1. A theoretical investigation of the intravenous glucose tolerance test has been carried out based on recent findings on the kinetics in man of insulin production, distribution, disposal and action, and of glucose turnover and distribution.
2. A good fit to published data on four groups of subjects required a scheme that includes two extravascular glucose spaces and separate venous, arterial and capillary volumes. The fit to the data was little affected by variations within the physiological range of venous and arterial volumes, cardiac output, glycosuria and the properties of the less-accessible glucose pool.
3. The only variables needed to account for the differences between the groups were kinsulin (a measure of the mean sensitivity of insulin-dependent tissues to insulin action) and the readily accessible glucose space.
4. Three published schemes for insulin kinetics were used. They were all consistent with the data and gave very similar relative values of kinsulin in the four groups.
5. It is shown that a rigorous interpretation of the test requires a knowledge of the hepatic response to the glucose load during the test. These effects are not well characterized in pathological states, e.g. diabetes and injury. Consequently conclusions about insulin resistance in these states drawn only from the test are doubtful.