ACTIVATION OF THE HEXOSAMINE PATHWAY BY GLUCOSAMINE IN-VIVO INDUCES INSULIN-RESISTANCE IN MULTIPLE INSULIN-SENSITIVE TISSUES

We determined the effect of infusion of glucosamine (GlcN), which bypa sses the rate limiting reaction in the hexosamine pathway, on insulin- stimulated rates of glucose uptake and glycogen synthesis in vivo in r at tissues varying with respect to their glutamine:fructose-6-phosphat e amidotransferase (GFA) activity. Three groups of conscious fasted ra ts received 6-h infusions of either saline (BAS), insulin (18 mU/kg.mi n) and saline (INS), or insulin and GlcN (30 mu mol/kg.min, GLCN). [3- H-3]glucose was infused to trace whole body glucose kinetics and glyco gen synthesis, and rates of tissue glucose uptake were determined usin g a bolus injection of [1-C-14]2-deoxyglucose at 315 min. GlcN decreas ed insulin-stimulated glucose uptake (315-360 min) by 49% (P < 0.001) at the level of the whole body, and by 31-53% (P < 0.05 or less) in th e heart, epididymal fat, submandibular gland and in soleus, abdominis and gastrocnemius muscles. GlcN completely abolished glycogen synthesi s in the liver. GlcN decreased insulin-stimulated glucose uptake simil arly in the submandibular gland (1.3 +/- 0.2 vs. 2.0 +/- 0.3 nmol/mg p rotein min, GLCN us. INS, P < 0.05) and gastrocnemius muscle (1.4 +/- 0.3 vs. 3.1 +/- 0.5 nmol/mg protein.min), although the activity of the hexosamine pathway, as judged-from basal GFA activity, was 10-fold hi gher in the submandibular gland (286 +/- 35 pmol/mg protein.min) than in gastrocnemius muscle (27 +/- 3 pmol/mg protein.min, P < 0.001). The se data raise the possibility that overactivity of the hexosamine path way may contribute to glucose toxicity not only in skeletal muscle but also in other insulin sensitive tissues. They also imply that the mag nitude of insulin resistance induced between tissues is determined by factors other than GFA.