The study
European study proves insulin resistance ns not sole underlying driver of cardiometabolic risk

Insulin resistance, obesity, central obesity and a high insulin response each make an independent but partial contribution to the metabolic risk cluster known as Insulin Resistance Syndrome or Metabolic Syndrome, according to data from the Relationship between Insulin Sensitivity and Cardiovascular risk (RISC) study – the largest study of its kind using the ‘gold standard’ euglycaemic hyperinsulinaemic clamp technique, presented at the EASD congress.

The RISC study panel
Preliminary data presented for the first time demonstrate that participants whose beta-cell function was most impaired at baseline had a more than three-fold risk of developing either diabetes or pre-diabetes (impaired fasting glucose or impaired glucose tolerance) and a two-fold risk of developing abdominal obesity after 3 years.

“The RISC study demonstrates that insulin resistance is not the single, central cause of the onset of cardiovascular disease,” said Prof. Ele Ferrannini, RISC Project Co-ordinator, University of Pisa. “This is a significant finding because it sheds light on an up until now untested hypothesis that was often mistaken for an established fact – that insulin resistance is the primary driver of cardiometabolic risk.”

Conducted by the European Group for the study of Insulin Resistance (EGIR), RISC investigated the relative contributions of cardiometabolic risk factors by recruiting more than 1500 healthy volunteers from 19 centres in 14 European countries, performing a euglycaemic clamp to measure insulin resistance (in 1338 subjects) and an OGTT to calculate insulin exposure. No previous study has used both direct measures of insulin resistance and insulin response together. Other risk factors were measured following a standardised protocol.

At baseline, BMI was positively related to all cardiovascular disease (CVD) risk factors; waist circumference was related to higher blood pressure and serum triglycerides and lower HDL-cholesterol; insulin sensitivity was positively associated with postload glucose, free fatty acids, triglycerides and LDL-cholesterol levels, and negatively with HDL-cholesterol levels; and insulin exposure was associated with higher heart rate, blood pressure and fasting glucose and adverse levels of all lipid parameters. Furthermore, it was demonstrated that insulin resistance and hyperinsulinaemia (high levels of insulin in the blood) can be found in isolation and are not necessarily dependent upon each other, which has been widely assumed up until this point.

In addition, RISC demonstrates that while obesity is strongly associated with insulin resistance, physical activity is beneficially associated with insulin sensitivity even in the more obese. Further, in the RISC study habitual physical activity is inversely and independently related to carotid artery stiffness (but not intima-media thickness [cIMT]). This benefit of physical activity appears to increase with increased activity and is not mediated by its influence on CVD risk factors (such as blood pressure, central obesity, plasma lipids and insulin levels).

Physical activity was measured at baseline in 807 participants, quantitatively with an accelerometer. Insulin sensitivity was positively related with total physical activity and the intensity of this activity and negatively with the number of hours of sedentarity per day; the relationships appeared to be stronger in the more abdominally obese men and women than in the lean participants. In addition, total activity was still related with insulin sensitivity even after adjusting for sedentarity: a person who was sedentary at work could compensate by being physically active during leisure or commuting time.

“The message both for individuals and governments is crystal clear,” said Prof. Mark Walker, University of Newcastle-Upon-Tyne. “The prevention of obesity and encouragement of physical activity will promote cardiometabolic health for all people, irrespective of their socioeconomic background. It is important to stress that the benefits of physical activity include a decrease in age-related arterial stiffness, as well as some compensation for being overweight or obese and it will be interesting to see whether these benefits translate into a cardioprotective effect in the RISC long term follow up,”

RISC has also established a high quality DNA resource for future genetic studies, comprising 1311 participants from the cohort. Analyses are beginning to demonstrate how common gene variants can influence insulin sensitivity, for example the FTO polymorphism through increased adiposity, and CVD risk with the adiponectin-11377 locus, in otherwise healthy subjects. Further, beta cell function, a key player in progression to diabetes is also related with genetic variants in the RISC cohort. The relationship between genetic factors and the progression of cardiovascular risk will be further elucidated with the longitudinal analysis of the RISC cohort.