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Increases in glutamine:fructose-6-phosphate aminotransferase (GFAT) protein levels directly activate flux through the hexosamine biosynthetic pathway. This pathway has been involved as a fuel sensor in energy metabolism and development of insulin resistance. We screened the 5′-flanking region of the human GFAT gene for polymorphisms and subsequently genotyped 412 nondiabetic, metabolically characterized Caucasians for the two single-nucleotide polymorphisms (SNP) at positions −913 (G/A) and −1412 (C/G) with rare allele frequencies of 42% and 16%, respectively. The −913 G SNP was associated with significantly higher body mass index and percent body fat in men (P = 0.02 and 0.004, respectively), but not in women (P = 0.47 and 0.26, respectively). In the subgroup of individuals (n = 193) who underwent hyperinsulinemic-euglycemic clamp, an association of the −913 G SNP with insulin sensitivity independent of body mass index was not detected. Moreover, the −913 G allele in a group of 71 individuals who had undergone magnetic resonance spectroscopy was associated with higher intramyocellular lipid content (IMCL) in tibialis anterior muscle (4.21 ± 0.31 vs. 3.36 ± 0.35; P = 0.04) independent of percent body fat and maximal aerobic power. The −1412 SNP had no effect on percent body fat, insulin sensitivity, or IMCL. In conclusion, we identified two polymorphisms in the 5′-flanking region of GFAT, of which the −913 SNP seems to alter the risk for obesity and IMCL accumulation in male subjects.

Copyright © 2005 by The Endocrine Society
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