Serum true insulin concentration and the risk of clinical non-insulin dependent diabetes during long-term follow-up

Background There is considerable evidence that insulin resistance with comp ensatory hyperinsulinaenia is an early and modifiable defect in the pathoge nesis of non-insulin dependent diabetes (NIDDM). Current data, however, are largely based on studies that have used insulin assays which cross-react w ith proinsulin and other insulin precursors. Using a specific assay, we hav e addressed the hypothesis that an elevation of serum true insulin concentr ation, 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 nondiabetic men aged 40-59 years, from 18 British towns, have been fol lowed for incident cases of physician-diagnosed NIDDM for an average of per iod 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 co ncentration 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 a nd 95% range, adjusted for time of sampling) was significantly higher in me n who subsequently developed NIDDM than in the rest of the cohort, 19.5 mU/ l (4.3-88.2) versus 12.2 mU/1 (2.7-54.0), P < 0.0001. There was a highly si gnificant linear trend of increasing risk of NIDDM by quintile of serum ins ulin which was not attenuated substantially after adjustment for age and bo dy mass index (BMI) and additional lifestyle and biological factors associa ted with serum insulin and risk of NIDDM. However, in men with non-fasting serum glucose greater than or equal to 6.1 mmol/l at baseline (80th percent ile, 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 major ity of cases of adult onset NIDDM in this population are characterized by t he early development of insulin resistance with compensatory true hyperinsu linaemia.