The intestinal fatty acid binding protein (IFABP) is present in humans in two forms which differ by a alanine to threonine substitution at amino acid 54. In vitro, the threonine form (Thr54) is characterized by a two-fold higher binding affinity for long chain fatty acids than the alanine form (Ala54). The Thr54 form also is associated with higher plasma insulin concentrations and insulin resistance in the Pima Indians. This project examines whether the in vitro binding differences are physiologically significant. Net dietary fatty acid absorption, the kinetics of appearance of dietary fatty acids into plasma, and the time course of lipid oxidation are determined following a standard test meal incorporating [l-13C]-palmitic acid as a tracer of fatty acid metabolism in healthy subjects homozygous for either the Thr54 form or the Ala54 form of IFABP. A total of 22 subjects (11 Thr54 and 11 Ala54 homozygotes, 14 males and 8 females) have been studied, thus far. The groups were similar in age, weight, and % body fat. Resting and 24-hour energy expenditure and 24-hour RQ also did not differ between the groups. The total amount of label appearing in breath over 24-hours as a percentage of administered dose was not significantly different (28+/-2% v 30+/-2%), but there was a tendency for less label to be oxidized in the last 9 hours of the meal test in the Thr54 homozygotes than the Ala54 homozygotes (4.7+/-0.5% v 6.1+/-0.4%, P < 0.06). Total absorption of the label was not significantly different between the groups. We are currently completing the measurements to determine the plasma lipid responses to the mixed meal.