Insulin resistance, CV risk and physical activity
Adiponectin, insulin resistance and carotid thickening

The RISC study (Relationship between Insulin Sensitivity and Cardiovascular risk) is a European cohort designed to examine whether insulin resistance predicts cardiovascular disease.

The study began in June 2002 when healthy men and women, aged 30 to 60 years, were recruited from 19 centres in 14 European countries; insulin resistance was evaluated using the euglycaemic hyperinsulinaemic clamp in 1338 individuals.

To define the relationship between insulin resistance and cardiovascular disease, it is important to understand how lifestyle and genetic factors influence these conditions. A key task of the RISC study was to establish a high quality DNA resource for future genetic studies, and this was achieved for 1311 subjects in the RISC cohort.

This resource has been used to examine the relationships between common variants in candidate genes and insulin sensitivity as determined by the clamp and carotid artery intima-media thickness (cIMT) as a marker of cardiovascular disease. To date we have genotyped common variants in a number of candidate genes, including PPARG and ADIPOQ. Investigating the Pro12Ala variant of PPARG, we confirmed that Ala allele carriers were more insulin sensitive in comparison to homozygous carriers of the Pro allele. Adiponectin has been shown to influence insulin action and is encoded by ADIPOQ. Three promoter SNPs (-11426, -11391, -11377) and SNP45 in ADIPOQ were genotyped. Circulating adiponectin levels were found to be decreased in carriers of the -11426G allele and homozygous carriers of the -11391G allele. A novel association between cIMT and variation at -11377 was identified that was independent of circulating adiponectin levels and classical CVD risk factors.

These analyses are starting to demonstrate how common gene variants can influence insulin sensitivity and cardiovascular disease risk in otherwise healthy subjects. How common gene variants influence the progression of insulin sensitivity and cardiovascular risk will emerge with the longitudinal analysis of the RISC cohort.