BACKGROUND: There is considerable evidence that insulin resistance with compensatory hyperinsulinaemia is an early and modifiable defect in the pathogenesis of non-insulin dependent diabetes (NIDDM). Current data, however, are largely based on studies that have used insulin assays which cross-react with proinsulin and other insulin precursors. Using a specific assay, we have addressed the hypothesis that an elevation of serum true insulin concentration, reflecting insulin resistance, is an early event in the pathogenesis of NIDDM. METHODS: We have used a prospective cohort study design in which a group of 5550 non-diabetic men aged 40-59 years, from 18 British towns, have been followed for incident cases of physician-diagnosed NIDDM for an average of period of 14.8 years (range 13.5-15 years). We have estimated the incidence of physician-diagnosed NIDDM by quintile of non-fasting serum true insulin concentration at entry into the study. RESULTS: There were 168 cases of clinically diagnosed NIDDM among the group of 5550 men during follow-up. Mean serum insulin at entry (geometric mean and 95% range, adjusted for time of sampling) was significantly higher in men who subsequently developed NIDDM than in the rest of the cohort, 19.5 mU/l (4.3-88.2) versus 12.2 mU/l (2.7-54.0), P < 0.0001. There was a highly significant linear trend of increasing risk of NIDDM by quintile of serum insulin which was not attenuated substantially after adjustment for age and body mass index (BMI) and additional lifestyle and biological factors associated with serum insulin and risk of NIDDM. However, in men with non-fasting serum glucose > or =6.1 mmol/l at baseline (80th percentile, n = 1125, 82 cases), the risk of NIDDM, adjusted for age and BMI, was higher in the first quintile of serum insulin than in all other quintiles. CONCLUSION: These findings are consistent with the hypothesis that the majority of cases of adult onset NIDDM in this population are characterized by the early development of insulin resistance with compensatory true hyperinsulinaemia.