Analysis of a large study population revealed a group of eight healthy men whose tolerance to oral glucose was markedly greater than their tolerance to iv glucose (disparate group). The physiological basis of the anomalous performance was investigated using a variation of the hyperglycemic glucose clamp technique. This technique allows separation of the effects of hyperglycemia and intestinal insulinotropic factors on B-cell response. The eight subjects with disparate tolerance tests were compared to eight healthy control subjects whose tolerances on the two tests were very similar. The disparate performers showed 1) higher basal circulating gastric inhibitory polypeptide (GIP) levels, 2) lower immunoreactive insulin (IRI) responses to hyperglycemia (iv glucose alone), 3) enhanced GIP response to oral glucose, and 4) enhanced IRI response to oral glucose. These results may be interpreted as indicating a role for GIP in the improved tolerance for oral glucose, although other unknown gastrointestinal hormones could theoretically also be involved. Enhanced release of GIP after oral glucose may compensate for the reduced IRI release in response to hyperglycemia. The mechanism underlying the enhanced GIP response in these studies remains to be explored. It will be of interest to follow these subjects to see whether their anomalous gut beta-cell balance has any long term pathogenetic implications.