Leptin and adiponectin were measured in stored fasting serum samples of 2,097 individuals from two large epidemiological cohorts, using previously described assays [4, 5]. All individuals had HOMA-derived insulin sensitivity (HOMA-S) estimated using an online calculator (www.dtu.ox.ac.uk/homa) . In addition, 1,226 individuals in the European Group for the Study of Insulin Resistance (EGIR) Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study had insulin sensitivity measured using the hyperinsulinaemic–euglycaemic clamp technique. Insulin sensitivity was expressed as the ratio of the mean glucose infusion rate (M, adjusted for fat-free mass) to the mean plasma insulin (I) over the final 40 min of the clamp (M/I).
Medical Research Council Ely Cohort
The study design, methods and measurements for this predominantly Europid-population-based cohort study in Ely, Cambridgeshire, UK have been described previously . Briefly, individuals were recruited between 1990 and 1992, using a sampling frame of all non-diabetic adults living in Cambridgeshire. Participants attended the testing site after an overnight fast, and had blood samples drawn once. Written informed consent was obtained. Approval for the study was obtained from the Cambridge Local Research Ethics Committee.
EGIR RISC study cohort
This prospective, observational cohort study involved participants from 19 centres across Europe, as described previously . Healthy men and women aged between 30 and 60 years were included. Exclusion criteria were hypertension, dyslipidaemia, prevalent diabetes, pregnancy, treatment for obesity, known cardiovascular or chronic lung disease, weight change of 5 kg in the preceding 6 months, cancer within the previous 5 years or renal failure. However, unlike the Ely cohort, individuals with incident diabetes diagnosed at the time of their study visit were included in the current analysis. Local ethics committee approval was obtained by each recruiting centre, and all participants provided written informed consent. During the hyperinsulinaemic–euglycaemic clamp, exogenous insulin was administered as a primed-continuous intravenous infusion at a rate of 240 pmol min−1 m−2 simultaneously with a variable 20% (wt/vol.) glucose infusion. This was adjusted every 5 to 10 min to maintain plasma glucose levels within 0.8 mmol/l of the target glucose level (4.5–5.5 mmol/l). The M/I value for insulin sensitivity was calculated from the integral of the glucose infusion rate during the final 40 min of glucose infusion, divided by the steady-state insulin concentration.
Descriptive statistics are presented as means with 95% confidence intervals. Non-normally distributed data were log transformed prior to analysis, using the natural log (e). In order to compare the LAR with other standard indices of insulin resistance (fasting insulin and HOMA-S), linear regression models were used to separately derive standardised beta coefficients (β ± standard error) between log LAR, log HOMA-S and log fasting insulin (as predictors) and log M/I (as outcome). Correlations between these measures were calculated using Pearson’s correlation. Analyses were stratified by study cohort and by sex, because there were significant interactions for the LAR with sex and with study cohort.