AN AMINO-ACID SUBSTITUTION IN THE HUMAN INTESTINAL FATTY-ACID-BINDINGPROTEIN IS ASSOCIATED WITH INCREASED FATTY-ACID-BINDING, INCREASED FAT OXIDATION, AND INSULIN-RESISTANCE

The intestinal fatty acid binding protein locus (FABP2) was investigat ed as a possible genetic factor in determining insulin action in the P ima Indian population. A polymorphism at codon 54 of FABP2 was identif ied that results in an alanine-encoding allele (frequency 0.71) and a threonine-encoding allele (frequency 0.29). Pimas who were homozygous or heterozygous for the threonine-encoding allele were found to have a higher mean fasting plasma insulin concentration, a lower mean insuli n-stimulated glucose uptake rate, a higher mean insulin response to or al glucose and a mixed meal, and a higher mean fat oxidation rate comp ared with Pimas who were homozygous for the alanine-encoding allele. S ince the FABP2 threonine-encoding allele was found to be associated wi th insulin resistance and increased fat oxidation in vivo, we further analyzed the FABP2 gene products for potential functional differences. Titration microcalorimetry studies with purified recombinant protein showed that the threonine-containing protein had a twofold greater aff inity for long-chain fatty acids than the alanine-containing protein. We conclude that the threonine-containing protein may increase absorpt ion and/or processing of dietary fatty acids by the intestine and ther eby increase fat oxidation, which has been shown to reduce insulin act ion.