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 µg/h), insulin (0.25 mU · kg -1 · min -1 ), glucagon (0.5 ng · kg -1 · min -1 ), growth hormone (6 ng · kg -1 · min -1 ), and tritiated glucose infusion and indirect calorimetry; and 2) on a separate day, an identical 5-h clamp but at hyperglycemia (~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. (1), and several studies have demonstrated decreased insulin sensitivity (2-6), impaired activation of muscle glycogen synthase by insulin (5,6), and subtle defects of insulin secretion (2,4,7) in such subjects. Most recently, we demonstrated increased glucosemediated glucose disposal at basal insulin in insulin-resistant normoglycemic first-degree relatives of patients with DM2 (2), using the Bergman minimal model (8). From the latter study, we hypothesized that the increase in glucose sensitivity (S g ) might be a novel compensatory mechanism by which these relatives maintain normal glucose tolerance (2). This scenario was consistent with an earlier large-scale longitudinal follow-up study in normoglycemic relatives of 2 parents with DM2 in whom a decreased S g and decreased insulin sensitivity (S i ) both predicted an increased risk of future development of diabetes (9). In contrast, Doi et al. (10) noted a decreased S g with normal S i and decreased first-phase insulin secretion in normoglycemic relatives of Japanese DM2 patients. However, the estimation of S g may be influenced by the extent of the acute insulin secretory response, i.e., the lower the first-phase insulin response, the lower the S g (11-13). Concern has also been expressed as to whether the minimal model technique using unlabeled glucose accurately measures S g (14,15).Glucose-mediated glucose disposal is an important factor controlling glucose tolerance (16,17), but which metabolic pathways are involved is uncertain (18)(19)(20). Acute hyperglycemia itself is known to enhance peripheral glucose uptake (19-24) associated with enhanced glucose oxidation and gluFrom the Diabetes Research Centre