20 normoglycemic first degree relatives of non-insulin-dependent diabetes mellitus (NIDDM) patients were compared with 20 matched subjects without any family history of diabetes using the intravenous glucose tolerance test with minimal model analysis of glucose disappearance and insulin kinetics. Intravenous glucose tolerance index (Kg) was similar in both groups (1.60±0.14 vs 1.59±0.18, x 10-2 minm-, NS). However, insulin sensitivity (Si) was reduced (3.49±0.43 vs 4.80±0.61, x 10-4 mind per mU/liter, P = 0.05), whereas glucose effectiveness (Sg) was increased (1.93±0.14 vs 1.52±0.16, X 10-2 min-, P < 0.05) in the relatives. Despite insulin resistance neither fasting plasma insulin concentration (7.63±0.48 vs 6.88±0.45, mU/liter, NS) nor first phase insulin responsiveness (Phil) (3.56±0.53 vs 4.13±0.62, mU/liter min' per mg/dl, NS) were increased in the relatives. Phil was reduced for the degree of insulin resistance in the relatives so that the Phil x Si index was lower in the relatives (11.5±2.2 vs 16.7±2.0, x 10-4 min 2 per mg/dl, P < 0.05). Importantly, glucose effectiveness correlated with Kg and with basal glucose oxidation but not with total glucose transporter 4 (GLUT4) content in a basal muscle biopsy. In conclusion we confirm the presence of insulin resistance in first degree relatives of NIDDM patients. However, insulin secretion was altered and reduced for the degree of insulin resistance in the relatives, whereas glucose effectiveness was increased. We hypothesize that increased glucose effectiveness maintains glucose tolerance

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