Insulin resistance and cardiovascular disease: cause or consequence?
05 / 2003 - 04 / 2007
- BACKGROUND: Insulin resistance is a key predictor for the development of type 2 diabetes mellitus and appears to be important in the pathogenesis of cardiovascular disease (CVD). CVD is the leading cause of morbidity and premature mortality in Europe, although prevalence rates differ between geographical regions. Type 2 diabetes, which enhances the risk of CVD 3- to 5-fold, is increasing. The degree of insulin resistance is influenced by genetic and environmental factors (e.g. obesity and physical inactivity). Previous studies could not rule out the possibility of insulin resistance being the consequence rather than the cause of underlying subclinical CVD. Also, available studies are based on hyperinsulinaemia, a far from perfect surrogate measure of insulin resistance. To study the role of insulin resistance determined by the gold standard, the euglycaemic hyperinsulinaemic clamp, in the pathogenesis of CVD, a prospective study among healthy subjects will be carried out by the European Group for the Study of Insulin Resistance. - OBJECTIVES: 1. To establish whether insulin resistance predicts future development of CVD risk factors (hypertension, dyslipidaemia, diabetes) and atherosclerosis, as determined by change of intima media thickness (IMT). 2. To determine genetic and environmental contributions to insulin resistance. - METHODS: In 1500 men and women, aged 30 to 60 years, from 22 European centres in 13 countries, we will measure: insulin sensitivity by a tracer-modified euglycaemic insulin clamp that yields an estimate of insulin action on both glucose uptake and glucose production (measurements will be standardised); carotid artery IMT, recorded by certified sonographers; physical inactivity: questionnaire and combined heart rate and movement sensors; obesity and body composition: anthropometry, bio-impedance and dual X-ray absorption photometry; genetic analyses: DNA extracted from whole blood, genotyping in central laboratories; indices of CVD: ECG, ankle brachial pressure index, Rose questionnaire; CVD risk factors including glucose tolerance, blood pressure, heart rate, lipid levels, homocysteine, inflammatory and haemostatic factors, smoking and alcohol habits, socio-economic factors and family antecedents. After 3 years the examinations will be repeated, except for measures of insulin sensitivity, and physical activity. - EXPECTED RESULTS: An answer to the question of whether insulin resistance is the underlying defect leading to diabetes and CVD. This will have implications for the development of prevention and treatment strategies. This proposal concerns the Dutch contribution, consisting of 75 subjects. - RELEVANCE FOR CARDIOVASCULAR DISEASES: This study is expected to provide evidence about the role of insulin resistance in the aetiology of diabetes and CVD. If the results of the study confirm that insulin resistance is the underlying defect leading to the development of CVD, it will allow for the development of better, targeted prevention and treatment strategies. Furthermore, it will justify the development of drugs aimed at improving insulin sensitivity. If the results of the study indicate that insulin resistance is not a risk factor but rather a consequence of cardiovascular disease this will alter the present axiom. It will reveal the need for new hypotheses, and alternative ways of prevention and treatment of CVD.