DIFFERENTIAL-EFFECTS OF GLUT1 OR GLUT4 OVEREXPRESSION ON HEXOSAMINE BIOSYNTHESIS BY MUSCLES OF TRANSGENIC MICE

Transgenic mice that overexpress GLUT1 or GLUT4 in skeletal muscle wer e studied; the former but not the latter develop insulin resistance. B ecause increased glucose flux via the hexosamine biosynthesis pathway has been implicated in glucose-induced insulin resistance, we measured the activity of glutamine:fructose-6-phosphate amidotransferase (GFAT ; rate-limiting enzyme) and the concentrations of UDP-N-acetyl hexosam ines (major products of the pathway) as well as UDP-hexoses and GDP-ma nnose in hind limb muscles and liver in both transgenic models and con trols. GFAT activity was increased 60-70% in muscles of GLUT1 but not in GLUT4 transgenics. GFAT mRNA abundance was unchanged. The concentra tions of all nucleotide-linked sugars were increased 2-3-fold in GLUT1 and were unchanged in GLUT4-overexpressing muscles. Similar results w ere obtained in fed and fasted mice. GFAT and nucleotide sugars were u nchanged in liver, where the transgene is not expressed. We concluded that 1) glucose transport appears to be rate limiting for synthesis of nucleotide sugars; 2) chronically increased glucose flux increases mu scle GFAT activity posttranscriptionally; 3) increased UDP-glucose lik ely accounts for the marked glycogen accumulation in muscles of GLUT1- overexpressing mice; and 4) glucose flux via the hexosamine biosynthet ic pathway is increased in muscles of GLUT1-overexpressing but not GLU T4-overexpressing mice; products of the pathway may contribute to insu lin resistance in GLUT1 transgenics.