The objective of this study was to investigate the associations of total and abdominal obesity with variation in proinsulin concentration in a Native Canadian population experiencing an epidemic of type 2 diabetes mellitus (DM). Between 1993 and 1995, 728 members of a Native Canadian community participated in a population-based survey to determine the prevalence and risk factors for type 2 DM. Samples for glucose, C-peptide, and proinsulin were drawn after an overnight fast, and a 75-g oral glucose tolerance test was administered. Type 2 DM and impaired glucose tolerance (IGT) were diagnosed using World Health Organization criteria. Height, weight, waist circumference, and percent body fat were measured. In 1998, 95 individuals who, at baseline, had IGT or normal glucose tolerance with an elevated 2-h glucose level (> or = 7.0 mM) participated in a follow-up evaluation using the same protocol. After adjustment for age, sex, C-peptide concentration, per cent body fat, and waist circumference, proinsulin was found to be significantly elevated in diabetic subjects, relative to subjects with both impaired and normal glucose tolerance (both P < 0.0001); and the concentration in those with IGT was higher, compared with normals (P < 0.0001). Among nondiabetic subjects, proinsulin showed significant univariate associations with percent body fat, body mass index, and waist circumference (r = 0.34, 0.45, 0.41, respectively, all P < 0.0001). After adjustment for body fat and other covariates, waist circumference remained significantly associated with proinsulin concentration in nondiabetic subjects (r = 0.20, P < 0.0001). In prospective analysis, adjusted for covariates (including baseline IGT and follow-up glucose tolerance status), baseline waist circumference was positively associated with both follow-up and change in proinsulin concentration (r = 0.27, P = 0.01; r = 0.24, P = 0.03, respectively). These data highlight the detrimental effects of abdominal obesity on beta-cell function, and support the hypothesis that beta-cell dysfunction occurs early in the natural history of glucose intolerance.