To investigate the association between insulin resistance and diabetic nephropathy, peripheral insulin sensitivity indices (M/I values) were evaluated via euglycemic-hyperinsulinemic clamp in 45 non-obese, non-insulin-dependent diabetic (NIDDM) subjects. The patients were divided into four groups: 18 with normoalbuminuria (urinary albumin excretion rate [AER] < 30 mg/24 h, stage I), 10 with microalbuminuria (30 < or = AER < or = 300 mg/24 h, stage II), seven with overt proteinuria (AER > 300 mg/24 h, stage III), and 10 with uremia (serum creatinine levels > 2.0 mg/dL, stage IV). There were no significant differences in age, body mass index (BMI), fasting plasma glucose, or hemoglobin A1c (HbA1c) among the four groups. No significant difference in M/I values was seen between stage I and stage II (6.30 +/- 0.73 and 5.95 +/- 0.85 mg/kg/(min per microU/mL) x 100, respectively). M/I values in the stage I and stage II groups were strongly correlated with BMI (r = -.790, P = .0001 and r = -.785, P = .007, respectively). M/I values in the stage III group (4.53 +/- 0.51) were lower than in the stage I group, although not significantly so. M/I values in the stage IV group (3.16 +/- 0.37) were significantly lower than in the stage I group (P = .025). In multiple regression analysis with a model in which age, sex, BMI, HbA1c, and creatinine clearance (Ccr) were included as independent variables, BMI and Ccr were demonstrated to be significant and independent contributors to insulin sensitivity indices as the dependent variable (beta = -0.716 and beta = 0.272, respectively, R2 = .564, P < .0001). In conclusion, the present cross-sectional study demonstrated in non-obese NIDDM patients with nephropathy that microalbuminuria did not affect peripheral insulin resistance, but uremia did, as in nondiabetic patients, and that the peripheral insulin resistance was significantly contributed to by the degree of obesity and uremia.