With the aim of investigating glucose-mediated glucose disposal (glucose effectiveness [GE]) in 15 (3 female and 12 male subjects) insulin-resistant normoglycemic relatives of patients with type 2 diabetes (DM2), and 15 age-, sex-, and BMI-matched control subjects without a family history of DM2, we performed 2 studies: 1) a 5-h euglycemic near-normoinsulinemic pancreatic clamp with somatostatin (360 microg/h), insulin (0.25 mU x kg(-1) x min(-1)), glucagon (0.5 ng x kg(-1) x min(-1)), growth hormone (6 ng x kg(-1) x min(-1)), and tritiated glucose infusion and indirect calorimetry; and 2) on a separate day, an identical 5-h clamp but at hyperglycemia (approximately 12 mmol/l) over the last 2 h. Fasting plasma insulin (PI) concentrations were elevated in the relatives compared with control subjects (49 +/- 6 vs. 32 +/- 5 pmol/l, P < 0.04), whereas plasma glucose (PG) was not (5.6 +/- 0.1 vs. 5.5 +/-0.1 mmol/l). At the end (i.e., 4.5-5.0 h) of the euglycemic clamp (PG, 6.1 +/- 0.4 vs. 5.6 +/- 0.1 mmol/l; PI, 78 +/- 5 vs. 73 +/-6 pmol/l), peripheral glucose uptake (Rd(euglycemia)) was decreased in the relatives (2.93 +/- 0.08 vs. 3.70 +/-0.23 mg x min(-1) x kg(-1) fat free mass [FFM], P < 0.005), due to a decreased nonoxidative glucose disposal (0.83 +/-0.21 vs. 1.62 +/- 0.19 mg x min(-1) x kg(-1) FFM, P < 0.01), but hepatic glucose production (HGP) was increased (1.97 +/-0.19 vs. 1.50 +/- 0.13 mg x min(-1) x kg(-1) FFM, P < 0.05). At the matched end of the hyperglycemic clamp (PG, 12.7 +/-0.2 vs. 12.6 +/- 0.2 mmol/l; PI, 87 +/- 5 vs. 78 +/- 7 pmol/l), peripheral glucose disposal (Rd(hyperglycemia)) (5.52 +/- 0.22 vs. 5.92 +/- 0.29 mg x min(-1) x kg(-1) FFM, NS), nonoxidative glucose disposal (2.93 +/- 0.18 vs. 2.78 +/- 0.25 mg x min(-1) x kg(-1) FFM, NS), and HGP(hyperglycemia) (1.20 +/- 0.09 vs. 1.37 +/-0.23 mg x min(-1) x kg(-1) FFM, NS) were all identical. When the effectiveness of glucose itself on glucose uptake and production [(Rd(hyperglycemia) - Rd(euglycemia))/deltaPG and (HGP(euglycemia)- HGP(hyperglycemia))/deltaPG] was calculated, the relatives had a 22% increase in peripheral uptake (0.022 +/- 0.002 vs. 0.018 +/- 0.002 mg x min(-1) x kg(-1) FFM per mg/dl), due to a significantly increased nonoxidative glucose metabolism and enhanced suppression of HGP (0.0076 +/- 0.0021 vs. 0.0011 +/- 0.0022 mg x min(-1) x kg(-1) FFM per mg/dl, P < 0.05). In conclusion, in insulin-resistant relatives of DM2 patients, whole-body glucose-mediated glucose disposal is increased by GE enhancement of the muscle nonoxidative glucose pathway and by GE enhancement of the suppression of HGP. These mechanisms may represent a compensatory mechanism to the ongoing insulin resistance of these relatives.