PPAR gamma system and glucose: metabolism

Shared metabolic abnormalities with insulin resistance and endothelial dysfunction

Glucotoxicity Lipotoxicity Inflammation

Insulin resistance

Endothelialdysfunction

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

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”

Relationship between blood glucose and cardiovascular pathology

1% 28%

HbA1c Mortality risk*

*independent of age, blood pressure, cholesterol, smoking habbits or BMI

Stratton IM et al. BMJ 2000;321:405-412

Intervention to effect better control means fewer complications

EVERY 1% reduction in HbA1C

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

Beyond glucose lowering: Effects of antidiabetic agents

TZD MetforminInsulin

secretagogues* AGI

Insulin resistance

Hypertension or or

Altered hemostasisPAI-1tPA

or or

NANA

DyslipidemiaTGHDL-CLDL 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