Discordant effects of glucosamine on insulin-stimulated glucose metabolismand phosphatidylinositol 3-kinase activity

The impact of increased GlcN availability on insulin-stimulated p85/p110 ph osphatidylinositol 3-kinase (PI3K) activity in skeletal muscle was examined in relation to GlcN-induced defects in peripheral insulin action. Primed c ontinuous GlcN infusion (750 mu mol/kg bolus; 30 mu mol/kg min) in consciou s rats limited both maximal stimulation of muscle PI3K by acute insulin (1) (1 unit/kg) bolus (I + GlcN = 1.9-fold versus saline = 3.3-fold above fast ing levels; p < 0.01) and chronic activation of PI3K following 3-h euglycem ic, hyperinsulinemic (18 milliunits/kg min) clamp studies (I + GlcN = 1,2-f old versus saline = 2,6-fold stimulation;p < 0.01). To determine the time c ourse of GlcN-induced defects in insulin-stimulated PI3K activity and perip heral insulin action, GlcN was administered for 30, 60, 90, or 120 min duri ng 2-h euglycemic, hyperinsulinemic clamp studies. Activation of muscle PI3 K by insulin was attenuated following only 30 min of GlcN infusion (GlcN 30 min = 1.5-fold versus saline = 2.5-fold stimulation; p < 0.05). In contras t, the first impairment in insulin-mediated glucose uptake (Rd) developed f ollowing 110 min of GlcN infusion (110 min = 39.9 +/- 1.8 versus 30 min = 4 2.8 +/- 1.4 mg/kg.min, p < 0.05), However, the ability of insulin to stimul ate phosphatidylinositol 3,4,5-trisphosphate production and to activate gly cogen synthase in skeletal muscle was preserved following up to 180 min of GlcN infusion. Thus, increased GlcN availability induced (a) profound and e arly inhibition of proximal insulin signaling at the level of PI3K and (b) delayed effects on insulin-mediated glucose uptake, yet, (c) complete spari ng of insulin-mediated glycogen synthase activation, The pattern and time s equence of GlcN-induced defects suggest that the etiology of peripheral ins ulin resistance may be distinct from the rapid and marked impairment in ins ulin signaling.