Monday, June 21, 2021

Random musings on uncoupling (7) DNP and metformin

NAFLD, NASH, ALD and alcoholic steatohepatitis (ASH?) are all associated with the accumulation of lipid within liver cells. The two primary culprits are fructose and alcohol. Both undergo rapid metabolism to acetyl CoA (+/- lactate) with the potential to generate lipid within hepatocytes as a result.

Sadly life is never quite that simple. Certainly some of the liver lipid does indeed come from the metabolism of fructose or ethanol, but back in this post there are the papers which suggest fructose acts systemically to induce acute insulin resistance in adipocytes and so releases fatty acids which transfer to the liver (and visceral fat) stores:

Fructose and lipolysis

and this post points out the same about ethanol:

Alcohol and weight loss

Hepatic lipid delivery should trigger hepatic insulin resistance and the resultant persistence of metabolic substrate in the blood should signal to the hypothalamus that there are plenty of calories available, ie it's not time to eat yet. You have only to look at the hepatic response of FGF21 production, which increases thermogenesis, in response to both alcohol or fructose to see this in action. FGF21, when not produced in response to starvation (which it is), signifies that the liver sees enough calories to stimulate thermogenesis in excess of obligate needs.

So what goes wrong in fatty liver disease?

The action of insulin on hepatocytes is to suppress glucose release, facilitate lipogenesis and facilitate triglyceride formation. You just have to ask yourself, is there any dietary component which facilitates the excessive action of insulin? Which might make a perfectly reasonable process into a lipid-storage overload pathology?

Could that be linoleic acid? Which induces a failure to resist caloric ingress at times when that would be appropriate.

Fatty liver disease, from fructose or ethanol, looks to me very much like the result of excess insulin action on hepatocytes. The same linoleic acid which produces this accumulation of lipid in adipocytes  will also facilitate accumulation in hepatocytes and facilitate the conversion of benign fatty liver into inflamed hepatitis though its lipoxide derivatives.

We've known for years that a high saturated fat diet protects against NASH: 

Long term highly saturated fat diet does not induce NASH in Wistar rats

provided it is very low in PUFA. In fact the low PUFA is probably more important than the high saturated fat content.

If we accept this chain of thought, fatty liver represents an accumulation of lipid in response to linoleic acid facilitated excessive action of insulin. It happens because while the oxidation of linoleic acid generates enough ROS to allow insulin signalling to occur, it does not allow the generation of enough ROS to limit insulin's actions when the hepatocytes are full. Exactly as for adipocytes.

So hepatic lipid accumulation is a consequence of excess insulin signalling, and only once the ability to accumulate any more intrahepatic lipid has been exceeded does the generation of ROS become adequate to resist insulin's caloric ingress/retain signal. After that, hepatic insulin resistance will occur, glucose will no longer be retained and the liver will no longer be a sump for absorbing FFAs.

Systemic levels of FFAs and glucose will rise and the rest of the body will have to go in to anti-oxidant defence mode, AKA whole body insulin resistance. Hunger will plateau and weight will stabilise.

So. The primary problem is the excess storage of (largely adipocyte derived) FFAs as intra hepatocellular triglyceride, beyond the point where this is adaptive.

It cannot happen without the LA facilitated augmentation of insulin signalling. This does not happen if the lipids being oxidised within the liver are predominantly saturated, as in the NASH prevention paper above.

Looking at hepatic lipid accumulation in these terms suggests that blunting insulin signalling might he a simple solution. Hence the efficacy of 2,4-dinitrophenol. You could view DNP as acting as a caloric sump for hepatocytes, burning off the fat and introducing a caloric deficit. Or you could speculate that all that is needed is a small drop in mitochondrial membrane potential, to produce a reduction of insulin signalling to approximately offset the augmentation induced by LA, and the problem would self correct.

I tend to favour the latter option. But then I would.

My personal view is that this is what low dose DNP does. It blunts insulin signalling in hepatocytes. Blunted insulin signalling blunts lipid accumulation and the liver never accumulates enough lipid intermediates to generate insulin resistance. Without the enhanced insulin signalling sequestering calories into lipid stores the liver will allow more glucose and FFAs in the systemic circulation which will reduce hunger. This might not be enough to generate detectable weight loss in a few weeks of a rodent study but it just might over a few years.

The parallel with metformin is that I consider metformin's core action at therapeutic dose rates is the inhibition of the mitochondrial component of the glycerophosphate shuttle, limiting FADH2 input to the CoQ couple and so limiting the ROS generation which is needed to maintain insulin signalling (and to markedly reduce insulin-induced insulin resistance, but that's another story). It does this at micromolar concentrations in the cytoplasm, where it can easily access mtG3Pdh.

Metformin and DNP both reduce the generation of ROS needed to maintain insulin signalling, all be it by different mechanism. Insulin signalling is blunted. Excess lipid (and glucose) storage is inhibited. There might be a trivial loss of weight due to reduced hunger.

ASIDE Obviously as metformin/DNP reduce ROS and insulin signalling they allow increased fat oxidation, largely via AMPK, and some "new" ROS will be generated to replace those suppressed by metformin/DNP. But the "cost" of these "new" ROS is fat loss. Which is a win overall for metformin/DNP/obesity END ASIDE.

Interestingly both metformin and vintage DNP increase lactate formation systemically, presumably because glycolysis is still on going, especially when glucose levels are raised post prandially, and the activation of the pyruvate dehydrogenase complex is blunted in proportion to the blunting of insulin signalling. Hence pyruvate to lactate becomes the preferred route to continue glycolysis.

Also both are longevity drugs, even using old fashioned plain DNP in rodent drinking water

Blunting insulin signalling certainly does interesting things.

I have tried to resist insulin for decades. So far, so good...



Sudhi said...

Sir, could you please tell us if it's dangerous to use any type of anesthetic after getting vaccinated against Covid-19 ?

Justin said...

Fascinating and awesome post Peter. I love session IPA's and probably consume way to many on a regular basis. I always try and have my ALT/AST levels checked on a regular basis though and so far, so good. My pufa intake is probably pretty low as my main fat sources are heavy cream, full fat cheese, butter and beef tallow. My last two liked panels have been outstanding with HDL up around 90, normal LDL levels (whatever that means) and very low Trigs (maybe around 40). I was worried about my fasting bg constantly being around 100 to 105 (physiological IR?) so had my A1C checked and they were in the normal range (high 4 to low low 5). I do 18 hour intermittent fasts on a regular basis though. I definitely stay lean. Lol!!! That being said, I still worry about the alcohol consumption. Can you diagnose fatty liver with an ultrasound? I seem to remember that being a viable diagnostic tool and would make sense given the different densities.

Peter said...

Sudhi, sorry, no idea.

Justin, it probably depends on your operator, their machine and the degree of change. Clinically I found hepatic ultrasound disappointing, though it is not without its uses...


karl said...

How I wish there was a dialog between Petro and Lustig here... on this exact topic.. I wish
someone would set this topic up as a dialog between Petro and Lustig? What a video clip it would make! Can anyone make some phone calls to set it up?

If my hunch is correct - that the HUGE T2D pandemis is at least in part multi-factorial via fructose and LA - it could explain a bunch of things - suggests a 4 group experiment - control, control+fructose, control+LA, and control+LA+fructose. ( the control feed should be from a single batch and LA and fructose simple additions).

The other bit - ROS is thought to cause damage to MT - RO also is also thought to regulate the number of MT. What trade offs are happening here? What would the hypothesis of the effect of this combo be?

Key effects:
1. LA + fructose likely effects the number of senescent cells - aging.

2. Is there a cancer rate link from the combo of fructose+LA ?

3. LA + fructose might lead to mitochondria disease - as in ME/CFS fibromyalgia?

Why isn't understanding this the number one priority in research? The quality and length of life makes this THE number one health issue of our time. I just so the world burn through Trillions of dollars due to the risk of CoVid - over time - the risk of T2D is MUCH bigger. Where are the adults in the room? Are the institutions so corrupt - so dysfunctional that no one can see the elephant?

Justin said...

Karl, my gut feeling is they don't want to figure out the root cause. The would probably loose billions in profit if the did. If there is one thing I hate in this world, it's cancer. Lost to many friends and family from it. Currently have some fighting it right now including my boss/friend. I think of this song everytime I think of cancer and all of the people I love that it has taken from me.

Justin said...

Sorry for all of the spelling mistakes there. I promise I'm not normally that bad, but real easy to fat finger on the phone when you're dead tired lying in the bed. Lol

Martin Sip said...

Thanks for the post Peter. I especially like the metformin connection, which remind me of question whether metformin still has "longevity" effects even in metabolically healthy people whose insulin signaling is not tempered with by linoleic acid. Would metformin be in such cases neutral or negative? Any idea?

Captain Sunset said...

Peter, At the risk of changing the subject, could you give your views on Ivermectin with regard to SARS2/Covid-19/Vaccines? As an ex-fish farmer I have some knowledge of Ivermectin, but as a Vet I'm sure you have a far better understanding of it. As for me, I'm inclined to go with a logical mix of Ivermectin and Ivorcummins. Sorted.

Peter said...

Martin, I think probably so, the suppressed insulin gene dose in Jim Johnson's group mice on quite conservative LA chow was effective so I'd guess metformin imitates this. The much bigger question is whether it provides any detectable benefit if you are not on a carbohydrate/insulin based diet. Not a lot of glycolysis or glycerophosphate shuttling going on under deep keto....

Captain, not really. I think your ivorcummins might be effective, it tends to work with significant integrity.


Justin said...

These posts are really stirring up some old memories for me. I remember lots of anecdotes about DNP "fever". Makes sense if it can stimulate significant amounts of uncoupling. Definitely one of the more dangerous drugs that bodybuilders sometimes use.

altavista said...

You're a meat eater. You swim in it, not resist?

Peter said...

In the near absence of PUFA and starch sources I think what insulin I produce in response to the protein should be resisted appropriately by the palmitic acid. Not sweating about it.


Basti said...

Hi Peter
Amazing post explaining so much.

Would you think that alcohol/fructose in healthy lean subject on a zero % LA diet (except the amount coming from beef and butter) would contribute to NAFLD, NASH, etc then?
Or does the relative absence of LA make them behave like normal carbs (glucose/starch).
I mean, in a low LA situation, does it matter whether you eat carbs in the form of fructose or starch? Is it metabolically irrelevant now?
And if yes, is there a limit to which extend it applies?

Peter said...

Hi Basti, that's a very interesting question to which I have been giving some amount of thought. If you listen to Raphi's podcast with Herman Pontzer where they talk about the Hadza, with whom Pontzer lived and studied, they do at times eat a ton of honey. No obesity and no metabolic syndrome. I'm left wondering whether fructose increases insulin resistance in much the same amount as palmitic acid does, so limits obesity despite elevated insulin on a mixed diet background. So elevated insulin with elevated insulin resistance. Succinate esters appear to do this well, via ROS through complex II.

High insulin with supplementary PUFA = obesity, as you suggest.

And of course, most fructose is converted to palmitate in the intestinal lining cells, most of that which gets through is converted to palmitate in the liver and only a tiny fraction gets through to the systemic circulation...

Complicated and interesting. Also much of the effect of fructose on ROS generation is cytoplasmic, especially via NADPH oxidases, rather than mitochondrial.

Interesting subject.


Basti said...

Interesting. And thank you for your explanation :)
But very hard for me to wrap my head around fructose being potentially benign.