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Background: First degree relatives of patients with nan-insulin dependent diabetes mellitus are often reported to be insulin resistant. The aim of this study was to identify early metabolic abnormalities in this condition, and to determine whether alterations in those abnormalities occurred by regular physical training. Methods: We measured sensitivity to insulin by euglycemic glucose clamp technique and insulin response to oral glucose in 10 untrained offspring of NIDDM parents and 10 untrained control subjects, and compared these subjects both with 6 trained offspring of NIDDM parents and 6 trained control subjects with no family history of NIDDM. Results: The untrained offspring showed higher plasma glucose responses when compared with the other three groups. The mean area under the glucose curve was also significantly higher in the untrained offspring than in the other three groups(12.6+0.6 vs. 10.4+0.4, 9.6+0.5, 9.4+0.7 mmol/Lhr, respectively; P<0.05). The corresponding insulin response was significantly higher at 60 min of OGTT in the untrained offspring compared with the trained offspring and the trained control. The mean area under the insulin curve was significantly higher in the untrained offspring than in the trained offspring and trained controls(868+172 vs. 294+71, 287+43 pmol/Lhr, respectively; P<0.05). The glucose disposal rate measured by means of a euglycemic clamp was significantly lower in the untrained and trained offspring when compared with that of the untrained and trained control subjects, respectively(5.6+0.3 vs. 8.6+0.3 mg/kg/min; P<0.01 and 9.3+0.9 vs. 12.1+ 0.8 mg/kg/min, respectively; P<0.05), whereas it did not differ between the untrained control subjects and the trained offspring(8.6+0.3 vs. 9.3+0.9 mg/kg /min; P=NS). Conclusion: Above data support the concept that early metabolic abnormalities, as reflected by decreased insulin-stimulated glucose uptake in offspring of NIDDM parents may be ameliorated by increase in overall activity and physical training.