Glutathione in oxidative stress

Glutathione in oxidative stress

Glutathione is the body’s main internal antioxidant, and is diminished in cases of oxidative stress, that is, when too many free radicals and other reactive oxygen and nitrogen species are generated for the body and the cell to detoxify successfully. As glutathione is used in these detoxifying reactions, it needs to be regenerated; but if diet is inadequate, or reactive oxygen species overpower the system, glutathione remains low in a vicious cycle that never allows the body to get out of oxidative stress. This is an unhealthy situation, one in which diabetics are particularly prone. However, there’s definitely something that can be done about this: improve the diet by adding more protein, especially cysteine-rich protein such as whey, and/or supplement the amino acids necessary to produce glutathione, those amino acids being cysteine and glycine. (Glutamine is also needed for synthesis of the tripeptide glutathione, but it is not an essential amino acid, i.e. not necessary – in most cases – in the diet.)

In the following paper, the researchers found diminished glutathione in diabetics. Glutathione Synthesis Is Diminished in Patients With Uncontrolled Diabetes and Restored by Dietary Supplementation With Cysteine and Glycine.

Sustained hyperglycemia is associated with low cellular levels of the antioxidant glutathione (GSH), which leads to tissue damage attributed to oxidative stress. We tested the hypothesis that diminished GSH in adult patients with uncontrolled type 2 diabetes is attributed to decreased synthesis and measured the effect of dietary supplementation with its precursors cysteine and glycine on GSH synthesis rate and oxidative stress.
RESEARCH DESIGN AND METHODS

We infused 12 diabetic patients and 12 nondiabetic control subjects with [2H2]-glycine to measure GSH synthesis. We also measured intracellular GSH concentrations, reactive oxygen metabolites, and lipid peroxides. Diabetic patients were restudied after 2 weeks of dietary supplementation with the GSH precursors cysteine and glycine.
RESULTS

Compared with control subjects, diabetic subjects had significantly higher fasting glucose (5.0 ± 0.1 vs. 10.7 ± 0.5 mmol/l; P < 0.001), lower erythrocyte concentrations of glycine (514.7 ± 33.1 vs. 403.2 ± 18.2 μmol/l; P < 0.01), and cysteine (25.2 ± 1.5 vs. 17.8 ± 1.5 μmol/l; P < 0.01); lower concentrations of GSH (6.75 ± 0.47 vs. 1.65 ± 0.16 μmol/g Hb; P < 0.001); diminished fractional (79.21 ± 5.75 vs. 44.86 ± 2.87%/day; P < 0.001) and absolute (5.26 ± 0.61 vs. 0.74 ± 0.10 μmol/g Hb/day; P < 0.001) GSH synthesis rates; and higher reactive oxygen metabolites (286 ± 10 vs. 403 ± 11 Carratelli units [UCarr]; P < 0.001) and lipid peroxides (2.6 ± 0.4 vs. 10.8 ± 1.2 pg/ml; P < 0.001). Following dietary supplementation in diabetic subjects, GSH synthesis and concentrations increased significantly and plasma oxidative stress and lipid peroxides decreased significantly.
CONCLUSIONS

Patients with uncontrolled type 2 diabetes have severely deficient synthesis of glutathione attributed to limited precursor availability. Dietary supplementation with GSH precursor amino acids can restore GSH synthesis and lower oxidative stress and oxidant damage in the face of persistent hyperglycemia.

Cysteine is the rate-limiting step in glutathione synthesis, and generally supplementation with it in the form of n-acetylcysteine should be enough to rebuild glutathione levels. Ideally, whey protein should be used instead (in my opinion), since it also supplies glycine as well as branched-chain amino acids, which are healthful and likely to be in short supply in cases of oxidative stress.

My speculation is that many cases of oxidative stress come about because many people are not eating enough protein. In these cases, the body cannot generate enough glutathione because the amino acids are needed elsewhere. (This occurs with glutathione competition.)

So, oxidative stress, whether in diabetes, chronic fatigue, depression, or other states of illness can be ameliorated with diet and supplements. These are central components in my book, Smash Chronic Fatigue.

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6 comments
Puzzle Pirate says March 29, 2014

Hi Mangan! I sent you a Tweet about this and you said I should leave a comment here.

I some questions about fasting and weight loss.

For a little over 6 months now I’ve been doing fasting for weight loss. In that time I’ve lost about 70 lbs. Started at 290, now at 220.

My weekly schedule looks like this:

Saturday: 3 regular meals
Sunday: Fast
Monday: Fast until dinner time, have a small meal (ex: one chicken breast + one serving potatoes from a box)
Tuesday: Fast
Wednesday: Fast until dinner time, have a small meal
Thursday: Fast
Friday: Fast
Saturday: 3 regular meals
repeat

On fasting days I permit myself water, multivitamins, coffee, chicken or beef broth for salt & sodium (to prevent headaches), sometimes “nutrition” drinks for vitamins or general dehydration (these drinks don’t exceed 250 calories)

But I’m running into a problem. For the last month to month 1/2 I’ve been stuck around 220 and my weight no longer wants to budge. I’m 5’11”, male, 37 years old, and at 220 I’m still about 40 – 50 lbs overweight.

I really don’t think I’m at a point where my weight should be stalling like this. My caloric deficit has to be very high based on all of that lack of eating. Because of my job I’m basically sedentary, and I find it hard to exercise while fasting anyhow. But I have done 3 mile walks around my neighborhood for some added extra calorie burn.

At this point I’m really not sure what to do for more weight loss. This last week it looks like I might lose one pound for tomorrow’s weigh in at the most or even stay the stable from last week. There’s a lot of articles on the internet about “starvation mode” and “if you don’t eat *enough* you won’t lose weight” but most of them smell like BS, and even Weight Watches calls it a “myth”:

http://www.weightwatchers.com/util/art/index_art.aspx?tabnum=1&art_id=35501

Anyhow. If you have any ideas as to what I could do I’d appreciate it. Should I just assume this is some kind of “plateau” and continue on assuming weight loss will resume? Should I cut out my Saturdays of 3 regular meals? (There’s no way I’m eating enough calories on Saturdays to compensate for the rest of the week.)

If you need more personal / awkward / compromising / embarrassing information let me know.

Reply
    Mangan says March 29, 2014

    Well, you’re doing a lot of fasting. How’s your hunger? Is it difficult going so much without food? Also, it seems as if you’re eating fairly low fat, mod carb. So if you’re hungry, cut a little carb, add some fat. But you asked me about your plateau, and on the face of it that seems hard to figure, unless maybe your metabolism has dropped a lot, but you don’t say that.

    I agree about the BS behind not eating enough, but the starvation mode thing is real enough I think. On LCHF, metabolisms don’t seem to drop as much, and if you can throw in some resistance training, metabolism doesn’t drop much at all.

    I don’t know if that’s helped you, let me know. Personally I stay lean eating LCHF, very occasional 16 hour fasts.

    Reply
Puzzle Pirate says March 29, 2014

“How’s your hunger? Is it difficult going so much without food?”

Surprisingly it has been lacking. Only once during this entire experience did I ever feel any kind of “true hunger”. I don’t mean cravings like “I want a bag of Doritos” I mean only once did I ever feel “I *must* eat now!”. That happened early on and it was only after 10 consecutive days of fasting (never doing that again). I ate a can of tuna fish and felt fine afterwards. It surprised me I could eat so little and that was enough for me.

“unless maybe your metabolism has dropped a lot, but you don’t say that.”

How would I know if it has? I mean, I don’t really *feel* any different. Not sluggish or anything. The only thing that has changed is that I keep my house at a higher temperature than before because I get cold if it goes below 77 or 78 degrees. But is that from a slowing metabolism or from lack of insulation from body fat? Donno.

Also, I’ve had my thyroid tested multiple times over the years and it always came back OK.

I have done well on Low Carb diets in the past when trying to lose wight. Last time I was successful in getting some pounds off was my early 20’s… but guess what? I gave up because my weight stalled at around 220 back then too.

“I don’t know if that’s helped you, let me know.”

At this point just about any information would help! lol

I really don’t want to stay on a treadmill where the wight won’t come off. This week I think I’ll skip my “cheat day” and see if that helps but really at the weight I’m at I shouldn’t need to. I’ve also been thinking about trying other things like switching to low carb instead of fasting or maybe every other day fasting like those lab rats they made live double their lifespan (or however long).

Reply
    Mangan says March 29, 2014

    To the extent that I’m able to add anything useful, I’d say that the plateau is a very common issue when trying to lose weight, so you’re not alone. As for your metabolism, seems a mixed bag. A suggestion would be to go the ketogenic route (VL carb), but you might be there already with all the fasting you do. Other ideas: stick it out, add weight training.

    I don’t know, I’ve never been in that position myself. I’m stuck on a plateau trying to gain muscle, and it’s about impossible for me at this point.

    Reply
ProudDaddy says September 20, 2015

I, too, found this study and another by the same group that didn’t involve T2D. My biochemistry is a bit weak, so I had difficulty translating mmol dosages. Roughly, I figured they were taking about 10 grams of cysteine and about the same of glycine per day.

Since normal recommended dosages of NAC are about 1 gram/day, I wonder if I’m miscalculating. Help.

Reply
    P. D. Mangan says September 20, 2015

    PD, at one time I tried to calculate dosages for this study and I came up with figures that were in the same ballpark. That’s a lot. One thing to consider is that, due to costs, the scientists want to be sure to see results within a limited period of time, so they gave large amounts. Undoubtedly they considered that amount safe, but the patients were under doctors’ supervision also. I’ve seen other studies in which people (HIV patients) took up to 8 g NAC daily, although I don’t think I would take that much.

    Anyway, no, I don’t think you’re miscalculating.

    Reply
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