New Findings About What Metformin Really Does

As many of my readers know, there is no requirement that the companies that sell pharmaceutical drugs provide an accurate explanation of what it is that their drugs do or of how they do it. All that they have to prove is that the drug has an impact on some measurable phenomenon. The company may claim that a drug functions using a mechanism that is later proven to be untrue. This has been the case with the SSRI drugs which it turned out actually work by remodelling the nerves in the hippocampus, NOT by changing levels of serotonin.

Metformin, which has been used for decades, is another drug whose effect is well understood--it lowers blood sugar and reduces the amount of insulin needed to lower blood sugar. This has been interpreted to mean that it lowers insulin resistance.

But new findings are calling this into question, as we discover that metformin may actually be stimulating insulin release or blocking the liver's release of glucose rather than impacting insulin resistant cell receptors.

The first finding is one I stumbled over recently, one which seems to have gone unnoticed by the medical press. It is that metformin appears to boost GLP-1 levels. GLP-1 is an incretin hormone secreted in the gut which stimulates the beta cell to secrete insulin in the presence of high blood sugars. GLP-1 may also lower glucagon production at the same time. While Byetta and Januvia are higly promoted as being incretin drugs, some little known research suggests that metformin may also raise the level of GLP-1 in the body.

Enhanced secretion of glucagon-like peptide 1 by biguanide compounds. Yasuda N et al. Biochem Biophys Res Commun. 2002 Nov 15;298(5):779-84.

This was old news, but it may partially explain some of the stomach symptoms people experience with metformin. GLP-1 stops or slows stomach emptying and that often causes nausea--a side effect many people experience with metformin.

Meanwhile, some brand new findings are making metformin's function even more intriguing.

A mouse study published on May 15, 2009 suggests that Metformin lowers blood sugar by directly stimulating a gene in the liver which is not responding to insulin the way it should. When this gene is stimulated, the liver stops producing glucose. So rather than improving insulin sensitivity, what metformin may actually be doing is bypassing a broken insulin signaling system and doing the job itself that insulin should have done--making the liver stop secreting glucose. In this case metformin is not increasing insulin sensitivity, it is replacing insulin.

Metformin and Insulin Suppress Hepatic Gluconeogenesis through Phosphorylation of CREB Binding Protein Ling He et al,, Cell Volume 137, Issue 4, 635-646, 15 May 2009. doi:10.1016/j.cell.2009.03.016

You'll find this study explained in layman's language in today's edition of Diabetes in Control:

New Information on how Metformin works.

Metformin may also prevent beta cell death. Another new study published in the May 2009 issue of Diabetologia examined pancreases of autopsied organ donors with and without Type 2 diabetes and found increased evidence of beta cell apoptosis (cell suicide) in the beta cells of people with Type 2. This reconfirms the finding of an earlier pancreas autopsy study.

What is interesting, though, is that this study also found that

Metformin ameliorated autophagy alterations in diabetic beta cells and beta cells exposed to NEFA [nonesterified fatty acides], a process associated with normalisation of LAMP2 expression.

This suggests that metformin might work to prevent beta cell death due to apoptosis.

Autophagy in human type 2 diabetes pancreatic beta cells M. Massini et al. Diabetologia Volume 52, Number 6 / June, 2009, DOI 10.1007/s00125-009-1347-2.Pages 1083-1086

I was sent the full text of this article by a subscriber and it turns out that they are not talking about the effect of metformin on the pancreas when taken before death. Instead what they did here was rescue still living cells from dead organ donors, most of them dead of heart attack, separate the beta cells and culture them. Then they infused the cultures with the fats and a solution of metformin. The metformin prevented some genetic expression in the presence of the fat, but it is difficult to know whether this has much relevance to what goes on in your living pancreas. Or to what extent, being bathed in fats reflects what damages islets in diabetes.

Still it is interesting to see people attempt to find out the impact of metformin on gene expression, which is what is going on in both these studies.

Anecdotal Musings about Metformin

I am particularly interested in metformin of late, because I stopped taking it for a year and noticed that while my blood sugars stayed pretty much constant, I started gaining weight eating the diet on which I had, until then, successfully maintained a significant weight loss since 2003.

I went back on metformin in early April and, sure enough, seven weeks later my weight has dropped some 6 lbs while I have been eating the identical diet--and insulin doses--on which I had gained 6 lbs the previous month.

I am not insulin resistant. I usually use a tiny dose of insulin--2-3 units to cover up to about 60 g of carbs. (I don't eat 60 grams of carbs very often, but if I do I can cover it with 3 units.) When I am taking metformin my insulin dose might drop from 3 units to 2 units, so while that represents a large percentage drop, it but a very tiny drop in the actual amount of insulin used and the kind of dose an insulin sensitive person might use.

But metformin does appear to do something that makes it extremely hard for my body to gain weight. When I first started injecting insulin a few years ago, when I was still taking 1500 mg a day of metformin, I actually LOST weight using insulin. As soon as I stopped metformin I started packing on weight whenever I used insulin, even if my blood sugars were completely flat.

One thing I noticed was that metformin also changes the way my body gains and loses the weight associated with glycogen when I cut my carbs to a ketogenic level, (a topic discussed in detail HERE). If I am not using metformin and start eating a very low carb, ketogenic diet, I will drop 3 or 4 lbs of water weight within days. If I am taking metformin, I won't. On the other end, if I go over the ketogenic boundary when I am taking metformin I won't pack on that sudden 3 lbs water weight gain.

My guess is that metformin somehow interferes with the creation and/or burning of glycogen which may make the body more likely to burn fats instead of stored glycogen. I have been told that some body builders use metformin to hasten the process of getting into a ketogenic state.

Another observation which repeats what I found in the past is that while I am taking metformin, I do not need to take my blood pressure medication to keep my blood pressure in the normal range. When I stop metformin, I do.

The worst side effect I experience with metformin is exhaustion. While taking it I tend to drop off to sleep around 9:30 whereas when I stopped metformin I was much more energetic and always stayed up to 11. My muscles tire more easily too. These side effects were a major reason I stopped taking it. It also gives me a heart-burn like pain (without reflux) which is annoying though my doctor did tests which suggest I don't have an ulcer, though that is what it feels like.

However, gaining 6 lbs in one month eating about 1600 calories a day is also annoying, and I have been battling weight gain all year since I stopped the metformin. I spent more than 6 months of the last 12 eating a very low carb diet and controlling calories and still found myself at the highest weight I'd been in 6 years. So for now, I'm back to taking the metformin.

Once I get my weight stabilized I'm going to experiment to see if I can find the very lowest dose that is still effective for weight purposes. In the past, I found that I had to take 1500 mg to see any impact on my blood sugars, and then it only lowered them about 10-20 mg/dl per meal (or reduced the insulin dose by that 1 unit.)

I am hoping that less might still help prevent weight gain, but this new study that suggests that metformin is working by stimulating a gene that stops the production of glucose makes me wonder if I won't see weight prevention effects until I see that slight lowering of post-meal blood sugars that suggests that my liver's glucose production has been stopped.

What's your experience with metformin and weight gain, loss, or maintenance? Does your experience cast any light on any of these new findings?

 

Metastudy Confirms Metformin Appropriate Treatment for Prediabetes

A study that reviewed several previous studies about the impact of using metformin on the progression of prediabetes to diabetes confirms that yes, people with prediabtes who take metformin end up with better blood sugars after 3 years than those who don't and are therefore less likely to be diagnosed with full-blown diabetes.

This isn't original research, it's just a look at the major studies that have examined the impact of metformin on prediabetes. But because I hear from so many people with prediabetes whose doctors won't give them any help at all, I though it worth a look.

Treating prediabetes with metformin: Systematic review and meta-analysis Muriel Lilly, Can Fam Physician Vol. 55, No. 4, April 2009, pp.363 - 369

The key issue to remember here is that the concept that "prediabetes" progresses to "diabetes" which treats the two conditions as if they were separate diseases is flawed.

In fact, the medical definition of "diabetes" is completely arbitrary. A committee years ago chose some blood sugar test results and defined them as "diabetes." They could have--and many argue should have--chosen different test result numbers. But they chose the ones they did mainly, their own documentation showed, to diagnose people with diabetes as late as possible, because of the severe penalties the American medical system imposes on people who have pre-existing conditions.

You can read about how the diagnostic standards for diabetes were set HERE.

"Prediabetes" was also defined arbitrarily at the same time as "diabetes" was defined and as has been the case with diabetes, the definition has changed over the years.

But what you, the person with abnormal blood sugar, need to understand is that there's no sudden change in your health that happens when you get an official diabetes diagnosis. Any blood sugar that is elevated above normal for hours each day can and will damage your organs. So if your concern is to keep your nerves, heart, kidneys and retinas healthy your focus should be on keeping your blood sugars normal, not in avoiding a technical "diabetes" diagnosis.

With this in mind you can see why the argument the medical establishment uses to argue that "more research is needed" re the use of metformin in prediabetes is a red herring. The argument is this: "We don't know whether metformin is preventing diabetes or just masking the symptoms by lowering blood sugar."

Those who argue this point out that if people stop taking metformin, their blood sugar may go right up to where it would have been without it. So if that is the case, the metformin didn't "prevent" diabetes and there is no point in prescribing it.

But hold on a minute. The damage from "diabetes" is done by the elevated blood sugars, which clog capillaries, block kidney filtration units, and destroy the nerves of the autonomic nervous system that regulate the heart. If we lower blood sugar we avoid this damage. There has never been a single study that shows that people with "diabetes" by diagnosis who maintain completely normal blood sugars develop any of the complications of diabetes. These are caused by the exposure to high blood sugars, not the underlying dysfunction that caused the high blood sugars.

So if giving people metformin lowers people's blood sugar to where it isn't going up to diabetic levels, this is good no matter how you look at it. Even if it doesn't change a thing except their blood sugar levels.

The real problem with using metformin to "prevent diabetes" lies in how "diabetes" is diagnosed in these studies. Most doctors and studies diagnose diabetes as meaning that the patient's fasting blood sugars have risen over 125 mg/dl. Because metformin often lowers fasting blood sugar 5, 10 or 20 mg/dl, someone who might have a blood sugar of 128 mg/dl and be diagnosed as "diabetic" will take metformin, get a fasting blood sugar of 123 mg/dl and be diagnosed "Non-diabetic" in the studies.

This makes a pretty graph or two for the researcher but it doesn't make much functional difference in the health of this patient. Because functionally there isn't much difference in how much damage you are doing to your body with a fasting blood sugar of 123 mg/dl vs 128 mg/dl.

What is much more significant if you are trying to keep people from going blind or losing their kidneys is what happens to the blood sugar after meals--which is a statistic these large "diabetes prevention" studies rarely track since it requires much more expensive testing.

A person with the fasting blood sugar of 108 mg/dl may be be going up to 180 mg/dl after meals and coming back down to 100 mg/dl in two hours. Or they may be going up to 270 mg/dl and drifting back down to 108 in 4 hours. Both people are prediabetic, but the first person is much less likely to develop diabetic complications than the second. And, in fact, the second is technically diabetic given the ADA diagnostic criteria since they have random blood sugars over 200 mg/dl--except that their true diabetic state never gets discovered since the doctors and researchers only look at their fasting blood sugar.

What people with prediabetes need to understand is this. Organ damage starts when blood sugars spend a few hours a day over 140 mg/dl. It doesn't matter what the fasting blood sugar is. It matters how long blood sugar stays over 140 mg/dl. Neurologists studying neuropathy (nevre damage) have found no relationship at all between fasting blood sugar or A1c and the likelihood of developing neuropathy. They've found a very tight correlation between the rise in incidence of neuropathy and 2 hour blood sugar values that are 140 mg/dl and higher on glucose tolerance testing. (You can read more about studies linking organ damage to blood sugar levels HERE.)

So if you have prediabetes defined either by fasting blood sugar greater than 100 mg/dl or post-meal blood sugars that go over 140 mg/dl for significant periods of time the thing you really want to avoid is neuropathy, because it is among the earliest diabetic complications and one that affects all of your body. (The very earliest appears to be carpal tunnel syndrome.)

Almost half of all "newly diagnosed" Type 2s have neuropathy--a complication that can take up to a decade to develop in people diagnosed with sudden onset Type 1 diabetes. That tells us how damaging all those years of untreated "prediabetes" really are.

Metformin can help lower blood sugar, but if you are a person with prediabetes who tests your blood sugar after meals while taking metformin, you'll often see that your blood sugar will still go high enough to cause damage unless you also cut back on your carbohydrate intake.

But metformin definitely can help, and it can allow you to eat more carbs and still get decent blood sugar numbers, which in turn makes it easier to eat in a way that maintains health since it's a matter of cutting down rather than cutting out the carbs.

So as soon as you find your blood sugar is higher than normal, the better off you'll be if you take steps to get your blood sugar back down to the normal range. Whether or not you reverse the underlying condition that made your blood sugar abnormal is irrelevant. Most of us can't, contrary to what many doctors tell people. But as long as we can keep our blood sugar in the normal range, we'll feel much better, since fluctuating blood sugars make for rabid hunger and depressive mood swings, and we will also maintain the normal blood sugars that will keep our organs functioning in a normal way.

If you are not getting normal blood sugars with reasonable dietary changes and your doctor won't let you try a course of metformin, ask why, and if the reasons don't sound credible, find a doctor who will be a better partner with you in the struggle to maintain your health.

PS: Legitimate reasons not to use metformin are known liver and kidney problems.

If metformin does not lower your blood sugars and they continue to deteriorate, it is possible you have an autoimmune form of diabetes. Metformin does not help diabetes caused by damaged beta cells and immune disease and people whose blood sugar does not respond to metformin often turn out not to have Type 2 diabetes.