Activation of the hexosamine pathway by glucosamine in vivo induces insulin resistance of early postreceptor insulin signaling events in skeletal muscle.

Abstract

To explore potential cellular mechanisms by which activation of the hexosamine pathway induces insulin resistance, we have evaluated insulin signaling in conscious fasted rats infused for 2-6 h with saline, insulin (18 mU x kg(-1) x min(-1)), or insulin and glucosamine (30 micromol x kg(-1) x min(-1)) under euglycemic conditions. Glucosamine infusion increased muscle UDP-N-acetylglucosamine concentrations 3.9- and 4.3-fold over saline- or insulin-infused animals, respectively (P < 0.001). Glucosamine induced significant insulin resistance to glucose uptake both at the level of the whole body and in rectus abdominis muscle, and it blunted the insulin-induced increase in muscle glycogen content. At a cellular level, these metabolic effects were paralleled by inhibition of postreceptor insulin signaling critical for glucose transport and glycogen storage, including a 45% reduction in insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation (P = 0.02), a 44% decrease in IRS-1 association with the p85 regulatory subunit of phosphatidylinositol (PI) 3-kinase (P = 0.03), a 34% reduction in IRS-1-associated PI 3-kinase activity (P = 0.03), and a 51% reduction in insulin-stimulated glycogen synthase activity (P = 0.03). These alterations in postreceptor insulin signaling were time-dependent and paralleled closely the progressive inhibition of systemic glucose disposal from 2 to 6 h of glucosamine infusion. We also demonstrated that glucosamine infusion results in O-linked N-acetylglucosamine modification of IRS-1 and IRS-2. These data indicate that activation of the hexosamine pathway may directly modulate early postreceptor insulin signal transduction, perhaps via posttranslation modification of IRS proteins, and thus contribute to the insulin resistance induced by chronic hyperglycemia.

Acute glucosamine-induced insulin resistance in muscle in vivo is associated with impaired capillary recruitment

“…This may reflect an involvement by liver, a species difference in the handling of glucosamine, since similar plasma levels of GlcN did induce insulin resistance in the rat [31]. Or it may simply be the result of not achieving sufficiently high levels of intracellular metabolites of the glucosamine pathway in muscle cells.…”

“…While there is some evidence for the former, there are some discrepancies in the findings. One research group [31] reported that insulinstimulated IRS-1 tyrosine phosphorylation was reduced by glucosamine, whereas another [32] found this was preserved in glucosamine-treated rats. When measured 1 min after a bolus injection of insulin, PI3 kinase (PI3K) activity associated with IRS-1 was decreased by glucosamine infusion, on the other hand, when the activity was measured following 2 h of insulin infusion, no effect of glucosamine was observed [32].…”

“…When measured 1 min after a bolus injection of insulin, PI3 kinase (PI3K) activity associated with IRS-1 was decreased by glucosamine infusion, on the other hand, when the activity was measured following 2 h of insulin infusion, no effect of glucosamine was observed [32]. Also, it was found that glucosamine reduced insulinstimulated IRS-1-associated PI3K activity [31]; however, these measurements were taken at the end of a 6 h infusion of insulin and glucosamine. Interestingly, when this was measured after only 2 h infusion, glucosamine had no effect [31].…”

“…Also, it was found that glucosamine reduced insulinstimulated IRS-1-associated PI3K activity [31]; however, these measurements were taken at the end of a 6 h infusion of insulin and glucosamine. Interestingly, when this was measured after only 2 h infusion, glucosamine had no effect [31]. In contrast to this, impaired insulin stimulation of PI3K activity was seen as early as 30 min after glucosamine infusion [33].…”

Dietary fatty acid composition during pregnancy and lactation in the rat programs growth and glucose metabolism in the offspring

“…UDP-N-acetyl-glucosamine (UDP-Gl c NA c ) and UDP-N-acetyl-galactosamine (UDP-GalNA c ), are highly correlated with the degree of insulin resistance [15]. Others have also shown that incubation of multiple insulin-sensitive rat and human tissues with glucosamine to generate increased concentrations of UDP-Gl c NA c induces insulin resistance [16,17,18,19,20]. Streptozotocin-induced diabetes and sustained hyperglycaemia in normal rats also increase total UDP-hexosamine content in muscle tissue [21].…”