utilization Peripheral circulation Beta cells & GLPR Burcelin R et al. Diabetes 50:1720–1728, 2001 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. Incretins as therapeutic agents Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulindependent) diabetic patients. Nauck MA et al. Diabetologia 1993. 36:741-744. GLP1 agonists Exenatide Liraglutide Exenatide LAR 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. 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 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. 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 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. Contrasting actions of GLP1-R agonsits and DPP4 inhibitors GLP1R agonists DPP4 Inhibitors Administration Injection Orally available GLP1 concentrations Pharmacological Physiological Mechanisms of action GLP1 GLP1 plus GIP Activ. of portal gluc. sensor No Yes Increased insulin secretion Yes Yes Reduced glucagon secretion Yes Yes Gastric emptying Inhibited No effect Weight loss Yes No Expansion of beta cell mass Yes Yes Nausea/vomitting Yes No Potential immunogenicity Yes No Drucker D. J Clin Invest 2007; 117: 24-31 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-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. 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