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-induced insulin resistance. Glutamine:fructose-6- phosphateamidotransferase (GFAT) catalyzes glucose flux via HexSNP; its major products are uridine diphosphate (UDP)-N-acetyl hexosamines (UDP-HexNAc). We examined whether streptozotocin (STZ)-induced diabetes (4–10 days) or sustained hyperglycemia (1–2 h) in normal rats alters absolute or relative concentrations of nucleotide-linked sugars in skeletal muscle and liver in vivo. UDP-HexNAc and UDP-hexoses (UDP-Hex) were increased and decreased, respectively, in muscles of diabetic rats, resulting in an ∼ 50% 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-HexNAc:UDP-Hex ratio increased ∼40% (P < 0.01) and correlated strongly with plasma glucose concentrations. Changes in liver were similar to muscle but were less marked. GFAT activity in muscle and liver was unaffected by 1–2 h of hyperglycemia. GFAT activity decreased 30–50% in muscle, liver, and epididymal fat of diabetic rats, and this was reversible with insulin therapy. No significant change in GFAT mRNA expression was detected, suggesting post-transcriptional regulation. The 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 nucleotide sugars are essential substrates for glycoprotein synthesis, changes in their absolute or relative concentrations may affect signal transduction and contribute to insulin resistance.