Metformin trial reduces seizures and brain tumours in Tuberous Sclerosis | Hacker News Reader

Metformin trial reduces seizures and brain tumours in Tuberous Sclerosis

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While OP's trial is bigger, it should be noted that just like metformin treating epilepsy and T2 diabetes, a ketogenic diet also seems effective for this condition: https://pubmed.ncbi.nlm.nih.gov/16190943/

It is but compliance is generally lower in a world of Coke and donuts. People just want pills.

On the plus side, we're slowly making the public aware that the DNA theory of cancer isn't actually right and that carbohydrate metabolism is much more powerful.

> It is but compliance is generally lower in a world of Coke and donuts.

It's not just Coke and donuts. Even bacon and eggs don't reach the threshold of ketosis used in these studies. The pop-culture definition of a ketogenic diet is really more like Atkins or low-card than the ketogenic diets used in these studies.

Ketosis at this level requires not only restricting carbohydrates, but restricting protein intake as well. This usually means drinking heavy whipping cream and oils.

Heavy whipping cream or butter in coffee isn’t bad on a keto diet.

Ketogenic diets used in epilepsy go far beyond a bit of heavy whipping cream in your morning coffee.

A classic ketogenic diet would require significant quantities of heavy whipping cream (or MCT oil or other oils) with every meal, including snacks. Wikipedia has a good example: https://en.wikipedia.org/wiki/Ketogenic_diet#Classic

Doing a true ketogenic diet is hard work. Most of what people call ketogenic diets are actually more like Atkins or low-carb. Going into full ketosis requires significant protein restriction and augmenting with significant fat sources.

What do you consider “full ketosis?” Is that defined somewhere?

There are test strips available to indicate your ketone levels. You're in ketosis once your blood ketone levels are at or above 0.5 mmol/L.

I did not find it as hard as that. I did it once by going under the carb limit (think it was 20g) for a couple of days eating things like bacon, eggs, avocado, steaks, oil dressing salads etc and was using strips to check for some keytones. Admittedly wasn’t trying to go long term as I don’t know how healthy my diet was but I definitely noticed some of the saiety and weight loss benefits claimed so I don’t think these so called “pop keto” people are necessarily deluded if they get reults.

What’s the DNA theory of cancer that isn’t actually right?

If you're a layperson try "Tripping over the Truth" by Travis Christofferson. If you have some biology try "Cancer as a Metabolic Disease" by Seyfried.

How would that theory explain the association of radiation exposure with cancer, or sun exposure are cancer? Do those things alter your metabolism?

Damage to DNA and mitochondria is happening all the time, the question is what happens in the presence of high carbohydrate loads. If you read the books they'd tell you this.

How about cell cultures that are induced with viral vectors to become cancerous by the introduction of an oncogene? Do you think there is a difference in metabolism in the cells that become tumorigenic after transfection? If so why does it happen with introduction of an oncogene but not in the control vector when they have identical cell culture media/nutrients?

My bet is because more than one thing happens (some insult to the mitochondria in parallel, say) and/or because the gene is actually expressing something metabolic we don't understand. Seyfried (I think) actually points out the parallel metabolic influence of some therapies that we think are working genetically.

So if the gene, which is DNA, is expressing something that changes the metabolism, doesn’t that mean a change in DNA is ultimately responsible?

Edit: also if you could introduce a change in the cells that only changed the metabolism and didn’t alter DNA you could prove your theorem if you then caused them to be tumorigenic.

Of course you're right, and that's why the role of DNA in cancer is undeniable. It's possible to argue (what Warburg did in the 1920s) that insult to mitochondria can kick off cancer, but it's almost impossible to maintain that this can occur and progress into malignant cancer without somatic mutations being involved at some point. Without encoding to DNA, how will the cancer continue to behave malignantly across cell generations? A mutation free cancer cell is an oxymoron.

Yes and no, because it changes how you think about it.

If it's "just DNA" then we should focus on relevant therapies. But this is what we've done for 60 years and it hasn't gotten us very far. In fact depending on how you slice the numbers we've made almost no progress since chemo was "invented".

On the other hand if it's mitochondria and DNA damage is just one possible route, and damage happens all the time, then there are metabolic approaches. These include simple diet changes, metformin and all kinds of other things.

We need to abandon the "just DNA" paradigm. Epigenetics is far bigger than most understand, and DNA is far more malleable than most people know.

As both books (I think) say, the TCGA project was largely a failure for exactly these reasons: DNA is a big moving target and the cell-to-cell variance is very large.

There is a cancer called CML, it used to be fatal, now there are targeted chemotherapies that work by inhibiting a tyrosine kinase. The test for the cancer is detecting the fusion gene Bcr-Abl. People with CML take a pill daily that targets the protein that is made by that abnormal gene.

The DNA paradigm explains this very well. How does the book explain this treatment?

How about a stem cell transplant? Why do they cure certain cancers? Does the metabolism of the person donating their stem cells get taken up and adopted permanently by the recipient?

This is very tiring, and I mean that in a kind way. Honestly, whoever you are.

Let's look at the first Wikipedia sentence on tyrosine kinase as a starting point:

"A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell."

What's ATP? We both know what ATP is. Is ATP deeply part of metabolism? We both know it almost is a definition of metabolism. I want to shout at you. But I don't know who you are or how to connect with you.

Please, for the love of anything that you find Holy, instead of arguing with me on the internet do this: Read the books I recommended, and start looking for the links to metabolism like I just did for you instead of trying to "see DNA everywhere". You will go so much further and help all of us than just arguing with me.

I mean it in good faith, and I am just trying to challenge how throwing out the dna paradigm explains things better. I agree that metabolism plays an important role in cancer, and we don’t fully understand it. But, I take issue with your original claim that the current paradigm is wrong because it explains things that I have personally seen in the lab when I did lab workup, in my clinical work and in my family members who have cancer and are being treated with medications that work.

As to the atp issue, yes it is involved with metabolism but so so much more. If you have time read The Biology if Cancer by R A Weinberg. He does a good job of exploring the historical investigations as wellas the science.

> DNA theory of cancer isn't actually right and that carbohydrate metabolism is much more powerful

This is an unnecessary dichotomy. The Warburg effect has been theorized for almost a hundred years. It's not that only one of "DNA theory" vs. "cellular metabolism theory" can be right, the prevailing theory is that they are highly intertwined.

There are so many different cancer types, that stopping one kind doesn't affect the outcome of other kinds of cancer.

So, yes, some cancer types are fed on carbohydrates, and if that's what people eat, they will get those cancers.

If people have a better diet, a better kind of cancer will kill them. =)

It is very infrequent to actually die of "old age" at over 100.

And the common thing of all cancers is still they are DNA mutations.

Having said that, yes, people should avoid a carbohydrate heavy diet, not only because it helps against common cancers, but because metabolic disease is just getting sick without any unavoidable reason.

Ketogenic diets were originally proposed as an epilepsy treatment because it was known to be effective against certain types of seizures.

To be clear, a ketogenic diet is not as effective as modern anti-seizure medications. It can come close in about 1/3 of patients (~90% reduction in seizure frequency) but it's not effective for all patients and shouldn't be viewed as an alternative to medication for everyone.

A secondary problem is that the modern definition of a ketogenic diet has become muddied as it has entered mainstream dieting culture. Many people who claim to be on ketogenic diets aren't actually consuming enough fat, or are consuming too much protein, to technically pass the thresholds required to reach the ketone levels used in these studies.

The most common mistake is consuming too much protein. Contrary to popular belief, even fatty foods like bacon are not strictly ketogenic. In fact, it's difficult to reach classic ketogenic thresholds without augmenting with MCT oil, heavy whipping cream, or very large amounts of nuts. Most "keto" recipes online barely meet Atkins criteria, let alone full ketogenic diet ratios. Once people realize they have to literally drink heavy whipping cream or oils to stay in the levels of ketosis required for therapeutic effect, the medications don't sound so bad.

A bowl of 25% ground beef and 75% beef tallow is quite good.

> Once people realize they have to literally drink heavy whipping cream [..] the medications don't sound so bad.

sounds great tbh

Sounds great until you realize that although some health markers improve on a ketogenic diet, all cause mortality significantly increases:

https://www.escardio.org/The-ESC/Press-Office/Press-releases...

> Regarding the mechanisms underlying the correlation between low carbohydrate diets and death, Professor Banach noted that animal protein, specifically red and processed meat, has already been linked with an increased risk of cancer. He said: “The reduced intake of fibre and fruits and increased intake of animal protein, cholesterol, and saturated fat with these diets may play a role. Differences in minerals, vitamins and phytochemicals might also be involved.”

I wouldn't be surprised if most people doing keto have way, way less fiber than they should.

Another crappy diet study. Correlation does not equal causation, etc. etc. It’s well known that these sorts of studies have innate problems, but they are easy to do, and the researchers get a published paper out of the deal, so why not?

> Another crappy diet study. Correlation does not equal causation, etc. etc. It’s well known that these sorts of studies have innate problems

If you think scientists don't know that correlation does not imply causation, I'm happy to report to you that they, in fact, do. Separating out incidental correlation from causation is actually kind of the point of science, and by extension, medicine. The primary population that gets it wrong is the people that read a single study, and immediately conclude something based on that one study, like "oh hey ketogenic diets reduces bad cholesterol, it must be super good."

And it's simply intellectually dishonest (at best) to state that the motivation of the researcher is only to increase their paper count with presumable producing junk science, without presenting a shred of evidence to support such a claim(talk about bad science).

All this sort of study can do is to point to where there might be connections to follow up on by doing the real research: randomly assign people to diets and watch the results. But that step never seems to get done. Instead we have this endless series of “studies” which show us absolutely nothing.

You said that all cause mortality increases on a ketogenic diet, and this study shows no such thing.

> You said that all cause mortality increases on a ketogenic diet, and this study shows no such thing.

...

> The risks of all-cause and cause-specific death over an average 6.4-year follow-up rose with each fall in carbohydrate intake (see table), and remained significant after adjusting for all available factors that might have influenced the association (Model 2 in the table).

Quoted from the study.

It suggests exactly that thing. I suggest you read the study again.

You know why these don't get done?

Because that means that you're grabbing a large cohort of people, fixing their diets, and following them until a good number of them die.

The timescales required here, not to mention the cost, means that such studies are virtually unfeasible.

But increases diarrhea on a scale thought unfathomable? Every time you meet one of those 'life extension' types taking Metformin just know that they aren't living their best life in the bathroom.

Would you rather have tumours?

The GI side effects of metformin are usually short lived. They tend to last about a week or so after starting the drug or increasing the dose. Some people do have longer lasting side effects, but metformin is one of the best tolerated drugs we have.

I took metformin for about two weeks after being incorrectly diagnosed with T2 diabetes (I actually have T1, but some doctors seem to think it's impossible for adults to be diagnosed with it) and stomach / digestion / diarrhea issues only lasted about 2 days for me.

I take Metformin every day and have not had any side effects (including diarrhea).

Same here

I stopped a while back when I read that it reduces testosterone level significantly: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296448/#:~:tex....

Do you notice anything to support this?

nope - no side effects at all that I can tell

What's your reason for taking it? The purported longevity benefits?

Yes, I take it for the possible longevity benefits.

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