Glucosamine regulation of glucose metabolism in cultured human skeletal muscle cells: Divergent effects on glucose transport/phosphorylation and glycogen synthase in non-diabetic and type 2 diabetic subjects

Chronic exposure (48 h) to glucosamine resulted in a dose-dependent reducti on of basal and insulin-stimulated glucose uptake activities in human skele tal muscle cell cultures from nondiabetic and type 2 diabetic subjects. Ins ulin responsiveness of uptake was also reduced. There was no change in tota l membrane expression of either GLUT1, GLUT3, or GLUT4 proteins. While gluc osamine treatment had no significant effects on hexokinase activity measure d in cell extracts, glucose phosphorylation in intact cells was impaired af ter treatment. Under conditions where glucose transport and phosphorylation were down regulated, the fractional velocity (FV) of glycogen synthase was increased by glucosamine treatment. Neither the total activity nor protein expression of glycogen synthase were influenced by glucosamine treatment. The stimulation of glycogen synthase by glucosamine was not due totally to soluble mediators. Reflective of the effects on transport/phosphorylation, total glycogen content and net glycogen synthesis were reduced after glucos amine treatment. These effects were similar in nondiabetic and type 2 cells . In summary: 1) Chronic treatment with glucosamine reduces glucose transpo rt/phosphorylation and storage into glycogen in skeletal muscle cells in cu lture and impairs insulin responsiveness as well. 2) Down-regulation of glu cose transport/phosphorylation occurs at a posttranslational level of GLUTs . 3) Glycogen synthase activity increases with glucosamine treatment. 4) No ndiabetic and type 2 muscle cells display equal sensitivity and responsiven ess to glucosamine. Increased exposure of skeletal muscle to glucosamine, a substrate/precursor of the hexosamine pathway, alters intracellular glucos e metabolism at multiple sites and can contribute to insulin resistance in this tissue.