From these studies, apparently oral glucosamine is metabolized and has an effect although the underlying mechanism is unknown. It is thought to suppress the immune system which is advantageous when there is an autoimmune disease present. However, glucosamine is known to increase insulin resistance. It could be a two-edged sword if it helps arthritis by decreasing the immune system response, but since it also increases GAG, then it may aggravate rheumatoid arthritis.



Br J Community Nurs 2002 Mar;7(3):148-52

Glucosamine therapy compared to ibuprofen for joint pain.

Ruane R, Griffiths P.

Primary Care and Community Pharmacy, King's College London.

To determine the effectiveness of oral glucosamine with ibuprofen for the relief of joint pain in osteoarthritis a mini-review (Griffiths, 2002) of double-blind randomized controlled trials comparing the two was undertaken. The population was adult patients diagnosed with osteoarthritis at any site. The outcome was arthritic pain reduction. Searches on Medline, Embase, AMED, the Cochrane Library and the Merck index identified four trials. Of these, two studies were obtainable and were included in the review. Both compared 1.2 g ibuprofen daily with 1.5 g glucosamine sulphate daily, in three divided doses. The combined number of participants in the studies was 218. The results of these studies showed glucosamine to be of similar efficacy to ibuprofen. The conclusion is that glucosamine is effective in relieving joint pain associated with osteoarthritis. Glucosamine's pain-relieving effects may be due to its cartilage-rebuilding properties; these disease-modifying effects are not seen with simple analgesics and are of particular benefit. In practice glucosamine can be used as an alternative to anti-inflammatory drugs and analgesics or as a useful adjunct to standard analgesic therapy.

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Immunosuppressive effects of glucosamine
Linlin M et al

Running title: Glucosamine immunosuppression
The American Society for Biochemistry and Molecular Biology, Inc.
JBC Papers in Press. Published on August 9, 2002 as Manuscript M2049242002

Summary:
Glucosamine is a naturally-occuring derivative of glucose, and is an essential component of glycoproteins and proteoglycans, important constituents of many eukaryotic proteins. In cells, glucosamine is produced enzymatically by the amidation of glucose-6-phosphate and can then be further modified by
acetylation to result in N-acetylglucosamine. Commercially, glucosamine is sold over the counter to relieve arthritis. While there is evidence in favor of glucosamine’s beneficial effects, the mechanism is unknown. Our data demonstrate that glucosamine suppresses the activation of T-lymphoblasts and dendritic cells in vitro, as well as allogeneic mixed leukocyte reactivity in a dose dependent manner. There was no inherent cellular toxicity involved in the inhibition and the activity was not reproducible with other amine sugars. More importantly, glucosamine administration prolongs allogeneic cardiac allograft survival in vivo. We conclude that, despite its documented effects on insulin
sensitivity, glucosamine possesses immunosuppressive activity and could be beneficial as an immunosuppressive agent.

Introduction
Glucosamine is a naturally-occuring sugar that is synthesised by virtually all cells. Upon uptake, glucose is immediately phosphorylated and enzymatically converted into a series of substrates that will either be converted into glycogen, lipids, proteins or used to generate ATP and CO2. 2-3% of glucose-6-phosphate, the immediate intracellular glucose derivative following uptake, is diverted into a pathway known as the hexosamine biosynthesis pathway (1,2). The rate-limiting
enzyme, glutamine:fructose-6-phosphate amidotransferase is responsible for the commitment of glucose derivatives into the pathway, ultimately resulting in the formation of glycoprotein precursors (3). Glucosamine is not secreted outside of cells, but exogenously-added glucosamine is taken up by glucose-transporters (GLUT-2 and GLUT-4) and then phosphorylated (4,5).
In 1953, Quastel and Cantero demonstrated that glucosamine possessed tumor-inhibitory activity (6). Since then, a number of reports confirmed the tumoricidal activity of glucosamine (7-16). Glucosamine has been shown to inhibit nucleic acid and protein biosynthesis and irreversible damage to organelles in tumor cells, but not in normal cells (8-15,17-20). In addition, glucosamine also inhibits platelet aggregation and ATP release induced by Staphylococcus aureus, ADP, epinephrine and collagen (21). The mechanisms by which glucosamine acts are not completely clear, however, it has been shown to alter the ultrastructure of plasma and intracellular membranes (9,22), to inhibit membrane transport of nucleosides (14,15) and reportedly to shift its distribution from glycoproteins to glycolipids (22).
O’Neill et al. demonstrated that monosaccharides, especially aminosugars, were able to inhibit cytotoxic T-lymphocyte function in culture preventing target lysis in a CTL clone-specific manner (23). In 1989, Yagita el al. further demonstrated that free hexosamines were able to inhibit NK cell cytotoxicity in culture (24,25) and that hexosamine release by tumors could, in part, explain escape of tumors from immune cell lysis (24). Since then, other than the observation that Amiprilose, a synthetic monosaccharide, was able to attenuate T-cell activation in a dose-specific manner (26), no other work has been published on the utility of sugar derivatives, especially amino sugar derivatives
(glucosamine, mannosamine, lactosamine, fructosamine), as immunoregulatory agents However, a recent report by Gouze et al. demonstrated glucosamine-dependent inhibition of NF-kB activity in rat chondrocytes and IL-1b bioactivity by upregulation of the type II IL-1 decoy receptor (27).
Glucosamine has received considerable attention in the past five years as an agent that may be beneficial for arthritis in a number of studies (28-31). Sold mainly over the counter in various formulations (glucosamine sulfate, glucosamine sulfate with chondroitin sulfate), the manufacturers suggest that the beneficial effects of their compounds are due to the construction of joint cartilage, of which one of the constituents is glucosamine in the form of glycoproteins of structural proteoglycans. A recent study in humans demonstrated beneficial effects of glucosamine in arthritis, although no firm conclusions could be made (28). The actual mechanism by which glucosamine may benefit the patient remains unknown, although very recent investigation suggests that it may interfere with pro-inflammatory cytokine action on human chondrocytes (32).
Glucosamine, however, induces insulin resistance in the absence of high glucose or glutamine (2) as well as insulin resistance in isolated rat muscle (33). Glucosamine has also been shown to modulate the effects of insulin and glucose on pyruvate kinase (34), glycogen synthase (33,34) and transforming growth factor alpha gene expression (35). A short-term exposure of cultured rat
adipocytes to glucosamine decreases GLUT-4 activity and longer, 16 hour incubations, result in decreased GLUT-4 cell surface levels (36). Furthermore, glucosamine infusion can induce insulin resistance in normoglycemic, but not hyperglycemic rats and this is accompanied by impaired GLUT-4 translocation to the cell surface of skeletal muscle in response to insulin (37). Insulin sensitivity in rat cardiac muscle and liver has also been shown to be affected by glucosamine infusion (38). More importantly, acute glucosamine infusion into humans has been demonstrated to mimic some of the metabolic aspects of insulin resistance in human type 2 diabetes mellitus (39).