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.