EFFECTS OF DIABETES AND HYPERGLYCEMIA ON THE HEXOSAMINE SYNTHESIS PATHWAY IN RAT MUSCLE AND LIVER

In vitro studies suggested that increased flux of glucose through the hexosamine biosynthesis pathway (HexNSP) contributes to glucose-induce d insulin resistance. Glutamine:fructose-6-phosphate amidotransferase (GFAT) catalyzes glucose flux via HexSNP; its major products are uridi ne diphosphate(UDP)-N-acetyl hexosamines (UDP-HexNAc), We examined whe ther streptozotocin (Sn)induced diabetes (4-10 days) or sustained hype rglycemia (1-2 h) in normal rats alters absolute or relative concentra tions of nucleotide-linked sugars in skeletal muscle and liver in vivo . UDP-HexNAc and UDP-hexoses (UDP-Hex) were increased and decreased, r espectively, in muscles of diabetic rats, resulting in an similar to 5 0% increase in the UDP-HexNAc:UDPHex ratio (P < 0.01), No significant changes in nucleotide sugars were observed in livers of diabetic rats, In muscles of normal rats, UDP-HexNAc concentrations increased (P < 0 .01) and UDP-Hex decreased (P < 0.01) during hyperglycemia. The UDP-He xNAc:UDP-Hex ratio increased similar to 40% CP < 0.01) and correlated strongly with plasma glucose concentrations, Changes in liver were sim ilar to muscle but were less: marked. GFAT activity in muscle and live r was unaffected by 1-2 h of hyperglycemia, GFAT activity decreased 30 -50% in muscle, liver, and epididymal fat of diabetic rats, and this w as reversible with insulin therapy No significant change in GFAT mRNA expression was detected, suggesting post-transcriptional regulation Th e data suggest that glucose flux via HexNSP increases in muscle during hyperglycemic hyperinsulinemia and that the relative flux of glucose via HexNSP is increased in muscle in STZ-induced diabetes, Since nucle otide sugars are essential substrates for glycoprotein synthesis, chan ges in their absolute or relative concentrations may affect signal tra nsduction and contribute to insulin resistance.