Serum sex hormone-binding globulin (SHBG) and insulin-like growth factor-binding protein 1 (IGFBP-1) concentrations have been suggested to be useful markers of insulin sensitivity. As the production of both proteins is inhibited by insulin in the liver, we postulated that their concentrations reflect whole body insulin sensitivity only when the latter parallels changes in endogenous insulin secretion. To test this hypothesis, we determined SHBG and IGFBP-1 concentrations, whole body insulin sensitivity (euglycemic insulin clamp; serum free insulin, approximately 400 pmol/L), and serum insulin and C peptide concentrations in 13 type 1 diabetic patients lacking endogenous insulin secretion and 34 matched normal subjects. Whole body insulin sensitivity was 50% lower in the type 1 diabetic patients (20 +/- 3 mumol/kg.min) than that in the normal subjects (40 +/- 3 mumol/kg.min; P < 0.001). Despite this, serum SHBG (45 +/- 4 vs. 29 +/- 2nmol/L; P < 0.002) and IGFBP-1 (14 +/- 3 vs. 2 +/- 1 micrograms/L; P < 0.002) concentrations were increased in the type 1 diabetic patients. In the normal subjects, SHBG (r = -0.49; P < 0.01) and IGFBP-1 (r = -0.49; P < 0.01) were inversely correlated with serum C peptide and positively correlated with whole body insulin sensitivity (r = 0.54; P < 0.005 and r = 0.54; P < 0.005, respectively). In the type 1 diabetic patients, SHBG and IGFBP-1 concentrations were disproportionately increased when related to insulin sensitivity, but appropriate when related to estimated portal insulin concentrations. Serum T4, free testosterone, and estradiol concentrations were similar in both groups. We conclude that SHBG and IGFBP-1 reflect hepatic insulinization and can only be used as markers of insulin sensitivity in individuals with intact insulin secretion.