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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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« Single, Simple Numbers: Use At Your Own Risk | Main | Ranbaxy in Trouble »

February 26, 2009

Does Glucophage Make Alzheimer's Worse?

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Posted by Derek

Metformin, now there’s a drug story for you. It’s a startlingly small molecule, the sort of thing that chemists look and and say “That’s a real drug?” It kicked around in the literature and the labs in the 1960s, was marketed in Europe in the 1980s but was shopped around in the US for quite a while, partly because a lot of people had just that reaction. (It didn't help that a couple of other drugs in the same structural class turned out to cause lactic acidosis and had to be pulled from use). Bristol-Myers Squibb finally took metformin up, though, and did extremely well with it in the end under the brand name Glucophage. It’s now generic, and continues to be widely prescribed for Type II diabetes.

But for many years, no one had a clue how it worked. It not only went all the way through clinical trials and FDA approval without a mechanism, it was nearly to the end of its patent lifetime before a plausible mechanism became clear. It’s now generally accepted that metformin is an activator (somehow, maybe through another enzyme called LKB1) of adenosine monophosphate kinase (AMPK), and that many (most?) of its effects are probably driven through that pathway. AMPK’s a central player in a lot of metabolic processes, so this proposal is certainly plausible.

But never think that you completely understand these things (and, as a corollary, never trust anyone who tries to convince you that they do). A new paper in PNAS advances the potentially alarming hypothesis that metformin may actually exacerbate the pathology of Alzheimer’s disease. This hasn’t been proven in humans yet, but the evidence that the authors present makes a strong case that someone should check this out quickly.

There’s a strong connection between insulin, diabetes, and brain function. Actually, there are a lot of strong connections, and we definitely haven’t figured them all out yet. Some of them make immediate sense – the brain pretty much has to run on glucose, as opposed to the rest of the body, which can largely switch to fatty acids as an energy source if need be. So blood sugar regulation is a very large concern up there in the skull. But insulin has many, many more effects than its instant actions on glucose uptake. It’s also tied into powerful growth factor pathways, cell development, lifespan, and other things, so its interactions with brain function are surely rather tangled.

And there’s some sort of connection between diabetes and Alzheimer’s. Type II diabetes is considered to be a risk factor for AD, and there’s some evidence that insulin can improve cognition in patients with the disease. There’s also some evidence that the marketed PPAR-gamma drugs (the thiazolidinediones rosiglitazone and pioglitazone) have some benefit for patients with early-stage Alzheimer’s. (Nothing, as far as I’m aware, is of much benefit for people with late-stage Alzheimer’s). Just in the past month, more work has appeared in this area. The authors of this latest paper wanted to take a look at metformin from this angle, since it’s so widely used in the older diabetic population.

What came out was a surprise. In cell culture, metformin seems to increase the amount of beta-amyloid generated by neurons. If you buy into the beta-amyloid hypothesis of Alzheimer’s, that’s very bad news indeed. (And even people that don’t think that amyloid is the proximate cause of the disease don’t think it’s good for you.) It seems to be doing this by upregulating beta-secretase (BACE), one of the key enzymes involved in producing beta-amyloid from the larger amyloid precursor protein (APP). And that upregulation seems to be driven by AMPK, but independent of glucose and insulin effects.

The paper takes this pretty thoroughly through cell culture models, and at the end all the way to live rats. They showed small but significant increases in beta-secretase activity in rat brain after six days of metformin treatment. And the authors conclude that:

Our finding that metformin increases A-beta generation and secretion raises the concern of potential side-effects, of accelerating AD clinical manifestation in patients with type 2 diabetes, especially in the aged population. This concern needs to be addressed by direct testing of the drug in animal models, in conjunction with learning, memory and behavioral tests.

Unfortunately, I think they’re quite right. Update - in response to questions, it appears that metformin may well cross into the brain, presumably at least partly by some sort of active transport. There's some evidence both ways, but it's certainly possible that relevant levels make it in. With any luck, this will be found not to translate to humans, or not with any real clinical effect, but someone’s going to have to make sure of that. For those of us back in the early stages of drug discovery, the lesson is (once again): never, never think we completely understand what a drug is doing. We don’t.

Comments (23) + TrackBacks (0) | Category: Alzheimer's Disease | Diabetes and Obesity | Drug Industry History | Toxicology


COMMENTS

1. processchemist on February 26, 2009 9:02 AM writes...

Ah, metformin... studying a scaled up synthesis, a chemist I know collapsed while filtering in a buchner half a Kg of product (He woke up ok without consequences - I always tell this story to young people unwilling to use a mask to work with powders of APIs).

The PNAS story is interesting but: does metformin cross the BB barrier (I know nothing about it)?

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2. CF on February 26, 2009 10:28 AM writes...

The outstanding Alzhiemer's research published this year is very exciting. The PrP/a-beta article in Nature this week, and the APP/DR6 article last week are well worth reading.

As an aside I think PNAS should institute a policy that any articles which mention marketed products should be open access upon publication.

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3. Jesse on February 26, 2009 10:37 AM writes...

Metformin may not be permeable to BBB by passive diffusion, as you look at its structure. It still can pass across BBB by uptake transporters (OCTs specifically).

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4. CMC Guy on February 26, 2009 11:58 AM writes...

So has the first Lawsuit been filed yet claiming metaformin increased AD? Because it is a generic who gets sued and likewise who would be responsible for conducting the studies mentioned?

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5. retread on February 26, 2009 12:01 PM writes...

Derek: "There’s a strong connection between insulin, diabetes, and brain function."

Quite true. There are also strong connections between just about any significant illness and brain function -- hypertension, kidney disease, liver disease, lung disease -- you name it. Having any one of them makes it harder for your brain to function. All of them produce some degree of cognitive difficulty on their own, and if you have another problem going on in your brain (incipient Alzheimer's, mild cognitive impairment, previous head injury, previous stroke), they will add to (or worse multiply) the existing problems.

#2 "The outstanding Alzhiemer's research published this year is very exciting." Hopefully, it will lead to something. However, I've been hearing this sort of thing for 40 years now and we still don't have anything useful for Alzheimer's despite rather breathless propaganda to the contrary.

I'm the one who had to listen to this stuff when desperate families of patients brought it in, try the latest nostrum (assuming it wasn't actually harmful) and watch it fail, so excuse the cynicism. However, you are the people who (hopefully) will eventually produce something helpful, so be excited and keep on working. It is a fit use of your intelligence, even if you fail, as so many have before you.

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6. Rev. Howard Furst on February 26, 2009 12:31 PM writes...

The authors make a big deal about insulin ameliorating the negative effects of metformin, though they don't adequately address the little issue that insulin access to the brain is limited by the blood-brain barrier, whereas metformin does get into the brain. The effects of insulin on metformin-induced changes in beta-amyloid processing in vivo are most likely mediated by peripheral effects of the insulin. Likewise, Actos and Avandia are tissue-selective insulin sensitizers that probably have no direct effect on neuronal glucose utilization, so their possible effects on Alzheimer's would also haveto be peripheral, most likely vascular.

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7. john fitzgibbon on February 26, 2009 1:34 PM writes...

So given the recent literature links between type II diabetes/insulin sensitivity in the body and Alzheimers and the fact that lifestyle can significantly alter insulin sensitivity should we not start pushing different diets (low carb/low glycemic) and lifestyles as way to slow/prevent this disease.

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8. Ben on February 26, 2009 2:57 PM writes...

Derek, I think you're neglecting the obvious conclusion here -- diabetes cures Alzheimers...

In all seriousness, until I see a convincing mechanism of action for metformin, I think a lot of the discussion around linking AMPK to BACE is speculative goal-chasing where scientists look for exactly what they're looking for. This isn't to say the work isn't good, but before I'm willing to buy this conclusion, I'd like to see a credible MOA.

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9. K on February 26, 2009 3:40 PM writes...

Just to through another one in the mix...

I heard a talk once where the presenter said that patients on metformin showed a 40%* lower incidence of cancer.

*My memory of the precise percentage may have faded over time, but the figure was rather remarkable, even if 40% is wrong.

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10. Gretchen on February 26, 2009 4:05 PM writes...

1. Although fatty acids don't cross the BBB, ketones do, and the brain can run on 50% to 75% ketones when it has to, as with a low-carb diet, after a short period of adaptation.

2. Not a lot of insulin crosses the BBB. exogenous insulin seems to help with AD only when given intranasally.

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11. Dick G on February 26, 2009 5:35 PM writes...

So do we substitute a new FDA approved branded drug for Metformin only to find out, ten years from now, that it also leads to Alzheimers. Sadly both Diabetes(type2) and Alzheimers are preventable. Both result from a combination of genetic type, diets high in processed grains and modern vegetable oils (omega 6's). Yet the ADA and mainstream nutrition still are strong proponents of low fat high grain diets and they still encourage the substitution of polyunsaturates for saturated fats. Morbidity will not decrease unless we return to more traditional foods. The historical record of modern disease should be proof that the western diet and not saturated fats are the enemy.

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12. Matteblacke on February 26, 2009 7:52 PM writes...

Dick G:

Apologies for my slowness (possibly metformin related, who knows), but please remind me again how genetic type is a preventable cause of type 2 diabetes and Alzheimers?

Ben:

I agree with you, in that it is difficult to conclusively prove a MOA for a side-effect when the drug itself has an (as yet) unproven mode of action.

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13. Margaret M Polaneczky on February 27, 2009 11:25 PM writes...

Not to clutter up a scientific discussion with anecdote, but this post reminds me of a clinical scenario written by a fellow medical blogger in which Alzheimer's like dementia in an elderly patient was reversed upon discontinuation of her metformin.

http://dinosaurmusings.blogspot.com/2007/07/i-cured-her.html

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14. kevin horgan on March 1, 2009 8:07 PM writes...

Andrew Morris in Dundee has studied the relationship between cancer and metformin - apparently there is a ~ 40% reduction - the Scottish health system is structured to facilitate epidemiologic studies. Time to look at incidence of Dementia.

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15. kevin horgan on March 1, 2009 8:07 PM writes...

Andrew Morris in Dundee has studied the relationship between cancer and metformin - apparently there is a ~ 40% reduction - the Scottish health system is structured to facilitate epidemiologic studies. Time to look at incidence of Dementia.

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16. Dick G on March 2, 2009 12:29 PM writes...

Mattleback, The APOE4 allele is a widly recognized risk factor for the development of Alzheimer's. The incidence of Type II Diabetes is much more prevelant on some etnic types which suggests a genetic link. As for "genetic type is a preventable cause of type 2 diabetes and Alzheimers" these are your words.

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17. Stephanie on March 13, 2009 10:58 AM writes...

You previously visited AMPK and the brain with the AMPK suppressors and appetite suppressants Rimonabant and Taranabant.

Now you're saying metformin, an AMPK activator, may contribute to Alzheimer's.

A new study links AMPK to brain development:
Enzyme Is Essential Contributor to Brain Growth
www.newswise.com/articles/view/549973/?sc=rsmn

When scientists at Washington University School of Medicine in St. Louis selectively disabled the enzyme AMP-activated protein kinase (AMPK) in mouse embryos, overall brain size was reduced by 50 percent, the cerebrum and cerebellum were shrunken, and the mice died within three weeks of birth.

We clearly more research on AMPK's effect on the brain.

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18. Stephanie on March 13, 2009 11:06 AM writes...

This just gets stranger and stranger.

Found this in today's news about AMPK

Anti-Psychotics and Weight Gain
Written by Shamir Benji on March 8, 2009 - 6:48pm
http://www.empowher.com/news/herarticle/2009/03/09/anti-psychotics-and-weight-gain
A few recent animal studies have shown that anti-psychotic drugs can increase the activity of an enzyme known as the appetite-regulating enzyme commonly known as AMPK. Further, all anti-psychotics also limit the ability of insulin to work; the resulting insulin resistance has also been associated with weight gain.
So what are the treatment options for these individuals?
To begin with, all individuals who take anti-psychotics should be encouraged to eat healthy and enter into an exercise program. A decrease in calorie consumption is important.
A single study from China showed the anti-diabetic drug, metformin, did reverse the weight gain induced by anti-psychotics. These effects were observed in diabetics who were on anti-psychotic drugs. Metformin should not be taken by individuals with normal blood sugar because this can lead to a severe lowering of blood sugars that can be life threatening. This may not be of great importance in China, but in North America, prescribing a diabetic drug to a non-diabetic is one “great method” of generating a medical malpractice claim.

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19. Caleb Murdock on May 2, 2009 2:05 PM writes...

Taking Avandia for just two weeks gave me permanent tinnitus, and I suspect from my research that it was my brain which was affected and not my ears. If that's the case, then Avandia can get into the brain. My tinnitus now gets worse or better depending on how high my blood sugar is. There is so much that we don't know about the drugs that we use.

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20. Pasi Saario on November 9, 2009 4:25 AM writes...

I'm here for the first time. This metformin/AD article brought me here. Few things here I'd like to comment. This research is certainly not a good news for diabetics on metformin.

You wrote (as many others) that metformin is a AMPK activator. There has been evidence that metformin does also inhibit complex I of the mitochondrial respitatory chain. This may lower ATP-levels and thus activate AMPK.

I've understood that AD is a disease of neuronal hypometabolism and problems are mainly related to glucose/insulin-axis.

Complex I in mitochondria "burns" glucose derived NAPDH; fats deliver also FADH2 to complex II.

If metformin "shuts up" complex I in AD brain neurons, which may be functioning not so well in the first place, that may explain at least a part of the adverse effect.

Metformin may also affect lactate metabolism which is important for neurons.

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21. retread on November 9, 2009 11:01 AM writes...

#20 All dying cells show decreased metabolism. The problem (as it is with every biochemical parameter found in Alzheimer's disease ) is whether decreased metabolism (which has been well documented, even in preclinical states) is a cause of the disease or an effect of "the' underlying pathologic process(es).

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22. Karen on September 4, 2010 10:01 AM writes...

This was very very interesting. I googled to see if there was any connection with hypoglycemia and dementia. My Mother seems to get worse when her blood sugar drops. After giving her some karo syrup the next day she does better. Maybe it is not related but seems to help so that is why I googled this subject. I know hypoglycemia is opposite of diabetes,but her levels I am sure are changing everyday. Any input,comments?

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23. Deb on December 13, 2010 10:09 AM writes...

That study is strange in many ways.

- the metformin doses in this study are about 500 times higher than used for diabetes.
- insulin hardly crosses the brain barrier
- other recent work indicate that metformin may PROTECT from AD by inhibiting neurofibrillary tangles: http://www.pnas.org/content/early/2010/11/17/0912793107.full.pdf

All in all, we tend to have overreactions. So far is that metformine reduces overall mortality by close to 40% compared to other standard diabetes II treatments

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