May 27, 2009

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?

 

36 comments:

Anonymous said...

i do two 500 mg am/pm for the purpose of muscle uptake. i was getting no bang for my buck exercising. with the met, push ups became better. opposite of your tired. I portion control too much to measuer effect on weight, though the low carbs control bgs, my body has adjusted and is too damn efficient at converting protein to glucose- thus 270 to 220 is to now 240. just bill

Anonymous said...

here you are...with a grain of salt please
"also shows that metformin can reduce autophagic vacuole accumulation and autophagic beta cell death both in beta cells from type 2 diabetic patients and in NEFA-exposed beta cells from non-diabetic controls, a finding associated with restored LAMP2 expression. At the present time we can only speculate on the mechanisms leading to these effects. Metformin potentiates AMP kinase (AMPK) activity [14]. Beside several other actions, AMPK can inhibit the mammalian target of rapamycin (mTOR) [15]. Since mTOR inhibition leads to increased removal of autophagic material.."

Anonymous said...

Also in this study, improvement of islet function by metformin was not associated with a significant reduction of triglyceride content, but with normalization of glucose utilization and oxidation. These effects of metformin on glucose metabolism in islets are similar to effects at the level of peripheral tissues (18). Our results with the therapeutic concentration of metformin are similar to findings in rat islets, in which metformin caused reduction of FFA oxidation (10). Finally, treatment with drugs able to reduce plasma FFA levels or their oxidation, such as acipimox (6) or glitazones (19–21), can improve ╬▓-cell function, supporting the concept of interplay between FFAs and glucose metabolism. Another similar mechanistic approach...you get rid of lipo and gluco toxicity in the islets and they live longer.

Ian said...

Because there were issues with ticking the "Taking medication for diabetes" box instead of the "Managing diabetes with diet and exercise", I stopped taking 1000mg of ER for three months to see what effect it had.
My HbA1c remained at 5.4 and I didn't really notice any other effects, either.
I'm now using up the box I'd already bought and never noticed anything when I re-started either!

(Of course, 1000mg is a small dose, so that might not be surprising.)

Jenny said...

From the full text it appears that what they did was isolate beta cells from pancreases taken from recently dead multiorgan donors. Then they exposed these cells to a metformin solution and the nonesterified fatty acids and found that the metformin limited damage to the cells from the NEFAs.

This is a fairly artificial process so the relevance it has to living people is pretty attenuated.

I am going to change the main text of the blog post.

Scott said...

Interesting study ... if metaformin increases GLP-1, then that raises new questions about newer incretins (Byetta, Novo Nordisk's not currently FDA approved Victoza/liraglulitide) and whether the first line of treatment should be a cheap, generic version of metaformin instead. Although I'm type 1, my own endo commented to me recently that his opinion was that metaformin was one of the most effective type 2 meds available, and that he routinely prescribes that in lieu of newer, more costly drugs unless there's an adverse effect that warrants discontinuing metaformin. Still, the marketing of new drugs will not let a simple fact get in their way, but these studies do suggest more research into metaformin and it's mechanism of action is definitely warranted!

Jenny said...

Scott,

The study about the use of metformin for people with Type 1 was interpreted as suggesting it wasn't useful, but that is only if you look at A1c as the only gauge of usefulness.

Metformin allows Type 1s to lower their insulin dose, which has to be healthy and probably eliminates the weight gain that creeps up with middle age and is very insulin-related.

Metformin makes zero difference in my A1c, but I am sure I am a lot healthier not gaining weight than I am packing on 10 lbs each year which is what happens without it.

Trinkwasser said...

Fascinating, as always.

I hugely reduced my IR, well according to my lipid profile, but I still had this funky liver which would dump or withold glucose as it chose. I asked about metformin and was told this would not be available until my A1c was (then) over 8. I found Alpha Lipoic Acid did a similar job on relinking the broken control mechanism. Now I wonder if this is affecting the same protein.

This looks to be one of the mechanisms broken in our family. It would also be a likely candidate for glucose tolerance problems before this degenerates to "real" diabetes, which would make met a prime candidate for diabetes prevention - in patients with this particular broken mechanism.

Also how ironic that it was affecting incretins before they had been discovered.

Anonymous said...

My profile:
High risk genes for T1, (one of the highest but not the very highest), great BP, normal BMI, insulin sensitive and yes, this has been tested. I'm considered T2 & don't have antibodies for T1 - they have been tested. But have autoimmune issues associated with T1.
I use a very small amount of Met (375 per day - ya, that small). I ran out the other day and after 14 carbs then 14 an hour later - I tested one hour after that...I was at 212 without the Met. That's not much of anything and to be that high!! This is from someone who's last A1c was 5.3 and my FBS runs just under 90. This new info makes sense to me. Also I was reading about beta cell death - it seems to be much the same with T1 and T2... only with T1 they end up with the added autoimmune markers...but not always and it surprised me that children less than 5 years old some didn't have markers at all - they figured the process was so fast. Then...hummm....I've read that a study or two that think DR4 might be a marker for T2. As we know that's a BIG one for T1 (it's my primary bad one DQB1*0302). And it's more of a lack of insulin problem than resistance.
So with a number of T1's trying Met and finding it lowers their requirement and how I react to it. For me, it allows my system to get some rest and me too at night! Jenny...you are filling in more of my puzzle pieces! I couldn't figure out for the life of me why Met was working but when I went off that baby dose & had that bad reaction I knew I had to go back on it. I figured it was in the liver and it was a hormonal reaction.
Thanks for your blog :-)

Rachel said...

It makes me wish I could tolerate metformin and/or that it had some tangible benefit. I've tried it all to tolerate it - taking with/without food, calcium supplements, fiber supplements, lowering carb intake, increasing carb intake. As someone who has a demanding job, it was impeding my performance to be sick all the time.

Meanwhile, I didn't see that my blood sugars or A1C levels were any different than off metformin. Perhaps I wasn't absorbing the medication with getting sick from it all the time, I don't know.

This is huge news for those who can tolerate it and I won't deny that.

Krista said...

I lost 20 lbs over 3 months when I began on metformin ER, 1000 mg/day, but was also changing my diet and decreasing the amount of carbs, so it's difficult to say which factor had the most influence on my weight. My weight is now stable at pretty close to my ideal for my height, however, I've had to increase my daily metformin ER dosage to 1500 mg/day because my blood sugars and A1C have increase slightly after an initial decrease.

LynP said...

Thanks Jenny for blogging this. Guess I won't try so hard to reduce/get off Met (ER form) until I lose all my excess wt as it appears to do a lot that's really positive like maybe saving beta cells that might make the diff between managing T2 w diet & exercise (so far averaging 51 mins/day) versus having to take drugs.

scotempress said...

Rachel, I'm in the same bind. I have tried metaformin twice. First the standard ER and just recently Glumetza and one both ocassions I couldn't even get past the 500 mg level once a day. Does anyone know a way to get past the GI problems with met, most particularly the diarreha?

I found this site because I just heard about the possible link between pancreatitis and Januvia. I've been on the Januvia since October with no apparent side effects, but now I'm concerned. My mother died of pancreatic cancer when she was only 52 and this is one set of dice I don't feel like rolling.

I'm on the verge of calling my endo and telling them no more Januvia. I just recently started Levemir because the Januvia was making any substantial impact on the BG levels. I suppose I could just go on the Levemir alone, but I'm concerned about weight gain and lows.

I wish I could tolerate the met. It's cheap, a 90 day supply is only $10 at Walmart and I really need to lose between 100-120 pounds. Maybe third time is the charm.

Please, anybody know any secrets on getting past the GI problems with metformin, let Rachel and me and others like us know.

Trinkwasser said...

Some people find metformin is less noisy when taken mid-meal and with no or few carbs in the same meal, part of the problem may be that it blocks carbohydrate absorbtion so the carbs should you eat them have to go somewhere!

Having said which, like all drugs it just doesn't work well for some. You might trial Alpha Lipoic Acid which has some similar functions in some people, effects are generally mild and side effects usually absent. Either way, cutting those carbs will probably have more benefit than any medication.

Jim, the Guacamole Diet guy said...

I feel very uncomfortable with all these unknowns about what medications do. I refuse medications, and I am trying very, very hard to find dietary solutions to my Type 2 diabetes. Needless to say, my doctors are very unhappy with what they describe as my "noncompliance" -- which I actually see as being very compliant with how my body is designed to function: chemical-free.

Lisa said...

Thanks for your blog Jenny!

My fasting blood sugars were right at the borderline of being a type 2 diabetic, so last year my doctor started me on Metformin and the diarrhea was terrible after 2 months of taking it.

So my doctor switched me to Actos. I gained 10 lbs in a few months and I am already overweight and was working hard with diet to lose weight not gain more!

I recently stopped the Actos and have gone back to the Metformin but I always take the Metformin after the meal, not before, not during, only after and that seems to help a lot. I also find that while I was told to take 500 mg x 3 times a day, 2 times a day I don't get the diarrhea, where 3 times a day I do...

I clearly need to learn more as I don't know anything about some of the medical stuff you are all talking about, such as beta cells, but you have inspired me to learn more! Thanks!

Sherlock said...

I take 1000 mg of Metformin in the morning and at night. Fortunately, no digestive issues (which surprised me because my stomach is very sensitive to everything!!). I started also taking salsalate (which is known to lower blood sugar) about two months ago.

I backed slowly off the met so that I was taking only 500 morning and evening. My BS levels increased and I started gaining weight (no change in diet at all).

Up to that time, I had lost 20 pounds.

About 3 weeks ago I went back on 100- 2x day of the met and my weight has dropped again and bs has also dropped.

I still eat a relatively carb free diet (although I can eat wheat-based carbs in the morning and at lunch -- which is a good thing because I do love my sandwiches!!). No affect at all on my bs level.

After about 4 pm, I cannot eat any carbs except what is naturally in veggies and meat. I cannot add any starchy food, not even 5 little baby carrots or any kind of fruit. Except for pears -- for some reason I can eat a pear at any time of day or night and it has not affect on bs. Any other fruit (and believe me I've tried them all) will spike bs with just a few bites.

Now my bs is at normal non-diabetic levels. I see the endo this week and will find out if I need to back off either the salsalate or the met. I'd prefer to get off the sals and replace that with another anti-inflammatory because when I reduce the met, I start gaining weight again.

Sorry this was so rambling!

Jenny said...

Sherlock,

I have found that despite the claim that Metformin ER lasts 24 hours, it wears off by dinner if I take it first thing in the morning. Splitting the dose may give you better coverage at dinner.

Don't let the doc talk you into giving up the metformin or you will gain weight. I sure did.

Rairy said...

Have you found anything to help with the fatigue/muscle weakness you encountered with Metformin?

Its hard to continue with a med that makes me feel like I've been beaten with sticks. I'm still pre-diabetic and it does seem to help my fasting numbers so I dont want to give up on it yet.

PRIVATE said...

Not only do I start gaining weight when I try to stop taking Metformin, I also feel like I'm in some sort of brain fog. I stopped taking it for a few days and I ate the same meals I normally eat, and my numbers started creeping up much faster than usual and they stayed up longer. I heard that Metformin is derived from an herb, is this true ?

Jenny said...

There is an herb, French Lilac (also known as Goat's Rue) that has something in it similar to metformin, but it is poisonous.

The first drug using a chemical similar to that in the her, Fenformin, was developed in the 1950s but turned out to be dangerous and was taken off the market in 1978.

Fortunately, metformin. which has been used in the UK since 1958, does not have the same side effects as phenformin and because it has been in use for so long we have a very good idea of its effects and safety which are very good.

Emily said...

If you are experiencing muscle weakness and tiredness from this medication you need to call your doctor right away it could be acid lactosis. Rare but it eventually causes death. It should not cause muscle weakness or tiredness. Call doctor immediately!

Emily said...

I'm sorry its called lactic acidosis. Lol I'm a little dsylexic this morning.

Jenny said...

Emily,

Lactic acidosis is extremely rare and occurs in people taking metformin at the same rate as it does in those who do not.

Among people with diabetes who develop it the causes is almost always significant kidney failure and preexisting debility.

Tiredness and aches are normal side effects of metformin early on, and pass away.

I just read a discussion of this topic, with citations, in Endocrinology Today which you can read HERE.

Wendy said...

I was just diagnosed as being prediabetic and was put on 500 mg regular Metformin. I became horribly starved and felt like I was having sugar drops, so the doc switched me to Glumetza. With that, I got panicky and felt like I was having another sugar drop, especially after eating the next day. Have you ever heard of this? Is there a difference between Glumetza and Metformin ER? The pharmacist told me Glumetza lasts about an hour longer than the metformin ER. I don't like the cost.

Jenny said...

Wendy,

What you describe sounds like a false hypo. It happens when you are used to your blood sugar being too high and lower it. Your body reacts as if your blood sugar was dropping into a danger zone, but it really isn't.

You can determine if this is the problem by buying an inexpensive blood sugar meter (the Relion from Walmart will do) and testing your blood sugar when you feel fine and after you experience the shakiness. Unless you see a reading below 70 (or 75 on the Relion as it tends to read a bit higher) you are not actually having a hypo.

The "cure" is to wait it out for a few days and let your body adapt to normal blood sugars.

fletch said...

Metaformin raises Homeocystein levels so make sure yours are tested. Taking Folate and B12 can help lower the levels and are suggested by many doctors. If you do a search for metaformin and Homeocystein you will find many studies substantiating this information.

Jenny said...

Fletch,

That is simply not true. Raising homocysteine with B12 turns out NOT change the anything to do with heart disease. Metformin may lower B-12, in people who take it for many years, because it may affect that ability to absorb B-12 from the gut. When this happens you need shots, not pills. But this is a minor problem, rare, and a poor reason not to take Metformin, especially since numerous studies show it decreases the likelihood of heart disease.

Rachel said...

I gained over 20 lbs. in six weeks when my hypothyroidism turned into full blown Hashimoto's Thyroiditis around six months ago (what many on the fringe now think is merely the body's reaction to insulin resistance onset). Regardless of how much or little I eat or exercise, the scale does not budge. I also have many PCOS symptoms and Diabetes in my family, so I convinced my endo to prescribe me Metformin. I did not tell him that, as an informal trial run I took two doses of my mom's Metformin - 500mg one morning, 500 the next. I lost four pounds in those two days! When I got my prescription, however, my doctor had prescribed 750mg of Metformin ER, twice a day. It's been over a week now and my weight has not changed at all, though I eat much less and don't feel hungry. I know my "trial" was short and unscientific, but it seems the ER might affect weight loss differently from regular Metformin.

Jenny said...

Rachel,

It's more likely that the weight you lost when you started the metformin was due to the loss of glycogen in your liver. Metformin acts like a very low carb diet in the way it will cause this initial loss of glycogen. Glycogen can account for up to 12 lbs of weight, so losing one or two is very typical with metformin. Once that weight is lost, fat loss will be much slower.

Ethel Veeblefester said...

Hi Jenny,

I'd like to get back to the diarrhea that Metformin causes. I don't want to stop the Metformin because it controls my blood sugar so well, but if I have to go somewhere, I have to take an Immodium so I don't have an accident. I never know when it will hit. I can go a couple weeks and be fine, then out of the blue, I'm running for a bathroom. Is stopping all bad carbs the only way to control this? If carbs are the culprit, why am I fine many days? I'm trying to understand and stay compliant. Thanks :)

Jenny said...

Ethel,

I don't think it is carbs per se, but it may be starchy carbs that get digested by gut bacteria.

Is it possible that you have something else going on, like a sensitivity to gluten? That also causes that kind of stomach reaction.

Finally have you tried the ER form of metformin?

Unknown said...

Sugar free treats can do that, too.

Ethel Veeblefester said...

Jenny, I didn't have this problem before Metformin, so I know for sure it's that. I haven't tried the ER form. I'll ask for that when I need a refill. Thanks :)

Unknown, the only sugar-substitute that bothers me is called, I think, lactitol. The only other food that bothers me is green pepper and it's easy to avoid that.

Alan M. Smith said...

Re. GI distress and diarrhea while taking metformin: after three months I still have these side effects; however, after reading some of the posts here, I now recognize these symptoms are not a daily occurrence, but rather seem to happen sporadically. This suggests to me that a high dose of carbs might be the culprit, or at least a contributing factor to its severity. For instance, after taking my evening dose the previous day followed by a high carb "treat" before bed (yes, I know and have already been reprimanded), this morning (forgive my I indelicacy) I have spent two hours on the toilet. The sensation is not unlike a night after a jar of pickled jalape├▒os. I will now try to avoid large consumptions of carbs at one time and see it that alleviates the problem. Thanks, everyone, for your insights and contributions.

Jenny said...

Alan, Let us know what your further experiments come up with. Met works fine up to about 120 g a day, but after that it does seem to cause more problems, from what I've observed.

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