Comprehensive Guide to Glucosamine Sulfate

Glucosamine SulfateDr. James Meschino DC, MS, ND
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General Features
Glucosamine-6-phosphate is the precursor from which all proteoglycans are synthesized. Proteoglycans are found in the synovial fluid of joints, the vitreous humor of the eye, arterial walls, as well as bone and cartilage. They are major components of the extracellular matrix or ground substance, a gelatinous material that forms a meshwork between cells. Proteoglycans are proteins that contain many chains of glycosaminoglycans (formerly called mucopolysaccharides).
Glycosaminoglycans are long, unbranched polysaccharides composed of repeating disaccharide units. The repeating disaccharides usually contain an uronic acid or a glucuronic acid, and a hexosamine, and are frequently sulfated. All hexosamines are derived from glucosamine-6-phosphate. Hence the synthesis of glucosamine-6-phosphate is essential to the production of ground substance throughout our lives. This extracellular matrix is more than glue that holds cells together. It also serves as a barrier to microorganisms from reaching cells. Because they are long and negatively charged, glycosaminoglycans chains repel each other. As well, the proteoglycans occupy a very large space and act as “molecular sieves”, determining which substances approach and leave cells. Their properties also give resilience to substances such as cartilage, permitting compression and reexpansion (shock absorbing function)
There are at least seven types of glycosaminoglycans, which differ from each other based upon the monosaccharides present in their repeating disaccharide units:
1. Chondroitin sulfate
2. Dermatan sulfate
3. Heparin
4. Heparin sulfate
5. Hyaluronic acid
6. Keratan sulfate I
7. Keratan sulfate II
Except for hyaluronic acid, the glycosaminoglycans are linked to proteins, usually attached covalently to serine or threonine residues, and are hence also referred to as proteoglycans. Keratan sulfate I is attached to asparagine. The synthesis of all glycosaminoglycans is dependent upon the presence of glucosamine-6-phosphate.
The body normally synthesizes glucosamine-6-phosphate by the transfer of an amino group from the amide of glutamine to fructose 6-phosphate. Glucosamine can then be N-acetylated by an acetyltransferase enzyme to yield N-acetyl glucosamine-6-phosphate and N-acetyl galactosamine, which are then linked to UDP. Both N-acetyl glucosamine and N-acetyl galactosamine are used as monosaccharides to form various glycosaminoglycans. The glycosaminoglycans in joint cartilage are comprised of repeating units of glucuronic acid and N-acetyl galactosamine. It appears that as some people age, they lose the ability to manufacture sufficient levels of glucosamine-6-phosphate, and thus, there is a reduction in the synthesis of N-acetyl galactosamine and N-acetyl glucosamine. The result is that cartilage loses its ability to act as a shock absorber and erosion of cartilage and ground substance can lead to osteoarthritis. Radioisotope studies using C14 glucosamine indicate that glucosamine supplementation is a good substrate for a kinase enzyme which yields glucosamine-6-phosphate, which can then be used to form glycosaminoglycans.
The best form of glucosamine has been shown to be Glucosamine Sulfate. N-acetylglucosamine is a poor substrate for a kinase activity and glucosamine hydrochloride has poor supportive evidence for its use. It appears that the sulfur component of Glucosamine Sulfate may be critical to its beneficial effects on arthritis and other problems.
Glucosamine ingestion also has a concurrent effect on increasing collagen production by chondrocytes, helping to reverse the osteoarthritic process.
Clinical Conditions and Mechanisms
1. Osteoarthritis
Oral Glucosamine Sulfate has been shown to decrease pain and improve mobility in osteoarthritic patients without side effects, in a large number of double-blind, placebo controlled studies.
Mechanism: promoting the synthesis of glycosaminoglycans and collagen by chondrocytes. This may also have application in Rheumatoid Arthritis as well.10-16
2. Wound healing
Oral glucosamine may speed the healing of surgical wounds and may diminish scarring, keloids, adhesions, strictures.
Mechanism: Promoting the synthesis of hyaluronic acid by fibroblasts in the early stages of healing.
3. GI ulcers and inflammatory bowel disorders
In animal studies, glucosamine supplementation has been shown to be clinically useful for these conditions.
Mechanism: oral glucosamine increases production of heparan sulfate proteoglycans by the vascular endothelium, thereby improving the endothelium’s barrier function. Extravasation of leukocytes and metastatic cancer cells requires degradation of heparan sulfate. Heparan can inhibit neutrophil activation, adhesion, and chemotaxis and like glucosamine has been reported to be effective for managing inflammatory bowel syndromes.
Interestingly, the metastatic capacity of cancer cells tends to correlate with their ability to produce heparanase. It is concluded that heparan sulfate proteoglycans play an important role in stabilizing the subendothelial extracellular matrix, cross-linking proteins and reducing their susceptibility to proteolytic degradation. Heparan therapy has been successful in animals and humans with ulcerative colitis.
In both ulcerative colitis and Crohn’s disease there’s a marked deficiency in extracellular sulfated glycosaminoglycans in the mucosa (ulcerative colitis) and submucosa (Crohn’s disease), as well as along the vascular endothelium and subepithelial basal lamina
Dosage and Standardized Grade
For arthritic conditions and wound healing an oral dose of 500 mg taken three times per day is typical. In heavier patients and those on diuretics, the total daily dosage should be 20 mg/kg body weight. For arthritic patients improvement is usually noted within 8-12 weeks.
The best form of glucosamine is Glucosamine Sulfate.
Toxicity and Contraindications At the above recommended levels glucosamine sulfate is highly non toxic.
Rare side effects have included stomach upset, heartburn, diarrhea, nausea and indigestion. Patients with sulfa drug or sulfite allergies can still take Glucosamine Sulfate. It is impossible to be allergic to sulfur because it is an essential mineral for life. Individuals taking diuretics may need higher dosages (20 mg/kg body weight).29
There is some suggestion that glucosamine supplementation may increase insulin resistance in diabetics. The clinical importance of this remains to be determined
Drug-Nutrient Interaction
There are no well-known drug-nutrient interactions for Glucosamine Sulfate.
1. Murray M. Encyclopedia of Nutritional Supplements. Rocklin, CA: Prima Publishing; 1996. p. 336-42.
2. Marks DB, Marks AD, Smith CM, editors. Basic Medical Biochemistry: A clinical Approach. Baltimore, Maryland: Williams and Wilkins; 1996. p. 452-64.
3. McCarthy M. Neglect of glucosamine as a treatment for osteoarthritis-a personal perspective. Medical Hypotheses 1994;42:323-7.
4. McCarthy M. Glucosamine for wound healing. Medical Hypothesis 1996;47:273-5.
5. Palmoski MJ, Brankt KD. Effects of some nonsteroidal anti-inflammatory drugs on proteoglycan metabolism and organization in canine articular cartilage. Arthritis Rheum 1980;23:1010-20.
6. Roden L. Effect of hexosamines on the synthesis of chondroitin sulphuric acid in vitro. Arc Kemi 1956;10:345-52.
7. Karzel K, Domenjoz R. Effects of hexosamine derivatives and uronic acid derivatives on glycosaminoglycan metabolism of fibroblast cultures. Pharmacology 1971;5:337.
8. Kim JJ, Conrad HE. Effect of D-glucosamine concentration on the kinetics of mucopolysaccharides biosynthesis in cultured chick embryo vertebral cartilage. J Biol Chem 1974;249:3091-7.
9. Matalon R, Dorfman A. The structure of acid mucolpolysaccharides produced by Hurler fibroblasts in tissue culture. Proc Nat Acad Sci USA 1968;60:179-85.
10. Vidal RR, et al. Articular Cartilage Pharmacology: Parmacol Res Comm 10 1978;557-569.
11. D'Ambrosia E, Casa B, Bompani R et al. Glucosamine sulphate. A controlled clinical investigation in arthrosis. Pharmacotherapeutica 1982;2:504-8.
12. Vas AL. Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulfate in the management of osteoarthroses of the knee in out-patients. Current Med Res Opinion 1982;8:145-9.
13. Refinster JY, et al. Glucosamine sulfate significantly reduces progression of knee osteoarthritis (KOA). Arthritis Rheum 1999;42:292.
14. Delafuente JC. Glucosamine in the treatment of osteoarthritis. Rheum. Dis Clin North Am 2000;26(1):1-11.
15. Gottleib MS. Conservative management of spinal osteoarthritis with glucosamine sulfate and chiropractic treatment. J Manipulative Physiol Ther 1997;20(6):400-14.
16. Glucosamine Sulfate [monograph]. Altern Med Rev 1999;4(3):193-5.
17. Moriga M, Aono M, Murakami M, Uchino H. The activity of N-acetylglucosamine kinase in rat gastric mucosa. Gastroenterol Japonica 1980;15:7-13.
18. Vlodavsky I, Fuks Z, Bar-Ner M, et al. Lymphoma-cell-mediated degradation of sulfated proteoglycans in the subendothelial extracellular matrix: Relationship to tumor cell metastasis. Cancer Res 1983;43:2704-11.
19. Nakajima M, Irimura T, Di ferrante D, et al. Heparam sufate degradation: Relation to tumor invasion and metastsitc properties of mouse B16 melanoma sublines. Science 1983;220:611-2.
20. Ricovery W, Cappelletti R. Heparan sulfate endoglycosidase and metastatic potential in murine fibrosarcoma and melanoma. Cancer Res 1986;45:3855-61.
21. Nakajima M, Irimura T, Nicolson GL. Heparanase and tumor metastasis. J Cell Biochem 1988;36:157-67.
22. Vlodavsky I, Eldor A, Bar-Ner M, et al. Heparan sufate degradation in tumor cell invasion and angiogenesis. Adv Exp Med Biol 1988;233:201-10.
23. Clodavsky I, Korner G, Ishai-Michaeli R, et al. Extracellular matrix resident growth factors and enzymes: Possible involvement in tumor metastasis and angiogenesis. Cancer Metastasis Rev 9 1990;203-26.
24. Dwarakanath AD, Yu LG, Brookes C, et al. ‘Sticky’ neutropolis pathergic arthritis and response to heparin in pyoderma gangrenosum complicationg ulcerative colitis. Gut 1995;37:585-8.
25. Gaffney PR, O’Leary JJ, Doyle CT, et al. Response to heparin in patients with ulcerative colitis. Lancet 1991;337:238-9.
26. Gaffney PR, Doyle CT, Hogan J, Gaffney A. Paradoxical response to heparin in 10 patients with ulcerative colitis. Gastroenterology 1993;104:A703.
27. Murch SH, MacDonald TT, Walder-Smith JA, et al. Disruption of sulfated glycosaminoglycans in intestinal inflammation. Lancet 1993;341:711-4.
28. Lee JCL, Spittel JA Jr., Sauer WG, et al. Hypercoagulability associated with chronic ulcerative colitis: Changes in blood coagulation factors. Gastroenterology 1968;54:76-85.
29. Murray MT. The Healing Power of Herbs. 2nd Ed. Rocklin, CA: Prima Publishing; 1995.
30. Monauni T, Zenti MG, Cretti A, Daniels MC, Targher G, Caruso B, et al. Effects of glucosamine infusion on insulin secretion and insulin action in humans. Diabetes. 2000;49(6):926-35.
31. Shankar RR, Zhu JS, Baron AD. Glucosamine Infusion in rats mimics the beta-cell dysfunction of non-insulin-dependent diabetes mellitus. Metabolism 1998; 47(5):573-7.