Saturday, March 16, 2013

Protons: Meet the glycerol 3 phosphate shuttle

The next thing we have to think about is the glycerol 3 phosphate shuttle. This is a route in to the electron transport chain for cytoplasmic NADH, directly from the cytoplasm, no complex I involved.

There are two glycerol 3 phosphate dehydrogenases which make up the shuttle, just to confuse matters. Free in the cytosol there is cytosolic G3P dehydrogenase, which actually uses NADH to add a pair of hydrogens to a glycolysis intermediate (dihydroxyacetone phosphate) to form G3P.

The other G3P dehydrogenase really does dehydrogenate G3P, back to dihydroxyacetone phosphate. But this second G3P dehydrogenase is embedded in the outer surface of the inner mitochondrial membrane. And it contains an FAD/FADH2 moiety which takes these two hydrogens and uses them to reduce the CoQ couple, feeding electrons in to the electron transport chain.

So we are putting electrons from cytosolic NADH directly in to the ETC through FADH2. From the outside. And pumping no protons.

The G3P shuttle is very, very important.

In healthy cells the signal to reject excess calories picks on glucose, in the form of the development of insulin resistance, mediated by superoxide generated at complex I of the mitochondria. At iron sulphur cluster N-1a. The most simple way of doing this is to oxidise fully saturated fats (mmmmm, butter), generate a lot of FADH2, post a few electrons the wrong way through complex I and shut down glucose acceptance by the cell.

You can make glucose act as if it were butter through the G3P shuttle.

Think what happens if you are a Taterhead, just finishing your 4th plate of plain boiled, unsalted, unseasoned, unpeeled spuds.

Your FFAs, especially palmitate, are through the floor. Your glucose, given its own way, would be through the roof. Insulin is demanding that all cells accept glucose because no one wants a blood glucose of 30mmol/l. There is a shedload of NADH in both the cytoplasm and in the mitochondrial matrix. Electrons are pouring down the ETC but, in your post spud-prandial insulin induced stupor, you are not exactly sprinting to the gym.

You have to stop the supply of NADH pouring through complex I but, unless the NADH level is over three times the NAD+ level in mitochondria, you are not exactly going to get an electron on to N-1a excepting when there is a markedly reduced CoQ couple and a strong membrane potential. In the absence of palmitic acid (you're pigging out on fat-free spuds, don't forget) you need mitochondrial G3P dehydrogenase to pour electrons on to the CoQ couple, which allow the insulin/glucose induced membrane potential to push electrons back up the ETC to N-1a. And then SHUT DOWN THE BLOODY GLUCOSE SUPPLY.

You might just be able to do the same to deal with excess insulin. If insulin (from exogenous injection or an insulinoma) is allowing a free fall of glucose in to the cell and the cell really doesn't want all of this metabolic substrate, it has to say no. It was quite a while ago now but we have discussed insulin induced insulin resistance. Here's a possible metabolic mechanism. And the mechanism would kick in when the G3P shuttle goes in to overdrive, not when glucose becomes too low. Back to when we had the discussions about the Somogyi overswing... It's just a mimic of pigging out on spuds but without the spuds.

But the queen of insulin resistance generators is, of course, fructose. Fructose free falls through glycolysis to levels that the cells really cannot expect to use immediately. Of course a lot of it gets off loaded as lactate but there is still way more pyruvate than a cell can reasonably be expected to oxidise immediately. I consider this effect to be dose related. Eating the occasional apple might not kill you (gasp, there, I said it) but three Big Gulps per day probably has you well on your way.

Answer to fructose exposure is to shut down glucose supply to a level which compensates for the calories coming through from fructose. There can be no easier way than to reduce the CoQ couple using an FADH2 input. G3P dehydrogenase does this directly from the cytoplasm. It, like electron transferring flavoprotein dehydrogenase, is what I would describe as "complex II -like" in its action.

This smacks of physiological regulation to me.

Things get slightly more pathological where hyperglycaemia is overcoming insulin resistance. Or overcoming absolute insulin deficiency, as Sonksen and Sonksen pointed out. I'll come back to this in future posts.

There is quite a lot of support for this concept in Pubmed but here is an abstract I particularly enjoyed. Anyone thinking of indulging in a bit of Taterism should have a read first. A real giggle while you boil your spuds.

The wild type mice were funniest. For your delectation:

"The high carbohydrate diet induced hyperglycaemia, hyperinsulinaemia, and islet hyperplasia in the wild-type [mice]"

Oh, for the love of Taterism, does anyone remember the discussion of Barnard's victims and their progression of diabetes under a low sugar, high complex carbohydrate diet? Well, mice are not so different from people! In people we call this Taterism. Well, some of us do.

And look at the tweaked physiology in the same abstract. If you knock out mG3P dehydrogenase (ie you eliminate this "complex II-like" FADH2 reduction of the CoQ couple) you get increased insulin sensitivity (no reverse electron flow as there is no FADH2 route in to the ETC except complex II and we're not feeding fat).

Is this a good or a bad state to be in? That depends on degree and whether you are happy to push far more electrons down your ETC than you could possibly have a use for. An interesting question. I'm not in the queue to trial a mG3P dehydrogenase inhibitor (actually, it's called diazoxide and it does seem to help). Not eating carbs seems a rather safer bet.

[BTW if anyone has this high carb paper it would be nice to know which mice they used and what the diet was actually made of... Ta.]

Edit: Got it, many thanks Paul and Purposelessness. End edit

Which leads straight on to neurons.



Nigel Kinbrum said...

"Think what happens if you are a Taterhead, just finishing your 4th plate of plain boiled, unsalted, unseasoned, unpeeled spuds."
Can anyone eat more than 1 plate of plain boiled, unsalted, unseasoned, unpeeled spuds at a sitting? That's how the tater diet works. There's no food reward.

Also, insulin sensitive people don't suffer from hyperinsulinaemic comas after eating carbs.

Purposelessness said...

I can, Nigel.

Peter, full text:

love, Purp

Peter said...

Thanks Purp


Scott Russell said...

I'll second being able to put down a plate of potatoes no problem (doubly so for sweet potatoes, mmmm fructose).
And even in the post-workout window, where I have Glut4 on my side, I find there is no quicker way to make me fall asleep. Carbs at night work wonders.

Granted, I'm unsure if any of this is problematic in eucaloric scenarios.

Gadfly said...

Nigel, me ol' China, have you tried eating 10% of your food by weight in sugar yet?

karl said...

I wonder if genetic differences that effect the glycerol 3 phosphate shuttle explain some of the differences in tolerating carbohydrates we see?

Excellent posts -

Nigel Kinbrum said...

Gadfly said...
"Nigel, me ol' China, have you tried eating 10% of your food by weight in sugar yet?"
Gadfly, me ol' bean, what do you mean by "sugar"? If you mean table sugar i.e. sucrose, the answer is no.

Surely, the only people capable of eating four platefuls of insipid food like plain boiled, unsalted, unseasoned, unpeeled spuds or plain boiled, unsalted, unseasoned rice are bodybuilders, or somebody trying to make a point. Sweet potatoes don't count, as they taste nice.

Purposelessness said...

So Nigel asks who can eat lots of bland potatoes.

He then dismisses everyone who can.

Bland potatoes cause weightloss, QED.

Puddleg said...

FYI for those who like diagrams, the shuttle is the second illustration here.

Shuttles are a bit like anaplerosis. Metabolism regaining its balance with a few permissible lateral moves.

Purposelessness said...

For anyone in the Nick Lane/Hyperlipid/Mitochondria study group looking for extra credits, some germans looked at UCP1 using atom force microscopy, the results are pretty interesting:

Full text should be free.

Peter said...

George, I have some lovely diagrams of the mG3Pdh feeding reverse electron flow through complex I, other people think the protons way! Unfortunately they are looking at activated T cells, not neurons. In neurons we have a "normal" situation where cytG3Pdh is in the glia and mitG3Pdh is on the neuron mitochondial membrane. Like the lactate shuttle. Have some ace papers on mG3Pdh on the go. It seems to be a flavour of the month recently. I like.

Purp, I like this "To address these issues we have proposed that high membrane potential can potentiate the activation mediated by FA, overriding the inhibition by nucleotides" Interesting paper. FFAs uncouple. Uncouple to survive.


Nigel Kinbrum said...

Purposelessness said...
"So Nigel asks who can eat lots of bland potatoes.

"He then dismisses everyone who can."
ItsTheWooo dismisses those that she doesn't believe. Not a peep out of you, Purp. #Hypocrite

Purposelessness said...

@Nigel: I was not aware that I was Wooo. Huh. I think I need to rethink major life decisions now.

@Peter: I don't know, I thought it was pretty well-accepted that fatty acids/palmitate do some (mild?) uncoupling? It's often mentioned as a given in the papers I'm reading at the moment.
Of course I have also read the Dark Side interpretation of this: Palmitate uncouples beta cell mitochondria, makes free radicals, kills beta cells, FAT CAUSES DIABETES.

ItsTheWooo said...

Insulinoma patients are ubiquitiously very insulin resistant, although they lack the same phenotype as obesity related insulin resistance. The fact this is so even though insulinoma patients invariably start out chronically hypoglycemic and have average blood sugars much lower than normal due to neoplastic hyperinsulinemia is sufficient evidence to conclude insulin alone produces insulin resistance or at least contributes independently to it. Insulinoma patients will then progress to hyperglycemia/diabetes sometimes, actually, secondary to severe IR.
In other words, guyenet has no understanding of human pathophysiology of diseases, or even diseases pertaining to obesity, yet he is writing diet books. PhDumbass.

I've always felt my obesity is secondary or at least implicated with an insufficient SNS drive relative to PNS, resulting in inadequate fat oxidation and insulin excess. My blood glucose is always very low, my blood pressure too. I seem to have signs of insufficient catecholamines.

I've found very small doses of fruit such as berries, of all carbohydrate food choices, seem help most in preventing hypoglycemia/hunger. If fructose promotes insulin resistance and my problem is inadequate insulin resistance/blunted fat oxidation, it stands to reason fructose in small amounts can be beneficial.

Contrast this to eating starch or glucose where I only have hunger fatigue and hypoglycemia in direct relation to the amount of starch consumed. Fruit is not like this; I can eat much more fruit before problems set in... in fact I find eating just a little bit of something with fructose can actually antagonize hypoglycemia.

I have intuitively taken to eating small amounts of sucrose (in chocolate) or berries to benefit from this.

Fructose is demonized, but IMO fructose is highly valuable for certain types of obesity and hypoglycemia as it specifically antagonizes insulin action and can help prevent hypoglycemia and energy instability when consumed in small amounts.

@Purposelessness If YOU WERE WOO WHAT WOULD YOU DO DIFFERENTLY???!!! (probably not post that latest steubenville rape case blog entry, for starters! Yikes! I like my trolling medium spicy, this is too much intensity for me! Its like I accidentally dumped a whole jar chilli powder in the pot!)

ItsTheWooo said...

I observed a similar phenomenon when taking medication that promotes insulin resistance. I actually became less hungry and never had hypoglycemia, and my average sugars increased very slightly seems to be why.

Purposelessness said...

Oh god Wooo, Nigel is right, when I read your last entry I was like "I usually like Wooo's rants, but this one is a little intense and serious for me"

Are we really the same person?
I just meant I'd rethink our life, because, well, what decisions brought us to a place where we thought that we were a american blogger and at the same time some german comment only person?
Maybe Nigel meant that as a metaphor, or something. Maybe he is an anarcho syndicalist who believes in hard determinism and duality. Who watched too many Matrix movies. While eating plain white potatoes.
Dreaming about "bland, simple" french food.

Nigel Kinbrum said...

Purposelessness said...
"@Nigel: I was not aware that I was Wooo."
I never suggested that you were. Your reading comprehension sucks.

Purposelessness said...

You are an interesting fellow, Nigel. Of course Wooo dismisses those she doesn't believe, I think all of us do that. That was what I meant - you said no one can eat a lot of bland potatoes, then didn't believe anyone who came around and said so..

And I don't know, if you didn't imply that I am, in fact, Wooo, that comment makes no sense. Now don't go all Robb Wolf on me! I will come to your country, build a Crossfit Box directly in your driveway and build a statue of Gary Taubes were you can see it from your bedroom window. 500 feet tall. With a heavy cream dispenser. I will hire people who will go through your street and periodically yell things like "calories don't count!" "carbs cause obesity!"..

What were we talking about, again?

Scott Russell said...

I like the line "sweet potatoes don't count, as they taste nice."

More fun extra credit: look into fucoxanthin. Its a carotenoid found in seaweed that accumulates in adipocytes and increases UCP1 activity. So always eat some seaweed with your rice?

Nigel Kinbrum said...

Purposelessness said...
"You are an interesting fellow, Nigel."
Thank you. I'm taking that as a compliment. I use idiomatic English, so I guess that you Americans will sometimes not have a clue as to what I'm talking about.

What I meant was:- You make a fuss (a peep) when I don't believe somebody, but you don't make a fuss (not a peep) when Wooo doesn't believe somebody. Is that clearer?

I don't go Robb Wolf on anybody. I sometimes tease people to the point where they go Robb Wolf on me, though!

Purposelessness said...

I'm actually german, so you can be pretty sure that many wordplays and most idioms that aren't frequently featured on TV are lost on me.

Thats very clear now, thank you. And I actually meant that as a compliment - while I probably disagree with you on every single issue, you do have a sense of humor, and while you sometimes dish out you strike me as the kind of guy who can also be on the receiving end of an outdishment (now hows that for horrible english!). Those are qualities I value highly in blogcommenters I argue with!

I now get your point about Wooo, but I really don't think that matters. Only because I don't question someone's believes doesn't mean I agree with them.. the point I was trying to make was: Will you dismiss everyone who says that they can eat a lot of bland food without trouble? Thats not very good science, imho. Even for internetblogscience.

I thought you were alluding to the fact that some drama got started with Robb Wolf frequently mentioning the suction of his reader's comprehension.

Nigel Kinbrum said...

I looked at your blog, but I don't know your gender or what part of the world you live in.

I gave a list of people who can eat large amounts of insipid foods above. I assumed that you were neither a body-builder nor somebody trying to make a point.

I struggle to eat a bag of chips (fries for non-English people) and those are deep fried in oil and smothered in salt & vinegar. I "did a Wooo" and projected my experience onto everybody else!

My skin is as thick as an Elephant's after years of posting on message-boards. Somebody called me a f*cking c*nt and I just laughed at them (in writing). On my blog, I've accused my readers & other bloggers of poor reading comprehension, using weird (cognitive bias) filters and even insanity.

So, what was it we were disagreeing about, again?

Purposelessness said...

That's a really good question. I'm not sure to be honest.

Nigel Kinbrum said...

By the way, I interpreted "Now don't go all Robb Wolf on me!" as "Now don't lose your temper and tell me to go f*ck myself!"

If you read my blog, you'll see that I'm in favour of LC/VLC/Keto diets, so I'm not sure what we're disagreeing about either.

Calories? Food Reward theory? Something else?

Jane said...

Peter, there's something that's been bothering me. You say
'In healthy cells the signal to reject excess calories picks on glucose, in the form of the development of insulin resistance, mediated by superoxide generated at complex I of the mitochondria.'

My impression is that when GLUT4 in downregulated, CD36 also gets downregulated, meaning that fatty acids are excluded just like glucose. Of course fatty acids can still get in to some extent, straight through the membrane, but still this does suggest the cell is trying to exclude both glucose and fatty acids.

There's something else. The superoxide made in mitochondria has a very specific purpose: it gets made into H2O2 by MnSOD, and the H2O2 goes to the nucleus to activate transcription of many genes. This explains why extra MnSOD makes worms and flies live longer. Here's a paper about it.

'..Transcriptional profiling indicated that the expression of specific genes was altered by MnSOD in a manner opposite to their pattern during normal aging, revealing a set of candidate biomarkers of aging enriched for carbohydrate metabolism and electron transport genes and suggesting a true delay in physiological aging, rather than a novel phenotype. ..'

Anonymous said...

Dunno if this is related or not (my 45-years-ago high school chemistry struggles with this stuff) but if someone was a vegetarian and even practically a fruitarian, could that possibly lead to pancreatic cancer?

Puddleg said...

I'd agree with what wooo said; if i'm in ketosis and I eat fruit or a small amount of sugar that doesn't really break the spell the way that eating starch will, comparing carbs gram for gram.
It seems like some fructose, at low intakes, does assist the process. Or at least, doesn't really put the brakes on it.

I'm looking at 3 hepatitis C and diet epidemiology papers; 2 tie carbs to steotosis and/or fibrosis, one ties PUFA to steatosis, ORs fairly high.
One only looks at fructose and finds zero association between fructose and liver fibrosis.
One of the others finds a significant negative correlation between sweet consumption and fibrosis (or was it steatosis?).
Fructose, in other words, was protective there, except when included as part of total carbohydrate.
Without reading too much into that (sugar could denote alcohol abstinence) it doesn't really support Lustig's view that sugar is hepatotoxic.

Puddleg said...

Some references:


RESULTS:: Among 313 HCV males, 103 (33%) had advanced fibrosis and 89 (28%) had advanced inflammation. Median daily fructose intake was 46.8 g (interquartile range, 30.4 to 81.0). Dietary fructose intake across quartiles among males with advanced versus mild fibrosis was 21.4% versus 25.2%, 32.0% versus 24.8%, 24.3% versus 25.2%, and 22.3% versus 24.8%, respectively, and among males with advanced versus mild inflammation was 20.2% versus 25.5%, 41.6% versus 21.4%, 22.5% versus 25.9%, and 15.7% versus 27.2%, respectively. In multivariate analysis, there were no significant associations between daily fructose intake and advanced fibrosis. There was a significant association only between the second quartile of daily fructose intake (30 to 48 g) and advanced inflammation. CONCLUSIONS:: There were no significant associations between dietary fructose intake and hepatic fibrosis risk, as assessed by FibroSURE, in HCV-infected males.


alcohol was the independent factor most closely related to liver damage (OR 4.6; 95% CI 2.7-10.8)
PUFA - steatosis, OR 2.7
Carbohydrate - fibrosis OR 2.8
(calories and total lipids - fibrosis OR 1.8-1.9, but this includes carbohydrate and PUFA; no other macronutrient associations were identified. Soluble carbs, i.e. sugars, were measured but did not feature in the results)


In contrast, lower dietary intake of daily fat servings was positively associated with advanced fibrosis, with moderate intake conveying a significant 4-fold increased risk. Similarly, those with the lowest percentage of daily calories from sweets also had over 4-fold increased risk compared to those with high daily intake. However, moderate intake conveyed no increased risk (ORadjusted=1.03, 95% CI 0.32–3.28).

Study 2 was Italian, study 3 American.

Correlation blah blah causation blah blah absence of evidence blah blah and all that taken under advisement, but nonetheless the sugar stats in this context are suggestive in a "dog that barked in the night" way.

Jane said...

George, your third paper is really odd. It says liver fibrosis is associated with a LOWER intake of fibre, glutathione, protein and copper. Huh? Shouldn't those be protective?

'In multivariate analysis, lower dietary intake of copper and of fiber were both associated with strong decreased risk of advanced fibrosis, with approximately 14.3-fold and 7.1-fold statistically significant decreased fibrosis risk in those with lowest and moderate daily copper intake, and a 7.7-fold and 5.9-fold statistically significant decreased fibrosis risk with lowest and moderate daily fiber intake compared to those with highest daily intake. (Table 3) Lowest daily intake of both protein and of total glutathione also conveyed decreased fibrosis risk that approached significance.'

Then I found a paper suggesting that liver fibrosis may actually be protective.

'Liver fibrosis protects mice from acute hepatocellular injury'

BTW Lustig doesn't know that high fructose feeding causes copper deficiency.
'High fructose feeding induces copper deficiency in Sprague-Dawley rats: a novel mechanism for obesity related fatty liver'

Jane said...

Sorry, I meant to say, the paper says liver fibrosis is associated with a HIGHER intake of those things.

Scott Russell said...

This makes a lot of sense. Fibrosis is the repair of the injury. Kind of looking at scabbing to assess abrasions. If you limit the ability to scab, you will have less scabbing, but this doesn't effect the rate of abrasions.

Re: MnSOD, I always thought of MnSOD as the protection against superoxide. I know your pro-Manganese, so are you suggesting that problems are resulting from depletion of MnSOD resulting in superoxide damage to DNA?

Were the gene transcriptions upregulating metabolism? Longevity normally makes me think lowered metabolic rate, which isn't ideal for people in a state of overnutrition.

Peter said...

Jane, great link. To me hepatocellular injury is produced by two things. PUFA and/or fructose. Possibly includes alcohol. These are fuel sources which supply huge numbers of calories which CANNOT be refused by setting up insulin resistance. Failure of insulin resistance = cellular caloric overload, low NAD+/NADH and start on the road to cancer.

Freeing up iron appears to be classic for generation of fibrosis. BUT you can do exactly the same with copper. Transition metals and free radical generation. Back to my wife having to run rhodanine special staining on liver samples for those clinicians hunting genetic copper overload. Unfortunately cirrhosis is commonly associated with copper deposition without Wislon's disease, even if iron deposition is commoner. Excellent to see that iron [or copper?] induced fibrosis has a beneficial effect. I had been working on the idea that either copper or iron was being used to generate insulin resistance when the metabolic substrates either walk straight past the GLUT4 receptor (fructose) or refuse to generate insulin resistance in the first place due to being a fat with F:N ratio below 0.47. Insulin resistance is utterly crucial for healthy cells to regulate caloric intake, at the cell level.

Caloric overload is utterly unacceptable to cells. Gotta do something about it.

BTW I liked your comment elsewhere about SOD converting superoxide to H2O2 for long distance transmission of information from mitochondria to the nucleus. Very true even if I don't see Mn deficiency as significant in metabolic syndrome. It's also H2O2 which cancer cells use to control fibroblasts when they use them as metabolic slaves. Longer distance message using the same messenger.


Puddleg said...

Copper and glutathione could be markers for specific foods that are causitive of fibrosis in this context. Pork offal would be an obvious candidate, whether from pathogens or for other reasons still obscure. It seems unlikely that the small amount of glutathione in food could have any significant effect.

Yes, fibrosis is the scar and its rapid formation is protective against acute injury. But if it keeps going (as it will tend to do if the liver is fatty or if the HSCs are kept activated - as myofibroblasts - by alcohol or other triggers) you get increasingly hard-to-reverse tangles of matrix and eventual cross-linking. (liver scarring can normally be resorbed when it's served its purpose, using a zinc metalloprotein).
Retinol is a good example of an intervention that reduces fibrosis from liver injury at the cost of higher ALT scores and greater risk of hepatotoxicity.

Results: The rats that underwent biliary obstruc­tion and received vitamin A presented lower levels of hepatic hydroxyproline (p<0.001) as well as a lower
percentage o f collagen tissue than the untreated con­trol rats, but they presented higher AST and ALT serum levels (p<0.05,p<0.05).

Peter said...

Makes me think of the complete dogs dinner we make of managing hepatopathy. Good old ursodeoxycholic acid, supposed to be used to protect against elevated toxic bile acids, now thrown at all liver patients irrespective of bile acid status "Because it helps, antioxidant, blah blah". Huh. Ah, while checking the spelling on wiki you have to notice:

"A Cochrane review to evaluate if ursodeoxycholic acid has any beneficial effect in primary biliary cirrhosis patients included 16 randomized clinical trials with a total of 1447 patients. The primary outcome measures were mortality and mortality or liver transplantation. Although treatment with ursodeoxycholic acid showed a reduction in liver biochemistry, jaundice, and ascites, it did not decrease mortality or liver transplantation"

And I just have to wonder about using cytotoxics (colchicine???) because they inhibit fibrosis. The classical ploy of treating the numbers/symptoms. Wonder if any hepatopathy therapy does any good at all in conventional medicine.

Answers on a postage stamp to anyone other than me...


Jane said...

Peter, did you see a comment I wrote in reply to IcedCoffee? It seems to have disappeared.

BTW I think the difference between iron and copper, WRT to causing liver fibrosis or other bad stuff, is that normally there is no free copper in cells but there is free iron. Of course really sick people may have some free copper because they're not making the copper binding things properly. Scientists use copper to oxidise LDL in vitro, and people think it's copper that does it in vivo when it's actually iron.

There are so many papers in the literature saying copper is toxic, and when you look closely it's nearly all complete crap. I used to believe the people who say zinc deficiency is the problem, not copper deficiency, and gradually over the years I realised it's not true. Klevay suggested 40 years ago that heart disease is caused by a high zinc-copper ratio, and I think he was right.

Scott Russell said...

Might be a bit off topic, but I'm wondering about depletion of SOD in other areas. Cu and Zn for SOD in our cytoplasm, Mn for our SOD in mitochondria. If we lack the co-factors to reform SOD, might the unprotected superoxide be interacting with NO, leading to poor vasodilation and hypertension? What kinds of DNA damage might we see? Cancerous ones?

Puddleg said...

You can make a significant difference in HCV related cirrhosis and cancer long term by supplementing zinc (as carnosinate in long-term studies) probably not due to copper inhibition as zinc sulfate would be better at that. Probably due to provision of zinc as metalloprotein catalyst for dismantling matrix.

Naltrexone or nicotinamide seem better options than colchicine, similar effects but much less toxicity. But no single intervention is going to do it. You also need to support methylation, optimize SFA/PUFA and 3:6 ratios, limit carb/insulin. Step around the complex 1 malfunction in the ways you've described.

Jane said...

Hi IcedCoffee, may I offer a reply? There's a very interesting new paper about Mn, SOD, and diabetes. The authors had already found out that excess Fe stops Mn getting into mitochondria, causing diabetes in a mouse model of hemochromatosis. Now they've found that supplemental Mn prevents diabetes in mice without hemochromatosis on a high fat diet.

'...We have previously shown in a mouse model of hereditary iron overload that cytosolic iron levels affected mitochondrial manganese availability, MnSOD activity, and insulin secretion. ...To determine whether manganese supplementation offered glucose homeostasis under a situation of β-cell stress, we challenged C57BL/6J mice, which are more susceptible to diet-induced diabetes, with a high-fat diet for 12 weeks. Manganese was supplemented or not for the final 8 weeks on that diet, after which we examined glucose tolerance and the function of isolated islets. ... manganese treatment can increase insulin secretion to improve glucose tolerance under conditions of dietary stress.'

Now the important thing is that adding Mn to the drinking water didn't work, it had to be injected. And of course, the high fat diet might have caused diabetes in the first place by increasing Fe absorption and decreasing Mn absorption.

Jane said...

George, I wonder whether the effects of zinc in HCV related cirrhosis have to do with zinc displacing iron from membranes. Some people think this is how zinc supplements work. Perhaps they only work if you have iron overload.

'It has been suggested that zinc competes with iron for binding to cell membranes and certain proteins, displacing iron and reducing the formation of reactive oxygen species (14,15). This competitive interaction has been demonstrated by in vitro (16,17) and animal (6,7) studies, suggesting that zinc has a protective role against iron-mediated oxidative stress.'

Scott Russell said...

Very interesting papers indeed. I don't have access to the full text, so I have a few quibbles. Primarily, I'm wondering whether saturated fat inhibits Mn absorption per se, or if this is simply a manifestation of the higher superoxide generation of the more saturated fats depleting Mn-SOD. It seems odd that a physiological mechanism would have SFAs resist the absorption of something (semi)needed in their metabolism. I also remember reading that gut microbiota can influence trace mineral absorption, which makes me wonder how much can be extrapolated from mice fed purely synthetic diets.

And the form of Mn that is being used isn't specified, so I'd wonder about bioavailability. (This goes for food sources as well, sources never tell you the form of the minerals.) Good sources of Mn, i would guess bones?

Puddleg said...

@ Jane,

the best studies I've seen on zinc and HCV are ongoing long-term trials using polaprezinc, which is 30mg zinc as carnosinate. There have been significant reductions in first fibrosis then cancer over time.

The metalloprotein that dismantles collagen matrix uses zinc; the virus sequesters zinc in one of its own metalloproteins; I believe this was the rationale. Though there are probably multiple pathways.

The zinc gluconate/Fe study is very interesting in this regard, as phlebotomy is often studied as productive of benefits in the Japanese HCV population, which is where polaprezinc is being trialed.

In interpreting the diet studies I am only interested in high ORs. The alcohol OR, 4.7, is a good benchmark because this is plainly real harm, we know that from countless other studies. The ORs for PUFA and carbohydrate - 2.7 and 2.8 - are higher than those for calories or lipids, which are beginning to fall to the "red meat kills you" level (anything below 2 is not really worth the time of day).
There are correlations that are plainly meaningless. The Italian study has a strong correlation with vitamin A, yet both low and high intakes were so low that they were practically deficient.
In this case I suspect that vitamin A was a marker for a specific food such as pork offal.

Jane said...

It's odd, isn't it. But it seems to be the case that saturated fatty acids act on the Fe/Mn transporter in the gut to shift the balance towards Fe and away from Mn absorption.

It's also odd that adding Mn to the drinking water didn't work. The authors think it was excreted, and we know Mn undergoes enterohepatic circulation, meaning Mn that's actually needed is excreted in the bile and (hopefully) re-absorbed. Perhaps the purpose of this is to encourage friendly gut bacteria. Some kinds of lactobacilli like Mn a lot.

It looks as if we might need an awful lot more Mn in our diets than most of us are getting. Yes bones should be a good source, but I'm a bit doubtful about bone broth because it could be very high in Ca, P and Fe, which all inhibit Mn absorption.

Puddleg said...

Nuts, seeds and green tea are good manganese sources.

Sesame seeds are probably the best.
Tahini goes well with everything.

Manganese in 100g of 'sesame seeds':

Seeds, sesame seeds, whole, roasted and toasted - Manganese 2.496 mg
Seeds, sesame seeds, whole, dried - Manganese 2.46 mg
Seeds, sesame seed kernels, dried (decorticated) - Manganese 1.44 mg
Seeds, sesame seed kernels, toasted, without salt added (decorticated) - Manganese 1.427 mg
Seeds, sesame seed kernels, toasted, with salt added (decorticated) - Manganese 1.427 mg

Unknown said...


Yes, I adore plain boiled potatoes and they are useful for my training. I am leaner with starch and low to moderate fat.

Jane said...

George, that's very interesting about phlebotomy and HCV in Japan, I looked it up. It reminds me of something I read about AIDS: replication of HIV is promoted by Fe and inhibited by Mn. There are people who think the practice of giving Fe supplements (which can cause Mn deficiency) to pregnant women and children in the third world played a role in the AIDS epidemic there.

'Manganese blocks HIV replication'
'Anti-HIV effect of iron chelators: different mechanisms involved'

Puddleg said...

@ Jane,

that makes sense to me. Iron supplementation from eating SAD foods is potentially well in excess of RDA, on top of any iron the diet contains naturally.
60mg iron is the WHO pregancy supplement - that's gotta hurt.

Puddleg said...

Looking at my study 3) again I was amazed to find this:

Only one dietary factor, percentage of calories from sweets, was significantly higher in advanced fibrosis cases compared to mild fibrosis controls (p=0.048)

Did I misread it all those times? But no, it still also says this:

Similarly, those with the lowest percentage of daily calories from sweets also had over 4-fold increased risk compared to those with high daily intake.

Let's just say, the picture isn't all that clear.

Jane said...

I found that paper very confusing too. I've just checked and in Table 2 it says mild fibrosis cases had 20.4% calories from sweets and advanced cases 16.8%. So when it says % calories from sweets was HIGHER in advanced fibrosis, it's a misprint.

BTW I agree with what you said about the WHO and iron. I actually wrote to the WHO years ago. I was totally freaked out about what I'd found, and wrote to all sorts of people. I got absolutely nowhere.