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Papers In Press, published online ahead of print June 15, 2004
Hexos, Inc, Woodinville, WA 98072
Corresponding Author: Hexos{at}comcast.net
Glucose and glucosamine (GlcN) cause insulin resistance over several hours by increasing metabolite flux through the hexosamine biosynthesis pathway (HBP). To elucidate the early events underlying glucose-induced desensitization, we treated isolated adipocytes with either glucose or GlcN and then measured intracellular levels of glucose-6-P (G-6-P), GlcN-6-P, UDP-GlcNAc, and ATP. Glucose treatment rapidly increased G-6-P levels (T 1/2 < 1 min), which plateaued by 15 min and remained elevated for up to 4 hrs (glucose ED50= 4 mM). In glucose-treated cell, GlcN-6-P was undetectable; however, GlcN treatment (2 mM) caused a rapid and massive accumulation of GlcN-6-P. Levels increased by 5 min (~ 400 nmol/g) and continued to rise over 2 hrs (T1/2~ 20 min) before reaching a plateau at > 1,400 nmol/g (ED50= 900 uM). Thus, at high GlcN concentrations, unrestricted flux into the HBP greatly exceeds the biosynthetic capacity of the pathway leading to a rapid buildup of GlcN-6-P. The GlcN-induced rise in GlcN-6-P levels was correlated with ATP depletion, suggesting that ATP loss is due to phosphate sequestration (with formation of GlcN-6-P) or the energy demands of phosphorylation. As expected, GlcN and glucose increased UDP-GlcNAc levels (T1/2~ 14 to 18 min), but greater levels were obtained with GlcN (4-5 fold for GlcN, 2-fold for glucose). Importantly, we found that low doses of GlcN (< 250 uM, ED50= 80 µM) could markedly elevate UDP-GlcNAc levels without increasing GlcN-6-P or depleting ATP levels. These studies on the dynamic actions of glucose and GlcN on hexosamine levels should be useful in exploring the functional role of the HBP and in avoiding the potential pitfalls in the pharmacological use of GlcN.
J. Biol. Chem, 10.1074/jbc.M404133200
Submitted on April 14, 2004
Revised on June 15, 2004
Accepted on June 15, 2004
Dynamic actions of glucose and glucosamine on hexosamine biosynthesis in isolated adipocytes: Differential effects on glucosamine-6-phosphate, UDP-N-acetylglucosamine, and ATP levels
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