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Diabetes and Obesity

Dinitrophenol: A Possible Comeback

I’ve mentioned metabolic uncoupling as a possible diabetes therapy. The idea is that your mitochondria will plow though large amounts of lipids under these conditions, and there’s plenty of evidence that knocking down free fatty acids and tissue lipid stores would be of great benefit for Type II patients. The problem is that this therapy has a well-deserved reputation for having a low therapeutic index.
2,4-dinitrophenol is a pretty unlikely-looking drug, but it most certainly has metabolic effects. It was on the market for a while (many decades ago) as a weight-loss therapy, and no one can say that it won’t make you lose weight. The danger is that you lose it all the way down to your dry bone mass, though, because it doesn’t take much extra DNP to give you dangerous amounts of overheating and perhaps even a critical shortage of ATP, which frivolous organs like your heart and brain seem to have become dependent on. Various foolhardy types (extreme bodybuilders, etc.) have experimented with it since then, but it’s just too dangerous to recommend to anyone. Even short of death, there were other unpleasant side effects.
But there have been reports from time to time that the compound might still have legitimate uses, and a recent one from Gerry Shulman’s group at Yale is getting a lot of attention. Shulman is one of the world’s experts on diabetes and metabolism, and his lab has been working on DNP for some years now. The latest version is a time-release form of the drug, one that delivers up to 100-fold less Cmax than the standard human dose, if DNP can be said to have one.
This formulation does a dramatic job of reversing diabetes symptoms in rodent models, and fatty liver disease as well. Shulman is working on taking this toward human clinical trials, and the animal results make a good case. If this were any other drug showing these effects, people would be moving it forward as fast as possible – it’s just the history of DNP that’s going to make things more difficult. But we have the example of thalidomide – if that can find a therapeutic niche, anything can. The next key step will be rodent and dog tox studies, and if DNP can clear those, then I would see no reason not to take it on into Phase I and beyond. Who’d have thought?

23 comments on “Dinitrophenol: A Possible Comeback”

  1. Pete says:

    There is some pretty interesting physical organic chemistry associated with uncoupling of oxidative phosphorylation. It’s my understanding that these work because both neutral and ionized forms of compounds are membrane-permeable so that cells have to keep burning fuel to generate ATP to maintain the proton gradient. Delocalisation of charge seems to be the key and I’d guess that one could design away from both the nitro groups and the phenol. It’s been a while since I looked at this so there may well be other factors that I’m not aware of.

  2. SP says:

    Two nitro groups? Forget it, it will never get past the medchemists.

  3. Morten G says:

    Oh, okay so the idea is to have just enough DNP to allow the liver to dump extra energy from alcohol/fructose/galactose through heat rather than lipid synthesis. Not to make folks thin by converting all their body fat to heat.
    That actually makes good sense. I think. Some might complain about oxidative stress produced in the liver cells but it would probably still be less damaging than the alternative. I’d like to see it in something other than rodents but I guess that’ll be humans.
    PS Yes, the liver converts fructose and galactose into glucose – unless blood sugar is high and glycogen stores are full. Duh.

  4. Vader says:

    I thought fructose was pretty much always converted to lipids in the normal liver?

  5. Allchemistry says:

    #1. The other way around: the pH gradient across the inner mitochondrial membrane is the driving force for ATP synthesis by H+ ATPase. DNP dissipates the proton gradient, so the energy stored in the gradient is released as heat instead that it is stored in ATP.
    The proton gradient is generated when electrons are transported by the mitochondrial respiratory chain (e.g. from NADH to O2).

  6. anon the II says:

    Back in October you touched on this. Is niclosamide just a better (pk not potency) version of DNP?
    http://pipeline.corante.com/archives/2014/10/13/diabetes_progress.php

  7. Algirdas says:

    @5, pH gradient as driving force:
    I thought they demonstrated it conclusively in Peter Mitchell’s era that ATP synthase is reversible: give it enough ATP and it will generate H+ gradient.

  8. exGlaxoid says:

    If the time release helps to make it safer, then it is a reasonable way to lower blood glucose. Kinda like speeding up someone’s metabolism, but without as much exercise. Great for modern couch potatoes. But we need some way to slow down the diabetes trend, and anything might be a help.
    It would be nice if there were better ways, other than anabolic steroids, to build muscle mass up to increase metabolism in a more healthy way, but that has been tough to find a good solution to. There is a growing need for that type of product.

  9. Pete says:

    @5 Allchemistry, Thanks for the info. It’s been a long time since I looked at this and biochemistry was never my strong suit. I’d be interested if anybody is aware of other oxidative phosphorylation modes of action.

  10. JS says:

    DNP is (unfortunately) quite commonly used even by casual body-building enthusiasts, as it reduces body fat at a startling rate — far faster than aggressive anabolic steroid cycles and dieting.

  11. Allchemistry says:

    #7
    Like any catalyst, ATP-ase will accelerate the establishment of the chemical equilibrium, so yes, in the presence of enough ATP, ATP-ase acts as a proton pump fueled by ATP. In the mitochondrion (presence of proton gradient, high ADP) it will act as an ATP-synthase, driven by the energy stored in the proton gradient.

  12. Chris says:

    Not that I’d ever use DNP, as it’s illegal, but if I did, yeah, DNP is miserable. Imagine a really nasty flu, but combined with nasty carbohydrate cravings.

  13. Eric says:

    It’s interesting work, and they’ve done a lot. That said, I find the paper hard to follow with a lot of potential concerns (some of that is probably the horrible format in Science). If the crux of your argument is that you altered the PK profile and got better safety why don’t your figures show the PK and relate it to a true safety study?
    I had to dig through the supplemental figures to find PK data. When I did find it I can’t reconcile it with all of their claims. For example “the toxicity of a DNP derivative is predicted by the maximum concentration of DNP”. This clearly isn’t true for the AST data.
    On a side note – why are there two separate vehicle groups? It’s kind of important because the values for the two vehicles are different for liver TG, which is where they define the MED.
    I really do hope they have something useful. It’s just so hard to tell from this paper.

  14. antibi says:

    on the other hand… I wonder if any of these effects are due to activation/recruitment of anti-DNP antibodies?

  15. gippgig says:

    Would a DNP patch work? I suspect it would be readily absorbed thru the skin. Anyone test using a really tiny dose every hour?
    A couple of unrelated items:
    Periodic table fans may enjoy the periodic table of sweeteners in the Washington Post: http://www.washingtonpost.com/graphics/health/sweeteners-guide/
    This is nowhere near as bad as the legendary wine article but it’s still a lot of pseudoscience by a company that really should know better: http://www.swansonvitamins.com/blog/blogging-with-lee-2/stop-the-salt-shame-just-choose-the-right-salt?SourceCode=INTHIRRB1&utm_source=smartfocus&utm_medium=email&utm_content=newsletter-article-link&utm_campaign=INTHIRRB1&emv_mid=3173163&emv_rid=15208837297 (for the science see http://www.sciencebasedmedicine.org/pass-the-salt-but-not-that-pink-himalayan-stuff/)

  16. a. nonymaus says:

    So far as the nitro groups go, I guess that any smallish electron-withdrawing group would do if one is worried about off-target effects or pharmacokinetics.
    Re: 12
    I wonder if those side effects are general to mitochondrial uncouplers? If so, I don’t see this being effective for a patient population that can’t muster the willpower to exercise and step away from the biscuit platter for a bit.

  17. a says:

    This is what reddit’s r/steroid community has to say about DNP – autoclinical n=1 trials, LOTS of anecdata
    http://www.reddit.com/r/steroids/comments/23vbp1/compound_profile_dnp/
    still, interesting

  18. hypnos says:

    Well, what about a little diet and exercise? It’s not that difficult to loose weight after all – and just because we like to sell drugs as an industry doesn’t mean that the answer has to be a drug all the time.

  19. gippgig says:

    It’s very difficult to lose weight – a person’s body has a natural weight just like it has a natural temperature. Trying to lower your weight is about as easy and effective as trying to lower your body temperature. People should just accept that their natural weight is their natural weight.

  20. Gretchen says:

    @Hypnos, Yes it *is* difficult for some people, those with certain genes, to lose weight. Some people have been trying diet and exercise their entire adult lives, and it hasn’t worked. They need our compassion, not sneering.

  21. milkshake says:

    @16: Benzonitrile and pyridine are reasonably similar to nitrobenzene so presumably one can try cyanohydroxypyridines. But lots of things have to be in place – lipophilicity, halflife, tissue distribution. It is just decoupling mitochondrias is such a blunt and nasty way. Interestingly, meformin seems to act on mitochondria as well.

  22. gt says:

    Something I find to be a little troubling is the lack of data demonstrating that this is actually a mitochondrial protonophore. The mitochondria were isolated from the liver of treated mice and were shown to have increased TCA cycle flux. Increased TCA cycle flux does not necessarily mean uncoupling, and if the drug were acting via a cycling protonophore mechanism the mitochondrial isolation procedure would have likely removed it.
    It’s an interesting drug- I’m pretty skeptical of the mechanism until proven otherwise. There are some articles on mitochondrial protonophore validation if anyone is interested (here’s an open access one):
    http://www.sciencedirect.com/science/article/pii/S2212877813001233

  23. hypnos says:

    @Gretchen: I am *not* sneering at anyone and I fully understand that some people may need help to reach a certain weight. I am just not convinced that this help has to come in the form of a pill (that necessarily has some undesired side-effects and risks associated with it). Diet consulting, cooking courses, sports classes etc. should be able to cover most cases.
    I fully acknowledge that there are some industries with massive marketing budgets that try to sell as much fat and sugar as possible – and that is not helping.

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