1. PPAR gamma system and glucose: metabolism

2. Shared metabolic abnormalities with insulin resistance and endothelial dysfunction Glucotoxicity Lipotoxicity Inflammation Insulin resistance Endothelial dysfunction Adapted from Reaven GM. Panminerva Med. 2005;47(4):201-10. Oxidative stress AGE formation Pro-inflammatory signaling Oxidative stress Pro-inflammatory signaling Pro-inflammatory factors Kinases/transcription factors AGE = advanced glycation end product

3. Thiazolidinedione (TZD) Therapy & Glucose 1995- PPAR  : identified as cognate receptor for TZD class of insulin sensitising drugs Extensive clinical trial data base shows consistent improvement in glycaemic control, whole body insulin sensitivity - mainly due to increased glucose disposal rates PPAR  activation expands adipose tissue and counterintuitively increases insulin sensitization……the “TZD paradox”

4. Relationship between blood glucose and cardiovascular pathology 1% 28% HbA1cMortality risk* *independent of age, blood pressure, cholesterol, smoking habbits or BMI Stratton IM et al. BMJ 2000;321:405-412

5. Intervention to effect better control means fewer complications EVERY 1% reduction in HbA 1C Reduced Risk* 1% Deaths from diabetes Heart attacks Microvascular complications Peripheral vascular disorders *p<0.0001 - 37% - 43% - 14% - 21% Stratton IM et al. BMJ 2000;321:405-412

6. Beyond glucose lowering: Effects of antidiabetic agents TZDMetformin Insulin secretagogues*AGI Insulin resistance  Hypertension  or  or  Altered hemostasis PAI-1 tPA   or   or   NA Dyslipidemia TG HDL-C LDL particle size  or   or    or   or   NA  or   or  NA C-reactive protein  NA * Sulfonylureas and meglitinides AGI = alpha glucosidase inhibitor Adapted from Granberry MC, Fonseca VA. Am J Cardiovasc Drugs. 2005;5:201-9 NA = data not available  = no change