Glucose-mediated glucose disposal in insulin-resistant normoglycemic relatives of type 2 diabetic patients

With the aim of investigating glucose-mediated glucose disposal (glucose ef fectiveness [GE]) in 15 (3 female and 12 male subjects) insulin-resistant n ormoglycemic 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 mu g/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 (similar to 12 mm ol/l) over the last 2 h. Pasting plasma insulin (PI) concentrations were el evated 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 . min(-1) . 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 . min(-1) . kg(-1) FFM, P < 0.01), but hepatic glucos e production (HGP) was increased (1.97 +/- 0.19 vs. 1.50 +/- 0.13 mg . min( -1) . 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 . min(-1) . kg(-1) FFM, NS), nonoxidative glucose disposal (2.9 3 +/- 0.18 vs. 2.78 +/- 0.25 mg . min(-1) . kg(-1) FFM, NS), and HGP(hyperg lycemia) (1.20 +/- 0.09 vs. 1.37 +/- 0.23 mg . min(-1) . kg(-1) FFM, NS) we re all identical. When the effectiveness of glucose itself on glucose uptak e and production [(Rd(hyperglycemia) - Rd(euglycemia))/Delta PG and (HGP(eu glycemia) - HGP(hyperglycemia))/Delta PG] was calculated, the relatives had a 22% increase in peripheral uptake (0.022 +/- 0.002 vs. 0.018 +/- 0.002 m g . min(-1) . kg(-1) FFM per mg/dl), due to a significantly increased nonox idative glucose metabolism and enhanced suppression of HGP (0.0076 +/- 0.00 21 vs. 0.0011 +/- 0.0022 mg . min(-1) . kg(-1) FFM per mg/dl, P < 0.05). In conclusion, in insulin-resistant relatives of DM2 patients, whole-body glu cose-mediated glucose disposal is increased by GE enhancement of the muscle nonoxidative glucose pathway and by GE enhancement of the suppression of H GP. These mechanisms may represent a compensatory mechanism to the ongoing insulin resistance of these relatives.