An amino acid substitution in the human intestinal fatty acid binding protein is associated with increased fatty acid binding, increased fat oxidation, and insulin resistance.
The intestinal fatty acid binding protein locus (FABP2) was investigated as a possible genetic factor in determining insulin action in the Pima Indian population. A polymorphism at codon 54 of FABP2 was identified 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 insulin-stimulated glucose uptake rate, a higher mean insulin response to oral glucose and a mixed meal, and a higher mean fat oxidation rate compared with Pimas who were homozygous for the alanine-encoding allele. Since the FABP2 threonine-encoding allele was found to be associated with 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 affinity for long-chain fatty acids than the alanine-containing protein. We conclude that the threonine-containing protein may increase absorption and/or processing of dietary fatty acids by the intestine and thereby increase fat oxidation, which has been shown to reduce insulin action.
Baier
L J
LJ
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Arizona 85016.
Sacchettini
J C
JC
Knowler
W C
WC
Eads
J
J
Paolisso
G
G
Tataranni
P A
PA
Mochizuki
H
H
Bennett
P H
PH
Bogardus
C
C
Prochazka
M
M
D000328:Adult; D000409:Alanine / Q000235:genetics; D000483:Alleles; D001130:Arizona; D001483:Base Sequence; D002151:Calorimetry; D002352:Carrier Proteins / Q000235:genetics*; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins; D010084:Oxidation-Reduction; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011446:Prospective Studies; D012307:Risk Factors; D013912:Threonine / Q000235:genetics; D025521:Tumor Suppressor Proteins
D002352:Carrier Proteins; C493404:FABP2 protein, human; C107608:FABP7 protein, human; C493405:Fabp2 protein, mouse; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D013912:Threonine; D005947:Glucose; D000409:Alanine