March 3, 2010

AMP-Kinase, Metformin and Resveratrol

AMP-kinase (AMP-k) is an enzyme which is involved in many of the processes that break down in people with Type 2 diabetes.

Wikipedia has this to say about it:
Activated by muscle contractions... It is expressed in a number of tissues, including the liver, brain, and skeletal muscle.

The net effect of AMPK activation is stimulation of hepatic fatty acid oxidation and ketogenesis, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, stimulation of skeletal muscle fatty acid oxidation and muscle glucose uptake, and modulation of insulin secretion by pancreatic beta-cells.
Translated into English this means that AMP-k turns on the liver's ability to burn fat and create ketones, that it lowers cholesterol and blocks the creation of fats (triglyceride) from carbohydrates, that it gets muscles burning fat and taking up glucose, and cuts back on insulin secretion.

AMP-k is partially regulated by the fat governing hormones leptin and adiponectin, hormones that are often out of control in people with Type 2 Diabetes. It has an effect on the hypothalamus which is the part of the brain that regulates appetite.

AMP-k is even more interesting when you learn that, as summarized in Wikipedia,
Under conditions of exercise, however, blood sugar levels are not necessarily high, and insulin is not necessarily activated, yet muscles are still able to bring in glucose. AMPK seems to be responsible in part for this exercise-induced glucose uptake.
Wikipedia points to THIS CITE to support that statement.

But interestingly, AMP-k expresses the most in muscles when people are not in good shape. The better trained a person is, the less AMP-k is produced.

MPK activation also produces physiological effects that appear to prevent myocardial injury during ischemia--i.e. it prevents damage to the heart muscle during a heart attack.You can read more about the technical details of how AMP-k protects the heart from heart attack in this review:

AMP-Activated Protein Kinase Conducts the Ischemic Stress Response Orchestra. Lawrence H. Young, et al. Circulation. 2008;117:832-840. doi: 10.1161/CIRCULATIONAHA.107.713115

What makes all this very relevant to people with Type 2 diabetes is this: There is evidence that what the diabetes drug metformin really does is that it activates AMP-k. This would explain many of its known effects: that it stops weight gain and can help with weight loss, that it lowers blood sugar, that it stops the liver from dumping glucose, that it lowers cholesterol and triglyceride levels, and that it appears to lower the risk of heart attack.

Role of AMP-activated protein kinase in mechanism of metformin action Gaochao Zhou et al., J. Clin. Invest. 108(8): 1167-1174 (2001). doi:10.1172/JCI13505.

Even more insight into how metformin works is given by this review:

AMPK: Lessons from transgenic and knockout animals. Benoit Viollet et al. Front Biosci. 2009; 14: 19–44.

It is important to note that the lab findings suggest that because metformin's impact is related to its ability to raise AMP-k it does not really "reduce insulin resistance," if by that we mean that it makes cell receptors more sensitive to insulin. Instead, what it seems to do to lower blood sugars--besides keeping the liver from dumping extra glucose inappropriately--is increase the ability of the muscles to take up glucose without the need for insulin.

Because metformin is easily available and cheap, doctors tend to ignore it in favor of newer, more hyped medications. This is a shame, especially since new and highly hyped substances may turn out to merely be repeating what metformin already does. For example, a study just published this month came up with compelling evidence that the health impacts of resveratrol, the substance found in red wine that is currently the subject of much hype and misleading supplement marketing is not due to resveratrol's impact on SIRT1, as was initially speculated. Instead resveratrol's effects appear to be caused by its ability to activate AMP-k. You can read about that finding here:

AMP-Activated Protein Kinase–Deficient Mice Are Resistant to the Metabolic Effects of Resveratrol. Jee-Hyun Um et al. Diabetes March 2010 vol. 59 no. 3 554-563. doi: 10.2337/db09-0482.

Since metformin is available as a cheap generic drug and the bogus resveratrol supplements and upcoming resveratrol-derived drugs are, or will be, extremely expensive, all this suggests metformin is probably an excellent, safe way to get whatever benefits are attributed to resveratrol.

However, in the course of my reading about AMP-k I learned a few other things which may point to some additional strategies that could help those of us who take metformin. One major finding is that in a natural state AMP-k gets produced in response to various stresses. It is not normally at high levels all the time which may be what happens when we take a drug that keeps it activated.

When AMP-k is kept "on" continuously, there are subtle hints that it may cause some bad things may happen. These studies point to this possibility--though I caution you not to overreact to these findings:

Diverse Cytopathologies in Mitochondrial Disease Are Caused by AMP-activated Protein Kinase Signaling Paul B. Bokko et al. MBoC March 1, 2007. doi/10.1091/mbc.E06-09-0881

Over-expression of AMP-activated protein kinase impairs pancreatic ß-cell function in vivo S K Richards, et al. Journal of Endocrinology (2005) 187, 225-235 DOI: 10.1677/joe.1.06413

Fortunately, another study suggests that the concentrations of metformin achieved by people who take the drug are "suboptimal" as far as raising AMP-k which might help prevent negative outcomes from taking it.

The Antidiabetic Drug Metformin Activates the AMP-Activated Protein Kinase Cascade via an Adenine Nucleotide-Independent Mechanism Simon A. Hawley et al. Diabetes August 2002 vol. 51 no. 8 2420-2425.doi: 10.2337/diabetes.51.8.2420

The long term data on the health of people taking metformin which has been in use for many decades is very good. They appear to have lower rates of heart attack and less cancer as well as slightly better blood sugars and better weight than those taking other competing drugs for insulin resistance or insulin deficiency.

However, the fact that AMP-k levels drop in people as they become more physically trained and hints that there may be problems with keeping an enzyme that naturally fluctuates at higher levels all the time got me thinking. I have found that with some other drugs, that taking a "drug holiday" now and then, which means stopping the drug for a week and then going back on it, gives me much better results than taking the drug all the time. This is particularly true for hormone supplements like estrogen which fluctuate in a natural state.

I had also noticed that metformin seemed to have much more impact on weight and even blood sugar the first few months after it is started. So for the past few months I have been experimenting with cycling off Metformin for a week every month and then going back on it. My doctor had assured me years ago that metformin is a drug that can be started and stopped without any negative effect.

Since I am a sample of one and have some very odd metabolic issues not common to most people with diabetes, my experience probably isn't relevant to others, though subjectively I do seem to be getting more impact out of metformin taking this way. It is worth experimenting with this if you are a person who had a strong response to metformin when you started it, only to see it wear off. In that case, it might be worth trying a cycling approach for a month or two to see if it helps.

My personal experience is that when I start metformin again I also get day or two of gastrointestinal symptoms characteristic of the drug. If this is a problem for you, you might not want to try the experiment.

Note: There are SOME drugs that are dangerous if you start them and then stop them without a doctor's help. Do not take a drug holiday from any drug without discussing the issue with a registered pharmacist. Pharmacists are much better informed about drug behavior and safety than are most doctors. Just make sure if you are in a pharmacy that you speak to a registered pharmacist, not an assistant, as the assistants do not have the training you need to get a good answer to this kind of question.



RLL said...

Hi Jenny - have you come across any information about why some of us are intolerant of Metformin - in my case reactivation of GERD. I have tried three times, different formulations and dosages, last time only 500 mg a day of a generic ER. Some have suggested the original non-generic may be better.

Jenny said...

I went through a patch where I had to stop taking Metformin because of gastric pain, but fortunately, it cleared up when I went off it for a few years.

When I started metformin again this past spring, I took Prilosec for the first week and it seemed to do the trick even after I stopped the Prilosec. A few other times since then, the heartburn has started to act up and I've started the Prilosec again and it took care of it.

Other than that, unfortunately, the only things I can suggest are taking the ER form all at once in the afternoon after you've got two meals in your stomach. That also seems to help me a lot.

Ian said...


There was some much-reported Scottish research last year showing how short periods of intense exercise had significant effects on glucose intake to the muscles, and I've noticed that my post-meal readings are much lower if I've done some serious hill-walking first.

I wonder if the drop in AMP-k production in fit people is related to the possibility that they're not pushing themselves as hard as the fatties?
I know that, as I got into shape, I could work a lot harder without muscle stiffness the next day, etc.

I stopped Metformin because I wanted to tick the "controlled by diet and exercise alone" box to avoid regular physicals for my job, but it seemed to have little effect anyway. If you control the carb input enough, you don't need to control the resulting sugar highs as much!

Susanne said...

You're right about pharmacists knowing more than Dr.s about pharmacology. I understand most physicians have one 4 credit class in pharmacology and the rest of their education comes from the big pharma companies. Scary thought....

Jenny said...


For some people even a very low carb diet isn't enough. And for others, metformin helps dramatically with weight loss even if they have their sugars controlled.

We all have such different metabolisms and metabolic flaws.

Fitnatic said...

I have been metformin for a while now and have not lost a pound. I have infact gained a lot of weight. But that is to blame on diet and sedentary lifestyle.
Also metformin in any form just does not agree with my stomach. I have lot of diarrhea multiple times a day...gassy beyond belief etc. The last couple of months I am off metformin and those issues have eventually gone away. I really wish Metformin worked for me. I see the only way to control my PCOS is with strict diet and a good exercise program.

Pubsgal said...

This is interesting stuff. I have type 2 and take metformin, and I'm a recreational athlete (5K, sprint triathlon), so I work out regularly. I typically go ahead and take it on race days, and was wondering how it would impact my performance to not take it the morning of a race, but from this, it sounds like that wouldn't have much of an effect.

Jenny said...


It takes a few days for metformin to wash out of your system, so not taking it the day of a race probably wouldn't have much effect.

I find I'm sleepy early in the evening after taking it nonstop for months at a time, but when I cycle on and off I don't get that happening and stay up later.

italiangm said...

The study described in the link below provides some clues as to how "...histamine 1 receptor (H1R) antagonism and activation of the appetite-stimulating enzyme AMP-protein kinase (AMPK) in the hypothalamus underlie the orexigenic* effects..." of certain meds.

* hunger stimulating

In this case they're speaking about antipsychotic meds, but there are many meds that antagonize H1R.

michael plunkett said...

I have had problems with the generic metformin ever since Medco refused to allow me get Glucophage and replace it with the generic. I know the active ingredient is the same but the pill isn’t. It went beyond the gas and stomach issues. I was on Gluc for about two years and worked past any issues and they were slight. I stopped taken any med and went low carb and have done very well. But after reading that metformin can help correct my metabolism issues, I now take Riomet, the liquid form of metformin. What do you know about it. It is far to sweet for me and they say no sigar but something crystallizes on the lip of the bottle like childrens cough medicine. It seems to work well without any of the problems I had with the generic save so gas, etc from starting again.

michael plunkett said...

Ian --- the fatties?? I hate to think what other terms you use to discribe people. Exercises dirty little secert is the fitter you are the harder you need to work. Next to a glucose meter, a heart monitor is my most valued instrument. It helps me get my Heart Rate where it needs to be when I work with my kettlebells. I work much harder now then when I was one of those fatties people stared at in the gym but the monitor keeps me on track. I hope evdryone gets one if excerise is the rout to improving your metabolism. Weight lose comes from diet and diet alone.

Jenny said...


You can find the official FDA prescribing information online for any drug. It will tell you exactly what is in it.

With Riomet here are the additional ingredients as listed in the Prescribing Information:

RIOMET contains 500 mg of metformin hydrochloride per 5 mL and the following
inactive ingredients: Saccharin Calcium, Potassium Bicarbonate, Xylitol, Hydrochloric
Acid, Purified Water and Cherry Flavor.

So the sweetness is saccarin and a small amount of xylitol. That shouldn't raise blood sugar, but it would taste nasty.

Boz said...

I find the longer I exercise, the longer the impact on my blood sugar. 3 hours of heart rate zone 3 cycling keeps me in the normal range w/o insulin for hours, while lower intensity walking does nothing for me. We are all different and react to exercise differently, just like we do with the various drugs. I take Lantus, Novolog, and Metformin.

It took a couple of months to normalize my digestive system after starting on Metformin, both diarrhea and heartburn. It sure was a lot better, though, than the side effects of Avandia, which left me with scars on my lower legs from water blisters and weight gain.

michael plunkett said...

Thanks Jenny- I'm still seeing how it works for me. I figured it wasn't sugar but stranger things occur in medicine. One point of exercise and BG control. It is not a short term solution for many. But a well thought out program (go strength before cardio) it is a powerful LONG term partner in good metabolism health. Steer glucose away from the blood and into your muscle with a strength training excerise- running, etc does not do that. I love Russian kettlebells.

Chris Kresser said...

Hi Jenny,

You mentioned the bogus claims being made about resveratrol. Have you written more about this elsewhere? I'm aware of all of the hype, but would be interested to hear the counterpoint.


Jenny said...

The most bogus of the claims for resveratrol relate to the pills being sold over the counter as supplements, because the doses that were found to have mild clinical effects on non-human lab subjects were far, far higher than the doses available in any of the pills.

It makes yet another expensive form of snake oil to sell to the ever-credulous supplement buyer.

Chris Kresser said...

Can I trouble you for a reference? I'd love to know what the therapeutic doses were in the studies, vs. what the pills are offering. Thanks for your reply!

Jenny said...

Switters, I don't have the time to hunt down those references, and I don't have them at hand, as they aren't relevant to the subject area I keep up with. Google should be able to find them for you. What I said about them isn't just my opinion it's very well known.