Abstract
A polymorphism in FABP2 that results in an alanine-to-threonine substitution 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 affected metabolic responses to dietary fat, in vivo. Eighteen healthy Pima Indians, 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 mass index. Plasma triglyceride, nonesterified fatty acid (NEFA), glucose, and insulin responses were measured after a mixed meal (35% of daily energy requirements, 50 g of fat) and after a high fat challenge (1362 kcal, 129 g of fat). NEFA concentrations were approximately 15% higher after the mixed meal and peaked earlier and were approximately 20% higher at 7 h in response to the high fat test meal in Thr54 homozygotes compared with Ala54 homozygotes. Insulin responses to the test meals tended to be higher in Thr54 homozygotes, but glucose and triglyceride responses were not different.The results of this study suggest that the Thr54 form of IFABP is associated with higher and prolonged NEFA responses to dietary fat in vivo. Higher NEFA concentrations may contribute to insulin resistance and hyperinsulinemia in individuals with this allele.
Highlights
A polymorphism in gene encoding intestinal fatty acid-binding protein (FABP2) that results in an alanine-to-threonine substitution at amino acid 54 of the intestinal fatty acid-binding protein (IFABP) is associated with insulin resistance in Pima Indians
Preliminary studies of the genetics of diabetes and its metabolic precursors in the Pimas suggested a linkage between insulin action, determined during a hyperinsulinemiceuglycemic glucose clamp, and polymorphic DNA markers on chromosome 4q in a region containing FABP2, the gene encoding the intestinal fatty acid-binding protein (IFABP) (4)
On the basis of these results, it was predicted that both nonesterified fatty acid (NEFA) and triglyceride responses to a dietary fat challenge would be higher in individuals homozygous for the Thr[54] allele than in persons homozygous for the Ala[54] allele
Summary
A polymorphism in FABP2 that results in an alanine-to-threonine substitution at amino acid 54 of the intestinal fatty acid-binding protein (IFABP) is associated with insulin resistance in Pima Indians. The threonine form (Thr54) has a higher binding affinity for long-chain fatty acids than does the alanine form (Ala[54]) We tested whether this polymorphism affected metabolic responses to dietary fat, in vivo. Pima Indians with the Thr[54] allele had higher fasting plasma NEFA concentrations and increased rates of lipid oxidation in vivo (5, 6) Those with the Thr[54] allele had higher insulin responses during oral glucose tolerance and mixed meal tests and were insulin resistant compared with those who were homozygous for the Ala[54] allele (5).
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