Effects of an Ala54Thr polymorphism in the intestinal fatty acid-binding protein on responses to dietary fat in humans

A polymorphism in FABP2 that results in an alanine-to-threonine substitutio n at amino acid 54 of the intestinal fatty acid-binding protein (IFABP) is associated with insulin resistance in Pima Indians. In vitro, the threonine form (Thr54) has a higher binding affinity for long-chain fatty acids than does the alanine form (Ala54). We tested whether this polymorphism affecte d metabolic responses to dietary fat, in vivo. Eighteen healthy Pima Indian s, half homozygous for the Thr54 form of IFABP and half homozygous for the Ala54 form, were studied. The groups were matched for sex, age, and body ma ss index. Plasma triglyceride, nonesterified fatty acid (NEFA), glucose, an d insulin responses were measured after a mixed meal (35% of daily energy r equirements, 50 g of fat) and after a high fat challenge (1362 kcal, 129 g of fat). NEFA concentrations were similar to 15% higher after the mixed mea l and peaked earlier and were similar to 20% higher at 7 h in response to t he high fat test meal in Thr54 homozygotes compared with Ala54 homozygotes. Insulin responses to the test meals tended to be higher in Thr54 homozygot es, but glucose and triglyceride responses were not different. The results of this study suggest that the Thr54 form of IFABP is associated with highe r and prolonged NEFA responses to dietary fat in vivo. Higher NEFA concentr ations may contribute to insulin resistance and hyperinsulinemia in individ uals with this allele.