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Insulin Resistance and Glucosamine Supplementation
 
Glucose has three main intracellular fates, and the specific metabolic fate is cell type dependent. The first step in all three fates is the phosphorylation of glucose into glucose-6-phosphate.  This step, which is catalyzed by hexokinase in non-liver cells essentially brands the glucose molecule for intracellular use, since glucose-6-phosphate cannot pass back out through the cell membrane. Subsequent utilization of glucose-6-phosphate presents the first metabolic fork. Conversion to glucose-1-phosphate initiates the glycogen synthetic pathway, whereas isomerization to fructose-6-phosphate leads to another metabolic fork. Fructose-6-phosphate can be used in either the glycolytic pathway for energy production or the hexosamine biosynthetic pathway. Entry into the hexosamine biosynthetic pathway requires the conversion of fructose-6-phosphate into glucosamine-6-phosphate in a transamidation reaction catalyzed by glutamine fructose-6-phosphate amidotransferase.  For glucose utilization by the hexosamine pathway this enzymatic step is the rate-limiting step. In comparison to the glycolytic and glycogen synthetic pathways the hexosamine biosynthetic pathway accounts for a very small percentage of glucose utilization. All three metabolic fates require glucose transportation into the cell. Intracellular glucose metabolism occurs rapidly, creating a concentration gradient favouring glucose transportation into the cell. In all cell types a family of glucose transport proteins, the GLUT family, mediates intracellular glucose transport. Members of the GLUT family function in either an insulin dependent or independent manner. Cell types expressing insulin dependent GLUT proteins undergo insulin stimulated glucose transport.  A rise in blood glucose concentrations signals an increase in insulin secretion from pancreatic ß cells. Insulin increases glucose utilization by promoting glycogenesis, inhibiting glycogenolysis, and stimulating glucose transport in insulin responsive cells. Insulin binding to the insulin receptor initiates a series of cytosolic protein phosphorylation events that ultimately have both short and long term metabolic effects. Short-term effects include the increase in glucose uptake by responsive cells, activation of glycogen synthase, and inhibition of glycogen phosphorylase. Skeletal muscle cells, heart muscle cells and adipocytes are insulin responsive cells. They express GLUT-4, which is mainly segregated intracellularly and translocates to the plasma membrane in response to insulin. Longer-term effects include transcription of the glucokinase gene, an isoenzyme of hexokinase that has a higher km for glucose and is not subjected to product inhibition by glucose-6-phosphate. Higher levels of glucokinase help lower blood glucose levels and play a role in the liver's blood glucose buffering ability. The liver relies on GLUT-2 for glucose transport, which has a higher capacity than GLUT-4 and does not require insulin for maximal glucose transport. Thus the liver glucose is at about the same concentration of glucose as the blood. Since the glucokinase km for glucose is much higher than normal blood glucose concentrations an increase in glucose leads to a proportional increase in the rate of glucose phosphorylation. Hence, hepatic glucokinase expression contributes to the maintenance of blood sugar levels. Insulin resistance is the phenomenon whereby tissues fail to respond to insulin. Causes include a decrease in the number or affinity of insulin receptors and abnormal port receptor responses such as decreased or improper GLUT translocation. Hyperglycemia and glucosamine are commonly used to induce insulin resistance. Long-term hyperglycemia has deleterious effects, so there must be a strong biological rational for insulin resistance. It appears to be a defence mechanism to prevent cell engorgement by oxidizable compounds. The first step in glucose utilization is the conversion to glucose-6-phosphate catalyzed by hexokinase (except in hepatocytes). Hexokinase has a very low km for glucose and is quite quickly saturated. It follows than that continued glucose transport in response to insulin into a cell already inundated with glucose would lead to excessive glucose build-up.  Since glucose is an osmotically active molecule, this could lead to increased osmotic pressure and cell damage.  The actual mechanism by which hyperglycemia induces insulin resistance in humans is unclear. A common theory is that accumulation of the products of the hexosamine biosynthetic pathway has a major role in insulin resistance. The hexosamine pathway, which under normal circumstances accounts for so little glucose utilization, is thought to serve as a fuel sensor for insulin-sensitive cells in order to prevent the cells from being inundated by glucose1, an osmotically active molecule.  This theory is largely based on findings of increased concentrations of hexosamine pathway metabolites in instances of insulin resistance. However from other work it is clear that not all products of the hexosamine pathway play a role in insulin resistance. For instance, intravenous administration of 100 gm of N-acetyl-D-glucosamine into healthy human subjects had no appreciable effect on blood sugar levels and insulin requirements2.  If the end product of the hexosamine did have an important role in insulin resistance then N-acetyl-D-glucosamine should have raised blood sugar levels and insulin requirements. The accumulation of an earlier hexosamine metabolite is the main contributor. The accumulation of glucosamine-6-phosphate seems to have an important role in insulin resistance. Overexpression of the enzyme, glutamine fructose-6-phosphate amidotranferase, in muscle and adipocytes results in decreased glucose uptake and insulin resistance3 4 5 . Whereas glutamine fructose-6-phosphate amidotranferase inhibition prevents high glucose levels from inducing insulin resistance6. Glucosamine transport and phosphorylation occur by the same carriers and enzymes as glucose7. Insulin administration has also been shown to increase glucosamine clearance from blood8. However, simple competition between glucose and glucosamine is not believed to be sufficient to explain glucosamine-induced insulin resistance9:  GLUT-1 and 4 seem to have similar affinities for glucose and glucosamine10 and extracellular concentrations of glucose are always higher than glucosamine even during glucosamine infusions11. As with hyperglycemia induced insulin resistance, accumulation of the end products of the hexosamine pathway do not play a significant role in glucosamine induced insulin resistance. In a study by Virkamäki and Yki-Järvinen in rats with glucosamine induced whole body insulin resistance, a 500-700-fold increase was measured in glucosamine-6-phosphate levels in rectus abdominis muscle and heart but only a 5-fold increase in tissue concentrations of uridine N-acetyl-D-glucosamine12. It was hypothesized that since glucosamine-6-phosphate is similar in to glucose-6-phsophate, glucosamine-6-phosphate should also be able to alter glycogen synthetase and hexokinase activity. Indeed, the accumulation of glucosamine-6-phosphate was sufficient to stimulate glycogen synthetase activity allosterically and inhibit hexokinase activity.  Glucosamine administration had paradoxical effects on glycogen synthetase and glycogen synthesis; despite glycogen synthetase activation total glycogen synthesis decreased. The decrease in glycogen synthesis could be explained by depletion of the uridine glucose pool, a substrate for the glycogen synthetase pathway. The uridine glucose pools may have been depleted because of hexokinase inhibition. Glucosamine is also thought to be competitive inhibitor of beta cell glucokinase. Glucokinase in beta cells has a role in sensing glucose and stimulating insulin secretion. Glucosamine infusions raises the glucose threshold for glucose stimulated insulin secretion and leads to higher plasma fasting glucose levels13. It is also interesting to note that both non-diabetic and type two diabetic human skeletal muscle cells showed similar results when treated with glucosamine14. Chronic glucosamine treatment in both cell types led to a reduction in glucose transport and phosphorylation as well as a reduction in glycogen synthesis. N-acetyl-D-glucosamine does not seem to induce insulin resistance. In a study published in 1961, intravenous administration of N-acetyl-D-glucosamine had no effect on blood glucose levels nor did insulin administration stimulate the removal of N-acetyl-D-glucosamine from the blood15. A later study published in 1964 also found that N-acetyl-D-glucosamine is metabolized in humans without an appreciable change in blood sugar concentrations and did so independently of insulin16. Thus, N-acetyl-D-glucosamine is thought to be useful as a sugar substitute in intravenous fluid for postoperative subjects and patients with diabetes and liver disease17. Given the differences between N-acetyl-D-glucosamine's intracellular transport and phosphorylation mechanism and that of glucose or glucosamine, it is not surprising that the molecule seems incapable of inducing insulin resistance. N-acetyl-D-glucosamine does not compete with either glucose or glucosamine for intracellular transport, and is converted to N-acetyl-D-glucosamine-6-phosphate by N-acetyl-D-glucosamine kinase18 rather than hexokinase. Once phosphorylated, N-acetyl-D-glucosamine enters the pathway downstream of glucosamine-6-phosphate. Thus it does not lead to an accumulation of glucosamine-6-phosphate, which has been implicated in causing insulin resistance. N-acetyl-D-glucosamine does lead to an increase in uridine N-acetyl-D-glucosamine. However, this accumulation is of little concern since in humans the accumulation of end products of the hexosamine pathway does not induce insulin resistance. N-acetyl-D-glucosamine supplementation has an advantage over glucosamine supplementation in subjects with elevated blood sugar levels or hyperinsulinemia19.  1 Monauni, T., M. G. Zenti, et al. (2000). "Effects of glucosamine infusion on insulin secretion and insulin action in humans." Diabetes 49(6): 926-35. 2 Gaulden, E. C. and W. C. Keating (1964). "The effect of intravenous N-acetyl-D-glucosamine on the blood and urine sugar concentrations of normal subjects." Metabolism 13(5): 466-72. 3 Patti, M. E., A. Virkamaki, et al. (1999). "Activation of the hexosamine pathway by glucosamine in vivo induces insulin resistance of early postreceptor insulin signaling events in skeletal muscle." Diabetes 48(8): 1562-71. 4 Uldry, M., M. Ibberson, et al. (2002). "GLUT2 is a high affinity glucosamine transporter." FEBS Lett 524(1-3): 199-203. 5 Monauni, T., M. G. Zenti, et al. (2000). "Effects of glucosamine infusion on insulin secretion and insulin action in humans." Diabetes 49(6): 926-35. 6 Ciaraldi, T. P., L. Carter, et al. (1999). "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." Endocrinology 140(9): 3971-80. 7 Virkamaki, A. and H. Yki-Jarvinen (1999). "Allosteric regulation of glycogen synthase and hexokinase by glucosamine-6-phosphate during glucosamine-induced insulin resistance in skeletal muscle and heart." Diabetes 48(5): 1101-7. 8 Levin, R. M., N. N. Krieger, et al. (1961). "Glucosamine and acetylglucosamine tolerance in man." J Lab & Clin Med 58(6): 927-32. 9 Virkamaki, A. and H. Yki-Jarvinen (1999). "Allosteric regulation of glycogen synthase and hexokinase by glucosamine-6-phosphate during glucosamine-induced insulin resistance in skeletal muscle and heart." Diabetes 48(5): 1101-7. 10 Uldry, M., M. Ibberson, et al. (2002). "GLUT2 is a high affinity glucosamine transporter." FEBS Lett 524(1-3): 199-203. 11 Virkamaki, A. and H. Yki-Jarvinen (1999). "Allosteric regulation of glycogen synthase and hexokinase by glucosamine-6-phosphate during glucosamine-induced insulin resistance in skeletal muscle and heart." Diabetes 48(5): 1101-7. 12 Virkamaki, A. and H. Yki-Jarvinen (1999). "Allosteric regulation of glycogen synthase and hexokinase by glucosamine-6-phosphate during glucosamine-induced insulin resistance in skeletal muscle and heart." Diabetes 48(5): 1101-7. 13 Monauni, T., M. G. Zenti, et al. (2000). "Effects of glucosamine infusion on insulin secretion and insulin action in humans." Diabetes 49(6): 926-35. 14 Ciaraldi, T. P., L. Carter, et al. (1999). "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." Endocrinology 140(9): 3971-80. 15 Levin, R. M., N. N. Krieger, et al. (1961). "Glucosamine and acetylglucosamine tolerance in man." J Lab & Clin Med 58(6): 927-32. 16 Gaulden, E. C. and W. C. Keating (1964). "The effect of intravenous N-acetyl-D-glucosamine on the blood and urine sugar concentrations of normal subjects." Metabolism 13(5): 466-72. 17 Gaulden, E. C. and W. C. Keating (1964). "The effect of intravenous N-acetyl-D-glucosamine on the blood and urine sugar concentrations of normal subjects." Metabolism 13(5): 466-72. 18 Hinderlich, S., M. Berger, et al. (2000). "Molecular cloning and characterization of murine and human N-acetylglucosamine kinase." Eur J Biochem 267(11): 3301-8. 19 Monauni, T., M. G. Zenti, et al. (2000). "Effects of glucosamine infusion on insulin secretion and insulin action in humans." Diabetes 49(6): 926-35. | |||||
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Notice: The information is intended to provide the reader with a comprehensive understanding of the science underlying the role of glucosamine and N-acetylglucosamine in the mammalian body. The scientific information on this site has been compiled from many different scientific sources. No specific therapeutic claims are made for any product. The information provided on this site is for general information purposes only and is not intended to qualify, supplement or replace that of your medical professional. These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease. Your healthcare giver should undertake diagnosing and treating your medical condition.
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