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Insulin resistance is an important risk factor for diabetes and other diseases. It has been important to estimate insulin resistance in epidemiological and genetic studies involving significant number of individuals. Complex and invasive protocols are impractical. Therefore, insulin sensitivity indices based on the oral glucose-tolerance test (OGTT) have been introduced. The aim of the present study was to assess the accuracy with which OGTT-derived indices would reflect changes in insulin sensitivity in the face of changes in other factors, such as rate of glucose absorption and/or B-cell function. A computer model was employed to predict excursions of plasma glucose and insulin after a 75-g oral glucose load. The model was then used to predict changes in these excursions, which would be observed with altered insulin resistance, with alterations in β-cell sensitivity to glucose and/or alterations in glucose absorption rates. Published indices of insulin sensitivity could then be calculated from the predicted curves, to ask whether changes in β-cell function or glucose absorptions rates might be misinterpreted (using the indices) as changes in insulin sensitivity. The model accurately represented OGTT data for a normal glucose tolerant subject, closely matching published data. Imposed 50% reductions or increases in insulin sensitivity alone in the model were reflected in only small changes in OGTT-derived insulin sensitivity values. More important, imposed alterations in β-cell sensitivity and glucose absorption without simulated changes in insulin sensitivity did change insulin sensitivity indices. These results indicate that caution is required for the interpretation of differences in OGTT-derived values of insulin sensitivity, because variation in factors other than insulin sensitivity per se appear to have the greatest effects on indices calculated from the OGTT alone.