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Dr. Rafn Benediktsson The Diagnosis of Diabetes rests on Glucose Values * should be confirmed on a second occasion
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Dr. Rafn Benediktsson Type 2 Diabetes: Development Adapted from Saltiel AR, Olefsky JM. Diabetes 1996;45:1661-1669. Insulin resistance and declining insulin levels with impaired glucose tolerance Type 2 Diabetes Insulin resistance Insulin resistance and hyperinsulinaemia with normal glucose tolerance Impaired -cell function
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Dr. Rafn Benediktsson What is Insulin Resistance? An impaired biological response to either exogenous or endogenous insulin An impaired biological response to either exogenous or endogenous insulin Biological responses could reflect: Biological responses could reflect: –metabolic (CHO, lipid or protein metabolism) and –mitogenic processes (changes in growth, differentiation, DNA synthesis, regulation of gene transcription) Anonymous. Diabetes Care 1998; 21:310-314.
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Dr. Rafn Benediktsson Insulin Resistance: Associated Conditions Atherosclerosis Type 2 diabetes Impaired glucose tolerance Polycystic ovarian syndrome Obesity (central) Dyslipidaemia Hypertension Microalbuminuria Hyperuricemia Decreased fibrinolytic activity Insulin Resistance
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Dr. Rafn Benediktsson Risk Ratios of CV Events in Adults with Diabetes Age 35-64 3 1.8 6.1 2.8 4 3.9 9.8 9.1 1.9 Adapted from Wilson & Kannel. In Ruderman et al. Hyperglycaemia, Diabetes and Atherosclerosis 1992:21 † † † † † † * † † † p <0.001 *p < 0.05 Risk Ratio
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Dr. Rafn Benediktsson Drug Treatment in T2DM Glucose (G) Carbohydrate Glucose DIGESTIVEENZYMES Insulin (I) I I I I I I I I G G G G G G G G I G G G Acarbose Reduces absorption Sulphonylurea Repaglinide Stimulates pancreas Metformin Reduces hepatic glucose output (? muscle / fat effects) Insulin “Replaces” pancreas
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Dr. Rafn Benediktsson Lowering HbA 1C Reduces Risk of Complications * UKPDS. Lancet 1998; 352:837 *Percent risk reduction for 0.9% decrease in HbA 1C
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Dr. Rafn Benediktsson UKPDS: Value of Good Blood Pressure Control in T2DM risk reduction 37% p=0.0092
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Dr. Rafn Benediktsson 36 28 23 18 0 5 10 15 20 25 30 35 40 PlaceboGemfibrozilPlaceboGemfibrozil Patients with Diabetes n=627, P=0.05 Patients without Diabetes n=1904, P=0.009 24% Risk Reduction 24% Risk Reduction % of Patients with CHD Death, Nonfatal MI, or Stroke VA - HIT Study: Effect of Gemfibrozil on Vascular Events - 5.1 Years Rubins HB, et al. N Engl J Med 1999;341:410 % Developing a CV Event
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Dr. Rafn Benediktsson Drug Treatment in T2DM Glucose (G) Carbohydrate Glucose DIGESTIVEENZYMES Insulin (I) I I I I I I I I G G G G G G G G I G G G Acarbose Reduces absorption Sulphonylurea Repaglinide Stimulates pancreas Metformin Reduces hepatic glucose output (? muscle / fat effects) Insulin “Replaces” pancreas Thiazolidinediones (TZD)
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Dr. Rafn Benediktsson TZD = thiazolidinedione PPAR - RXR = nuclear receptors TF = transcription factors TZD: Mechanism of Insulin Sensitization TZD PPAR RXR PPAR RXR TZD TF RNA DNA Protein – signalling – downstream events RECEPTOR INSULIN Saltiel & Olefsky. Diabetes 1996;45:1661
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Dr. Rafn Benediktsson
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Rosiglitazone Enhances Insulin Action by Modulating Tissue Lipid Supply Rosiglitazone and Insulin PPAR Preadipocyte Adipocyte Increased Differentiation Reversal of TNF -Induced Insulin Resistance Increased Insulin Sensitivity and Capacity for Glucose Disposal/Lipid Storage Reduced Lipolysis, Glycerol, & FFAs Availability Skeletal Muscle Liver Euglycemia Increased Glucose Disposal Reduced Hepatic Glucose Output PPAR GLUT-4 TG
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Dr. Rafn Benediktsson Effect of Pioglitazone on Insulin Resistance (HOMA R) Baseline IR: placebo 10.1, pioglitazone 30 mg 9.8 * p = 0.0002 vs baseline † p = 0.0001 vs placebo Rosenstock I, et al. Diabetologia 2000;43(suppl 1):A738 30.3* †
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Dr. Rafn Benediktsson Effect of Pioglitazone on Abdominal Fat Distribution Miyazaki Y et al. Diabetes 2000;49(SI);A299.
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Dr. Rafn Benediktsson TRIPOD: Buchanan et al. Diabetes 2001;50(S2):A327 Placebo for 30 months Troglitazone for 30 months 235 Latino women with GDM A % with diabetes 0 4 8 12 16 20 PlaceboTroglitazone B Observ. for 8 mo.: OGTT
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Dr. Rafn Benediktsson PCOS: Improvement in hirsutism by troglitazone % change in FG score PBOTGZ150TGZ300TGZ600 -20 -18 -16 -14 -12 -10 -8 -6 -4 -2 0 2 4 Azziz et al JCEM 2001;86:1626 *
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Dr. Rafn Benediktsson LOCF * p 0.05 vs. placebo -13.6 4.6 9.5 1.6 2.1 11.5 1.2 - 15.1 -20 -10 0 10 20 Glycaemic Non-Responders (45 mg) Total Cohort (45 mg) from placebo at 26 weeks HDL CholesterolLDL CholesterolTriglyceridesTotal Cholesterol (%) Baseline (mmol/L)3.281.056.27 2.93 * * 2.665.45 1.073.29 * Effect of Pioglitazone on Serum Lipids Effects by Glycaemic Response Takeda Pharmaceuticals America, Inc., data on file, study 001
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Dr. Rafn Benediktsson Inflammation: Effect of rosiglitazone on CRP N = 357, treatment for 26 weeks Greenberg et al @ EASD 2001
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Dr. Rafn Benediktsson PPAR activators inhibit migration of VSMC 0 50 100 PDGF % of migration compared to PDGF-BB -+++ 5 µM troglitazone 10 µM Marx et al.; Circ Res 1998; 83: 1097-1103
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Dr. Rafn Benediktsson Rosiglitazone inhibits the insulin-mediated increase in PAI-1 secretion in human subcutaneous adipocytes CTRL Insulin [nM] Mcternan @ EASD 2001
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Dr. Rafn Benediktsson Nitric oxide synthaase inhibition decreases the increased insulin action by piogllitazone in the fructose–fed rat 3 mU/kg/min insulin iv Glucose disposal rate [mg/kg/min] 0 2 4 6 8 10 12 STDFRUCT PIOGLITAZONE L-NMMA + ++- - - -- Koshinaka @ EASD A98
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Dr. Rafn Benediktsson The ischaemic obese Zucker rat heart * Sidell @ EASD 2001
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Dr. Rafn Benediktsson Rosiglitazone reduces atherosclerosis in ApoE KO mice Benson et al @ EASD 2001
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potential antiatherogenic effects potential proatherogenic effects VCAM-1, endothelin IL-6, prostaglandin, COX-2 apoptosis Tissue factor, TNF- ECs SMCs Mo / MØ CXC chemokines, endothelin, PAI-1 ECs SMCs Mo / MØ MMP-9; cytokines, SR A,I-NOS PAI-1 migration, MMP-9, Ang-II-receptor NO production CD 36 Foam cell formation apoptosis MCP-1, IL-8 PPAR PPAR ECs SMCs Mo / MØ ECs SMCs Mo / MØ TH-1 cytokines T-cells
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Dr. Rafn Benediktsson Niðurstaða Thiazolidinedione lyf eru leyfð á Íslandi sem meðferð við sykursýki Eingöngu sem viðbót við eitt annað per os blóðsykurlækkandi lyf TZD lyf ráðast að kjarna málsins – Insúlín viðnám – og þannig á ýmsa áhættuþætti hjarta og æðasjúkdóma In-vitro rannsóknir og dýratilraunir gefa vísbendingar um að TZD lyf geti hugsanlega tafið nýmyndun og framgang atherosclerosis Ekki eru til klínískar mannarannsóknir á áhrifum TZD á atherosclerosu eða dánartíðni !
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