Anti-Inflammatory Diet

All health care starts with diet. My recommendations for a healthy diet are here:
Anti-Inflammatory Diet and Lifestyle.
There are over 190 articles on diet, inflammation and disease on this blog
(find topics using search [upper left] or index [lower right]), and
more articles by Prof. Ayers on Suite101 .

Tuesday, September 16, 2008

Glucosamine Pain/Inflammation Relief

Glucosamine supplements work through effects on the gut that contribute to general anti-inflammation. It is thought that glucosamine interacts with tissue transglutaminase and blocks production of signaling molecules for chronic infammation. It should also be effective against inflammatory diseases of the intestines, joints and elsewhere.

Cartilage and other connective tissues are made up of collagen protein fibers embedded in a matrix of polysaccharide, chondroitin sulfate. The tightly packed, twisted proteins of the collagen in the negatively charged, acidic polysaccharide act like a fiber reinforced, dense gel that provides impact resistance for long bone joint surfaces, as well as the stretch-resistance and elasticity for tendon and ligaments. Collagen in cartilage is comparable to cellulose (crystallin neutral polysaccharide fibers) embedded in the acidic polysaccharide (pectin) of plant cell walls.

The connective tissue polysaccharides are glycosamino glycans, GAGs, the most intensely negatively charged molecules in the body. They are more negatively charged than the nucleic acids, and the proteins that bind to the negative charge of the phosphates of nucleic acids will preferentially bind to GAGs if they get a chance. An example of this is the removal of small, highly positively charged peptides, protamines, used to pack the chromosomes of sperm. These small proteins bind strongly and can only be removed from sperm chromosomes in fertilized eggs, by the brief introduction of GAGs. Heparin is the most negatively charged, most highly sulfated of the GAGs and protamine, is used medically to neutralize excess heparin that has been injected to block blood clotting.

GAGs are composed of alternating amino sugars, e.g. glucosamine, and uronic acids, e.g. glucuronic acid. These are among the most primitive of polymers and may have evolutionarily predated the nucleic acids. It was initially suspected that glucosamine supplements contributed directly to the production of the glucosamine-rich GAGs of the cartilage of joints and thereby helped to reduce joint pain. This is unlikely, however, because the level of glucosamine in the blood is normally vanishingly low and glucosamine supplements increase the level only a tiny amount. Further reflection on the negligible pain relief of meat that contains huge quantities of glucosamine in its connective tissue, confirms that supplemental glucosamine could not impact joint pain by its impact on GAG synthesis.

The usefulness of glucosamine in reducing inflammation and joint pain is based on its impact on the small intestine. I came to this conclusion through analysis of recent studies of inflammatory diseases of the intestines, e.g. celiac and inflammatory bowel disease. These diseases are autoimmune diseases in which the body produces antibodies to inappropriate proteins in the diet or of intestinal cells. The first step in the diseases is the shift to an inflammatory physiology of the intestines. The intestines normally respond to cellular antigens and food antigens with specific anti-inflammatory signals that actively suppress antibody production and lymphocyte activation, i.e. immunological tolerance. Infection of the intestines by a pathogen triggers an inflammatory physiology that is intolerant and immunologically aggressive. Antigens in this environment are presented to the immune system and antibodies are produced. Proteins with heparin-binding domains, e.g. nuclear proteins that would otherwise bind to nucleic acids or signaling proteins that bind to heparan sulfate proteoglycans, or allergens that have strong heparin-binding domains for unknown reasons, are strong immunogens in this context. An enzyme that is normally bound to the surface of the intestines, but is also brought into cells for additional signaling purposes, is tissue transglutaminase, tTG. In the gluten allergy disorder, celiac, antibodies are produced against the body’s tTG. This disorder is poorly understood, but I will try to use what is known to explain the use of glucosamine in pain relief.

Our focus in glucosamine pain relief is on the structure of glucosamine and how this molecular structure is integral to inflammation through the action of the enzyme tTG. Glucosamine is just a glucose sugar molecule with a nitrogen, amino group, added to one of the carbons. In a similar way, glutamine is just a glutamic acid with an amino group added to one end. Tissue transglutaminase is an enzyme that transfers the glutamic acid of glutamine from one molecule to another. As tTG transfers these glutamic groups, it forms intermediate structures with its own amino acids forming bonds to the glutamic group. Thus, wheat gluten, or gluten fragments with long stretches of glutamines, binds directly to make a tTG-gluten complex. Because tTG has strong heparin-binding domains, there is a tendency for the tTG-gluten complexes to be brought into intestinal cells and in an inflammatory physiological state, to be presented to the immune system for antibody production. As a result, antibodies to both tTG and gluten are produced as a consequence of certain forms of intestinal inflammation.

Another key observation was that many of the proteins involved in inflammatory signaling of the intestines are glycoproteins with unusual modifications of their attached sugar chains. Antibodies can be made and used to identify these unusual modifications. The modifications turned out to be attachment of glutamic acid through its carboxyl group to the amino group of the glucosamine of the glycoprotein sugar chains. It was this linkage that drew my attention, because it is similar to the way that tTG forms intermediates with the glutamines of proteins. It seemed obvious that tTG was the enzyme that was adding the glutamic acids (carboxylation) to the glucosamines of the intestinal glycoproteins! A search of the scientific literature revealed that glucosamine is in fact an inhibitor of tTG, showing that glucosamine binds to the enzyme, probably forming an intermediate as it does with glutamine.

The central piece of this complex puzzle was the observation that antibodies used to identify the carboxylated glycans (the sugar chains of the glycoproteins that have glutamic acid added) can block inflammation in inflammatory bowel disease. This suggests that some form of the glutamic acid/glucosamine conjugate to which the antibody binds is involved in inflammatory signaling. AGE receptors were implicated, because these receptors trigger inflammation and they are glycoproteins on the surface of the intestinal cells that are observed to by carboxylated with glutamic acids. AGE is an acronym for advanced glycation endproducts, the molecules formed at high blood sugar levels in diabetics, as glucose chemically interacts with the amino groups (frequently the lysines of heparin-binding domains) of proteins on the surface of the vascular system.

I think that glucosamine in supplements lowers inflammation and decreases pain by forming conjugates with glutamine through the enzymatic action of tTG. This action and the inactivation of tTG by the formation of tTG/glucosamine conjugates lowers inflammatory signaling and could perhaps block the formation of the toxic gluten/tTG/antibody amyloids characteristic of celiac. Glucosamine/glutamic acid conjugates may also be substrates for direct interactions with the AGE receptor.


Bill said...

Dr. Ayers,
What minimum dosage would you recommend of glucosamine? I seem to have most inflammation under control, and do not have many issues, apart from a cyst at the back of my knee that swells with exercise, but is not painful.

Dr. Art Ayers said...

Thanks for plowing through some of my earlier posts.

I think that glucosamine comes in 750 milligram pills. I usually take two a day.

Have you tried using Vicks Vaporub and castor oil to reduce or prevent the swelling? Just apply to the general area and it the Vicks should work within a couple of minutes. The castor oil will take longer, but will last longer too.

Anonymous said...

Dr. Ayers,
It's funny you mention Vicks.
I earlier pushed myself on a hill walk up to the local moors carrying 30 lbs, and the knee has swollen.
I bought some Vicks on your recommendation a few weeks ago, but have not tried it.
I'll rub some on the joint and apply now, and after exercise in future.
I will also try the glucosamine supplement.
Your prompt answers are always very much appreciated.

Mrs. Ed said...

Very interesting post. My doctor recommended Glucosamine to take whenever my fibromyalgia flares, which he says is realted to the celiacs or crohn's. If I am glutened I get fibro, but I also notice a slight tinge of it when I indulge in gf grains or sugar. If I stick to the SCD I do much better. It might be worth using glucosamine even when I don't have pain.

I know other folks with fibromyalgia and wonder why rheumatologists don't also send them for a gi check-up.

Anonymous said...

Does the source of glucosamine matter? Shellfish or corn? I try to avoid eating both of those, but as glucosamine, does it matter?

Dr. Art Ayers said...

Hi Mrs. Ed,
It is fun to see you digging through my old posts. I am sometimes shocked at both my old perspectives and insights. I occasionally read articles and put things together to solve a problem so fast that I forget that I have been there. I have searched on Google and found that the authority on the new subject is me in an old article.

As I indicate, I don't think that glucosamine is simple and a major part of its action is in the gut and different people will experience different results dependent on their gut flora.

It still puzzles me that we have such huge amounts of polymers of glucosamine in our diet from connective tissue in meat and even the walls of bacteria, that the tiny amounts in supplements should make no difference. So it must come down to how our gut flora digests these polymers and fails to provide free glucosamine to the upper part of the intestines. Dietary free glucosamine is available in the stomach and at the top of the intestines and may alter bacteria there or change the metabolism of the lining of those organs. Essentially none of the glucosamine gets into the blood.

The simple answer to your question of daily supplements with glucosamine is that it is cheap and has no side effects that are apparent, so if it avoids symptoms, it is cheap insurance.

Thanks for the questions and enjoy your reading.

Dr. Art Ayers said...

I don't think that the source of glucosamine matters.

secret agent girl said...

I tried a supplement containing glucosamine and chondroitin sulfate and disappointingly perceived no decrease in pain. (I also tried the castor oil idea to no positive effect.)

I wonder if I need to get inflammation more under control before it will help...?

I also think the studies show ambivalent/contradictory results to a higher degree than research on other supplements. I suppose it's worth trying to see if it helps an individual body; how dreary to have to cross it off the list and plod on trying to find some relief.

Karnisov said...

I read an article that said glucosamine is mostly destroyed by cooking. Would boiling meats preserve more of their glucosamine content?

Dr. Art Ayers said...

I don't think that glucosamine is altered by cooking, but it is present in meat polysaccharides in the same way that glucose is part of starch polysaccharides. That means that the glucosamine in meat is not released until the colon similarly to soluble fiber.

If glucosamine is eaten directly, then it has its impact in the small intestines and that appears to be the difference.

Thanks for the questions.

Anonymous said...

What do you think about this study?

Glucosamine causes the death of pancreatic cells

Dr. Art Ayers said...

That was an in vitro study, in which pancreatic beta cells were bathed in glucosamine. The glucosamine that you eat stays in your gut. I would not expect dietary glucosamine to affect serum glucosamine or the glucosamine level of pancreatic cells. I think that any glucosamine effects are gut-based.

Thanks for the question.

Anonymous said...

Sorry if my question sounds a bit stupid, but if it's the binding of tTG and glutamine that is inflammatory, should oral supplementation of l-glutamine be considered safe or not safe? And why?
Thank you for the answer

Anonymous said...

Can glucosamine cause insulin resistance?

Yesterday I bought some capsules to use for gut healing and knee inflammation, but before opening the bottle I googled glucosamine side effects/dangers. I normally do this before trying new supplements or meds because I have a lot of sensitivities. I got several returns relating glucosamine and insulin resistance, such as the following:

That one mentions obesity being a factor. I am not obese but somewhat overweight, and diabetes runs in my family. I'd really love some advice because I'm excited to begin taking the capsules.

Thanks very much for your help!

Unknown said...

Just yesterday started taking Glucosamine again, it's been 10/11 yrs. Very interesting in my case re: the dependence it has on gut flora. I got a lifetime diagnosis in 2008, the biggest mystery of my life which has to do with gut flora. The test yielding the diagnosis was a intestinal DNA indicating I was born with intestinal dysbiosis, specifically Clostridium Botulinum. It wasn't until I ran into a retired nurse just last yr who said MSM would pretty much be the cure. Very familiar with this and glucosamine, got very excited, hopeful. Longer story short, last month went thru a 3wk long detox, very critical, very disappointed that over a yr with MSM, now after major detox, I've not jumped in my health at all. Had been using a spray with Gluco/Msm in it and it started working like magic, thought I'd try Gluco. again. Would love to know what you think of my very unique case. Feel like I'm the only one in the world with this condition.

Thank you!

n A j A m said...

Hi Dr. Art,

Is this supplement recommended for Diabetic patients? What about Insulin resistance question?

Deidrejoy said...

Hello Dr. Art!

What do you think of the idea that relief from inflammation received from Glucosamine supplementation is due to the chitin binding to the lectins in our food instead of binding to our tissues, which spares one from the full impact of
those inflammatory properties?

Gil said...

yes, it is LECTIN in wheat, potatoes, tomatoes, peppers, eggplant, that cause the problem in the intestins making the gut leaky and those lectins than also go to joints where it cause the inflammation .... stop eating those foods and you might get better with supplements...but there are some that could help remove the existing lectins in the intestines also

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