Glucosamine effects in humans: a review of effects on glucose metabolism, side effects, safety considerations and efficacy.

Glucosamine is widely used to relieve symptoms from osteoarthritis. Its safety and effects on glucose metabolism are critically evaluated in this review. The LD50 of oral glucosamine in animals is approximately 8000 mg/kg with no adverse effects at 2700 mg/kg for 12 months. Because altered glucose metabolism can be associated with parenteral administration of large doses of glucosamine in animals and with high concentrations in in vitro studies, we critically evaluated the clinical importance of these effects. Oral administration of large doses of glucosamine in animals has no documented effects on glucose metabolism. In vitro studies demonstrating effects of glucosamine on glucose metabolism have used concentrations that are 100-200 times higher than tissue levels expected with oral glucosamine administration in humans. We reviewed clinical trial data for 3063 human subjects. Fasting plasma glucose values decreased slightly for subjects after oral glucosamine for approximately 66 weeks. There were no adverse effects of oral glucosamine administration on blood, urine or fecal parameters. Side effects were significantly less common with glucosamine than placebo or non-steroidal anti-inflammatory drugs (NSAID). In contrast to NSAID, no serious or fatal side effects have been reported for glucosamine. Our critical evaluation indicates that glucosamine is safe under current conditions of use and does not affect glucose metabolism.

[1]  J. Reginster,et al.  Structural and symptomatic efficacy of glucosamine and chondroitin in knee osteoarthritis: a comprehensive meta-analysis. , 2003, Archives of internal medicine.

[2]  M. Harris,et al.  The effect of glucosamine-chondroitin supplementation on glycosylated hemoglobin levels in patients with type 2 diabetes mellitus: a placebo-controlled, double-blinded, randomized clinical trial. , 2003, Archives of internal medicine.

[3]  W. Haase,et al.  Glucosamine sulfate compared to ibuprofen in osteoarthritis of the knee. , 1994, Osteoarthritis and cartilage.

[4]  T. Sugimura,et al.  Quantitative nutritional studies with water-soluble, chemically defined diets. IX. Further studies on d-glucosaminecontaining diets. , 1959, Archives of biochemistry and biophysics.

[5]  A. L. Vaz Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulphate in the management of osteoarthrosis of the knee in out-patients , 1982 .

[6]  S. Marshall,et al.  Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance. , 1991, The Journal of biological chemistry.

[7]  D. Gardiner,et al.  A Randomized Double-Blind Clinical Trial of the Effect of Chondroitin Sulfate and Glucosamine Hydrochloride on Temporomandibular Joint Disorders: A Pilot Study , 2001, Cranio : the journal of craniomandibular practice.

[8]  James W. Anderson,et al.  Meta-analysis of the effects of soy protein intake on serum lipids. , 1995, The New England journal of medicine.

[9]  J. Pujalte,et al.  Double-blind clinical evaluation of oral glucosamine sulphate in the basic treatment of osteoarthrosis. , 1980, Current Medical Research and Opinion.

[10]  J. Rindone,et al.  Randomized, controlled trial of glucosamine for treating osteoarthritis of the knee. , 2000, The Western journal of medicine.

[11]  Y. Henrotin,et al.  In-vitro evaluation of drugs proposed as chondroprotective agents. , 1992, International journal of tissue reactions.

[12]  G. Zanolo,et al.  Pharmacokinetics of glucosamine in the dog and in man. , 1986, Arzneimittel-Forschung.

[13]  D. Clemmons,et al.  Glucosamine induces resistance to insulin-like growth factor I (IGF-I) and insulin in Hep G2 cell cultures: biological significance of IGF-I/insulin hybrid receptors. , 2003, Endocrinology.

[14]  G. Hart,et al.  Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[15]  V. Welch,et al.  Glucosamine therapy for treating osteoarthritis. , 2005, The Cochrane database of systematic reviews.

[16]  S. Milewski Glucosamine-6-phosphate synthase--the multi-facets enzyme. , 2002, Biochimica et biophysica acta.

[17]  M. Buse,et al.  High glucose and glucosamine induce insulin resistance via different mechanisms in 3T3-L1 adipocytes. , 2000, Diabetes.

[18]  G. Scali,et al.  Glucosamine sulphate: a controlled clinical investigation in arthrosis. , 1981, Pharmatherapeutica.

[19]  H. Erb,et al.  Hematologic, hemostatic, and biochemical effects in dogs receiving an oral chondroprotective agent for thirty days. , 1996, American journal of veterinary research.

[20]  L. Revel,et al.  Antireactive properties of glucosamine sulfate. , 1991, Arzneimittel-Forschung.

[21]  Rovati Lc Clinical research in osteoarthritis: design and results of short-term and long-term trials with disease-modifying drugs. , 1992 .

[22]  J. Reginster,et al.  Glucosamine sulfate reduces osteoarthritis progression in postmenopausal women with knee osteoarthritis: evidence from two 3-year studies , 2004, Menopause.

[23]  T. Bliss,et al.  The genetic enhancement of memory , 2003, Cellular and Molecular Life Sciences CMLS.

[24]  P. Jobanputra Structural and symptomatic efficacy of glucosamine and chondroitin: relevant financial interest? , 2004, Archives of internal medicine.

[25]  J. Harding,et al.  The non-enzymic glycosylation of bovine lens proteins by glucosamine and its inhibition by aspirin, ibuprofen and glutathione. , 1989, Experimental eye research.

[26]  L. Revel,et al.  Antiarthritic effects of glucosamine sulfate studied in animal models. , 1991, Arzneimittel-Forschung.

[27]  G. Zanolo,et al.  Pharmacokinetics of glucosamine in man. , 1993, Arzneimittel-Forschung.

[28]  F. Jamali,et al.  Single dose pharmacokinetics and bioavailability of butyryl glucosamine in the rat. , 2006, Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques.

[29]  P. Vajranetra Clinical trial of glucosamine compounds for osteoarthrosis of knee joints. , 1984, Journal of the Medical Association of Thailand = Chotmaihet thangphaet.

[30]  L. Rovati,et al.  Absorption, distribution, metabolism and excretion of glucosamine sulfate. A review. , 2001, Arzneimittel-Forschung.

[31]  C. Giachetti,et al.  Absorption, distribution and excretion of radioactivity after a single intravenous or oral administration of [14C] glucosamine to the rat. , 1984, Pharmatherapeutica.

[32]  B. Dawson,et al.  The effect of glucosamine supplementation on people experiencing regular knee pain , 2003, British journal of sports medicine.

[33]  James W. Anderson,et al.  Breast-feeding and cognitive development: a meta-analysis. , 1999, The American journal of clinical nutrition.

[34]  G. Wu,et al.  Glucosamine inhibits inducible nitric oxide synthesis. , 2000, Biochemical and biophysical research communications.

[35]  R. Martuza,et al.  Inhibition of angiogenesis and growth of human nerve-sheath tumors by AGM-1470. , 1993, Journal of neurosurgery.

[36]  J. Olefsky,et al.  The effect of oral glucosamine sulfate on insulin sensitivity in human subjects. , 2003, Diabetes care.

[37]  J. Anderson,et al.  Effect of high glucose and high sucrose diets on glucose tolerance of normal men. , 1973, The American journal of clinical nutrition.

[38]  P. Span,et al.  Short-term glucosamine infusion does not affect insulin sensitivity in humans. , 2001, The Journal of clinical endocrinology and metabolism.

[39]  L. Rovati,et al.  Efficacy and safety of intramuscular glucosamine sulfate in osteoarthritis of the knee. A randomised, placebo-controlled, double-blind study. , 1994, Arzneimittel-Forschung.

[40]  J. Conquer,et al.  Effect of glucosamine supplementation on fasting and non-fasting plasma glucose and serum insulin concentrations in healthy individuals. , 2004, Osteoarthritis and cartilage.

[41]  T. Hammad,et al.  Efficacy of a combination of FCHG49 glucosamine hydrochloride, TRH122 low molecular weight sodium chondroitin sulfate and manganese ascorbate in the management of knee osteoarthritis. , 2000, Osteoarthritis and cartilage.

[42]  Eric Lejeune,et al.  Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial , 2001, The Lancet.

[43]  S. Snyder,et al.  Molecularly cloned mammalian glucosamine-6-phosphate deaminase localizes to transporting epithelium and lacks oscillin activity. , 1998, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[44]  W. Choi,et al.  Glucosamine-induced insulin resistance in 3T3-L1 adipocytes. , 2000, American journal of physiology. Endocrinology and metabolism.

[45]  P. Astrup,et al.  Glucosamine and experimental atherosclerosis. Increased wet weight and changed composition of cholesterol fatty acids in aorta of rabbits fed a cholesterol-enriched diet with added glucosamine. , 1977, Atherosclerosis.

[46]  H S Rosenkranz,et al.  An evaluation of the Escherichia coli WP2 and WP2 uvrA reverse mutation assay. , 1980, Mutation research.

[47]  M. Uldry,et al.  GLUT2 is a high affinity glucosamine transporter , 2002, FEBS letters.

[48]  T. Hammad,et al.  Oral treatment with a glucosamine-chondroitin sulfate compound for degenerative joint disease in horses: 25 cases , 1997 .

[49]  J. Fenton,et al.  Effect of longeing and glucosamine supplementation on serum markers of bone and joint metabolism in yearling quarter horses. , 1999, Canadian journal of veterinary research = Revue canadienne de recherche veterinaire.

[50]  K. Watanabe,et al.  Correlation between DNA-breaking activity of aminosugars and the amounts of active oxygen molecules generated in their aqueous solutions. , 1991, Agricultural and biological chemistry.

[51]  C. Meininger,et al.  Presence of glutamine:fructose-6-phosphate amidotransferase for glucosamine-6-phosphate synthesis in endothelial cells: effects of hyperglycaemia and glutamine , 2001, Diabetologia.

[52]  S. Gonnelli,et al.  [The efficacy and safety of glucosamine sulfate in the treatment of gonarthritis]. , 1996, La Clinica terapeutica.

[53]  E. Bonora,et al.  Effects of glucosamine infusion on insulin secretion and insulin action in humans. , 2000, Diabetes.

[54]  G. Hart,et al.  A role for N-acetylglucosamine as a nutrient sensor and mediator of insulin resistance , 2003, Cellular and Molecular Life Sciences CMLS.

[55]  L. Rovati Clinical research in osteoarthritis: design and results of short-term and long-term trials with disease-modifying drugs. , 1992, International journal of tissue reactions.

[56]  J. S. Brimacombe,et al.  Structure-activity relationships in the induction of single-strand breakage in plasmid pBR322 DNA by amino sugars and derivatives. , 1994, Carbohydrate research.

[57]  A. Lopes Vaz Double-blind clinical evaluation of the relative efficacy of ibuprofen and glucosamine sulphate in the management of osteoarthrosis of the knee in out-patients. , 1982, Current medical research and opinion.

[58]  M. Fischer,et al.  Glucosamine sulfate in osteoarthritis of the knee. , 1994, Osteoarthritis and cartilage.

[59]  A. Bignamini,et al.  Therapeutic activity of oral glucosamine sulfate in osteoarthrosis: a placebo-controlled double-blind investigation. , 1980, Clinical therapeutics.

[60]  A. Philippi,et al.  Glucosamine, chondroitin, and manganese ascorbate for degenerative joint disease of the knee or low back: a randomized, double-blind, placebo-controlled pilot study. , 1999, Military medicine.

[61]  D. Bagchi,et al.  Effects of oral glucosamine and chondroitin sulfate alone and in combination on the metabolism of SHR and SD rats , 2001, Molecular and Cellular Biochemistry.

[62]  Sebastian Schneeweiss,et al.  Relationship Between Selective Cyclooxygenase-2 Inhibitors and Acute Myocardial Infarction in Older Adults , 2004, Circulation.

[63]  L. Laine Approaches to nonsteroidal anti-inflammatory drug use in the high-risk patient. , 2001, Gastroenterology.

[64]  Tapadinhas Mj,et al.  Oral glucosamine sulphate in the management of arthrosis: report on a multi-centre open investigation in Portugal. , 1982 .

[65]  L. Rovati,et al.  Efficacy and safety of glucosamine sulfate versus ibuprofen in patients with knee osteoarthritis. , 1998, Arzneimittel-Forschung.

[66]  D. Felson,et al.  Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. , 2000, JAMA.

[67]  H. Murad,et al.  The effect of an oral supplement containing glucosamine, amino acids, minerals, and antioxidants on cutaneous aging: a preliminary study , 2001, The Journal of dermatological treatment.

[68]  E. Topol,et al.  Risk of cardiovascular events associated with selective COX-2 inhibitors☆ , 2002 .

[69]  K. Tanaka,et al.  Inhibitory effect of angiogenesis inhibitor TNP-470 on tumor growth and metastasis of human cell lines in vitro and in vivo. , 1993, Cancer research.

[70]  S Marshall,et al.  Coordinated regulation of glutamine:fructose-6-phosphate amidotransferase activity by insulin, glucose, and glutamine. Role of hexosamine biosynthesis in enzyme regulation. , 1991, The Journal of biological chemistry.

[71]  J. Hauptman,et al.  Serum concentrations of keratan sulfate, osteocalcin, and pyridinoline crosslinks after oral administration of glucosamine to standardbred horses during race training. , 2002, American journal of veterinary research.

[72]  K. Pavelka,et al.  Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study. , 2002, Archives of internal medicine.

[73]  L. Knodel Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs , 1994 .

[74]  J. Anderson,et al.  Effect of carbohydrate restriction and high carbohydrates diets on men with chemical diabetes. , 1977, The American journal of clinical nutrition.

[75]  M. Wolfe,et al.  Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. , 1999, The New England journal of medicine.

[76]  Gerald W. Hart,et al.  Glycosylation of Nucleocytoplasmic Proteins: Signal Transduction and O-GlcNAc , 2001, Science.

[77]  P. Major,et al.  Evaluation of glucosamine sulfate compared to ibuprofen for the treatment of temporomandibular joint osteoarthritis: a randomized double blind controlled 3 month clinical trial. , 2001, The Journal of rheumatology.

[78]  E. Topol,et al.  Risk of cardiovascular events associated with selective COX-2 inhibitors. , 2001, JAMA.

[79]  W. Shankland The effects of glucosamine and chondroitin sulfate on osteoarthritis of the TMJ: a preliminary report of 50 patients. , 1998, Cranio : the journal of craniomandibular practice.

[80]  J. Houpt,et al.  Effect of glucosamine hydrochloride in the treatment of pain of osteoarthritis of the knee. , 1999, The Journal of rheumatology.

[81]  A. Bignamini,et al.  Oral glucosamine sulphate in the management of arthrosis: report on a multi-centre open investigation in Portugal. , 1982, Pharmatherapeutica.

[82]  R. Makuch,et al.  Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. , 2000, JAMA.

[83]  R. Hughes,et al.  A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee. , 2002, Rheumatology.

[84]  S. Hill,et al.  Effect of Pre-Loading Oral Glucosamine HCl/Chondroitin Sulfate/Manganese Ascorbate Combination on Experimental Arthritis in Rats , 2001, Experimental biology and medicine.