1. Dr. Rafn Benediktsson The Diagnosis of Diabetes rests on Glucose Values * should be confirmed on a second occasion

2. 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

3. 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.

4. 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

5. 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

6. 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

7. 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

8. Dr. Rafn Benediktsson UKPDS: Value of Good Blood Pressure Control in T2DM risk reduction 37% p=0.0092

9. 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

10. 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)

11. 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

12. Dr. Rafn Benediktsson

14. 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 

15. 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* †

16. Dr. Rafn Benediktsson Effect of Pioglitazone on Abdominal Fat Distribution Miyazaki Y et al. Diabetes 2000;49(SI);A299.

17. 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

18. 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 *

19. 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

20. Dr. Rafn Benediktsson Inflammation: Effect of rosiglitazone on CRP N = 357, treatment for 26 weeks Greenberg et al @ EASD 2001

21. 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

22. Dr. Rafn Benediktsson Rosiglitazone inhibits the insulin-mediated increase in PAI-1 secretion in human subcutaneous adipocytes CTRL Insulin [nM] Mcternan @ EASD 2001

23. 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

24. Dr. Rafn Benediktsson The ischaemic obese Zucker rat heart * Sidell @ EASD 2001

25. Dr. Rafn Benediktsson Rosiglitazone reduces atherosclerosis in ApoE KO mice Benson et al @ EASD 2001

26. 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

27. 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 !