479440f6-a6d3-4d95-870e-ede175c4d2e0
title
Common variants in  glutamine:fructose-6-phosphate amidotransferase 2  ( GFPT2 ) gene are associated with type 2 diabetes, diabetic nephropathy, and increased  GFPT2  mRNA levels.
a47d80a8-01b8-4e6f-8723-681305f54683
abstract
Increased flux of glucose through the hexosamine biosynthetic pathway has been implicated in  insulin  resistance, altered  insulin  secretion, and diabetic nephropathy.  Glutamine:fructose-6-phosphate amidotransferase (GFPT) , the rate limiting enzyme in hexosamine biosynthesis, is encoded by the unlinked but highly homologous genes  GFPT1  and  GFPT2 . We tested the hypothesis that  GFPT2  sequence variation contributed to the susceptibility to type 2 diabetes mellitus (T2DM) and diabetic nephropathy in Caucasian and African-American individuals. We identified 11 single nucleotide polymorphisms (SNPs), of which seven were common. A single variant in exon 14,  I471V , altered the amino acid sequence, is conserved between human and mouse genes, and was associated with T2DM among Caucasians (P = 0.05). A trend to an association was noted with diabetic nephropathy among African-American individuals (P = 0.15). Several variants in the 3' untranslated region (UTR) and exon 18 were also associated with T2DM in Caucasian individuals (P < 0.05), and the SNP in the 3' UTR was associated with diabetic nephropathy in African-American subjects (P = 0.047).  GFPT2  mRNA levels in transformed lymphocytes from study subjects were significantly increased among African-American subjects compared with Caucasian individuals, regardless of diagnosis. Furthermore, the associated allele of the 3' UTR SNP was approximately 2-fold overexpressed. We propose that the 3' UTR variant results in increased  GFPT2  mRNA levels with resultant increased hexosamine flux. The  I471V  variant may contribute to altered protein function or may simply be in linkage disequilibrium with the 3' UTR.