INCREASED GLUTAMINE-FRUCTOSE-6-PHOSPHATE AMIDOTRANSFERASE ACTIVITY INSKELETAL-MUSCLE OF PATIENTS WITH NIDDM

Overactivity of the hexosamine pathway mediates glucose-induced insuli n resistance in rat adipocytes. Glutamine:fructose-6-phosphate amidotr ansferase (GFA) is the rate-limiting enzyme of this pathway. We determ ined GFA activity in human skeletal muscle biopsies and rates of insul in-stimulated whole-body, oxidative, and nonoxidative glucose disposal using the euglycemic insulin clamp technique combined with indirect c alorimetry (insulin infusion rate 1.5 mU . kg(-1) . min(-1)) in 12 mal e patients with NIDDM (age 54 +/- 2 years, BMT 27.5 +/- 0.9 kg/m(2), f asting plasma glucose 8.5 +/- 0.6 mmol/l) and 9 matched normal men. GF A activity was detectable in human skeletal muscles and completely inh ibited by uridine-5'-diphospho-N-acetylglucosamine (UDP-GlcNAc) in all subjects. GFA activity was 46% increased in the NIDDM patients compar ed with the normal subjects (9.5 +/- 1.3 vs. 6.5 +/- 1.2 pmol, P < 0.0 5). Whole-body glucose uptake was 58% decreased in patients with NIDDM (20 +/- 3 mu mol . kg body wt(-1) . min(-1)) compared with normal sub jects (47 +/- 4 mu mol . kg body wt(-1) . min(-1), P < 0.001). This de crease was attributable to decreases in both glucose oxidation (9 +/- 1 vs. 15 +/- 1 mu mol . kg(-1) . min(-1), NIDDM patients vs. control s ubjects, P < 0.002) and nonoxidative glucose disposal (11 +/- 2 vs. 31 +/- 4 mu mol . kg(-1) . min(-1), P < 0.001). In patients with NIDDM, both HbA(1c) (r = -0.51, P < 0.05) and BMI (r = -0.57, P < 0.05) corre lated with whole-body glucose uptake. HbA(1c) but not BMI or insulin s ensitivity was correlated with basal GFA activity (r = 0.57, P < 0.01) in NIDDM patients and control subjects. We conclude that GFA is found in human skeletal muscle and that all this activity is sensitive to f eedback inhibition by UDP-GlcNAc. Chronic hyperglycemia is associated with an increase in skeletal muscle GFA activity, suggesting that incr eased activity of the hexosamine pathway may contribute to glucose tox icity and insulin resistance in humans.