What is Metformin? (for weight loss, diabetes and…)
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What is Metformin?
Metformin is the most popular drug for type 2 diabetes. It’s unique because unlike most other drugs it lowers blood sugar without increasing insulin secretion.
Metformin is also used to treat polycystic ovary syndrome (PCOS), a condition of insulin resistance largely. Metformin is a mild insulin-sensitizing drug which may counteract insulin resistance. In this manner, it is thought to potentially lower the risk of endometrial cancers that are three times higher in women with PCOS.
Recently, it gained a lot of attention as an “anti-aging” drug with lifespan extension potential.
So is Metformin really this wonder drug? And how does it do all that it’s said to do?
How does metformin work?
Metformin lowers glucose production in the liver and makes muscle cells more sensitive to insulin. These muscle cells can thus take up glucose more easily.
So it reduces ‘baseline’ fasting blood glucose levels in the first place. And, if blood glucose shoots up after a carb-rich meal say, it’ll also help lower those post-meal glucose spikes. Through this double impact on blood glucose levels, metformin can mitigate some of the damage caused by diabetes control for a while [2, 3].
Metformin is usually the first drug prescribed to newly diagnosed diabetes patients. It cannot, however, stop the progression of diabetes as it doesn’t address the underlying causes. And the dose is often increased over time and combined with other medications.
When given to patients with prediabetes, metformin can decrease the risk to become diabetic. The medication is, however, less effective than lifestyle interventions.
While metformin is a good option and adjunct treatment for diabetics, it does not remove the major offending dietary elements; fast digesting carbs, an excessively high total carbohydrate intake and high omega-6 seed oils.
By removing these factors people often end up following a well-formulated low-carb or ketogenic diet. The road to get there can be confusing as outdated advice is still given, like use the glycemic index or count calories. Nutrita’s Insulin index or Keto gives you simple, reliable measures to guide you towards making smarter food choices.
Even though Metformin has been used for many years for the treatment of type 2 diabetes, its mechanism of action is still not fully understood.
Metformin is known to interfere with a cog in the machinery (complex 1) of mitochondria, those little organelles populating and powering your cells. For this reason, it is traditionally thought to exert its actions via this mechanism.
Your cell’s energy sensor (AMPK) senses this mild drop in energy resulting from the inhibition and responds by increased fat burning. Less glucose is released by the liver too, but whether AMPK activation is in indeed responsible for the glucose-lowering effects of metformin seems less and less likely.
Another way to explain its glucose lowering effects with compelling evidence is its interference with mtGPDH. This is a transporter like machine delivering important cargo needed by mitochondria to fuel the cell.
This interference threatens the cell’s energy state (redox status) and energy availability (enough ATP). This is thought to lead to a counterbalancing, protective action (especially from the diabetic’s perspective); less new glucose is created and pumped out by the liver into the bloodstream.
Can Metformin help you lose weight?
Metformin is known to be marginally beneficial for weight loss. How does it do that? Metformin stimulates the breakdown of fat. It also lowers your blood glucose, which leads to less insulin needing to be released.
Since insulin is a fat storing hormone, lower insulin levels make your stored body fat more accessible. You have plenty of energy stored as fat, so by making these stores accessible your metabolism can rely on more fat for energy; this helps normalize appetite and lose excess body fat.
An overproduction of insulin can eventually lead to insulin resistance. This is the phenomenon whereby cells become less and less responsive to insulin so more and more of it is needed to perform its action. Hence, this insulin-lowering effect of Metformin is especially beneficial for people who are insulin resistant.
Diabetics aren’t the only ones who are insulin resistant. Many people also have prediabetes (often without knowing it) or some kind of underlying insulin resistance. Having said that, although metformin facilitates weight loss for a while it is not an effective weight loss tool. It is more efficient over 3 months when used in combination with other drugs, such as GLP-1 agonists.
These benefits are likely easily lost by spiking your blood sugar with refined carbs. Metformin is much more efficient when combined with a low carb or ketogenic diet and may become unnecessary in many cases.
Metformin as an anti-aging drug
Scientists are still looking for the secret of healthy aging and metformin might take them a bit closer. One study observed that diabetes patients taking metformin lived longer than the control group without diabetes. Considering that diabetes is a risk factor for a variety of life-threatening diseases, this is an astonishing result.
However, as interesting as this correlation is we do not know if metformin improves longevity or if so, how. Metformin decreases insulin levels, IGF-signaling, inflammation, and oxidative stress.
It is also thought to activate AMPK and thereby inhibits mTOR. mTOR inhibition is known to be involved in mechanisms linked to increases in lifespan. AMPK and mTOR act as energy sensors and low nutrient-availability is well-known to improve longevity. Metformin seems to mimic calorie-restriction, which probably contributes to its life-extending effect.
Before you jump into taking metformin: it is even less clear if the life extension correlation in diabetics is even relevant to non-diabetics. Your efforts are still best focused on smart lifestyle changes – sorry!
Metformin for the treatment of PCOS
Polycystic ovary syndrome (PCOS) is a hormonal disorder that occurs in women and is associated with high levels of androgens (male hormones) and with insulin resistance. Common symptoms of PCOS are fertility problems, weight gain, skin problems and an increased risk of type 2 diabetes.
Insulin resistance is thought to play a causative role in PCOS. Insulin, together with IGF, stimulate the ovaries to release higher levels of testosterone. This leads to problems in the release of eggs during ovulation and often even pregnancy.
Metformin is used to treat infertility in women with PCOS and can also relieve other symptoms. Metformin’s beneficial effects are thought to be due to its insulin-sensitizing abilities. Clomiphene, an ovulation-inducing agent, is used as first-line therapy for infertility treatment in PCOS.
In non-obese women, metformin treatment results in pregnancy rates that are comparable to treatment with Clomiphene. This is, however, not the case in obese women, in which Clomiphene is more efficient.
But obesity is a risk on its own right and weight loss is recommended in any case when planning to get pregnant. Since metformin is only a weak insulin-sensitizing agent, it is feasible that the additional obesity-associated insulin resistance is too much for Metformin to be beneficial.
Besides increasing the chances of pregnancy, weight loss is known to improve PCOS symptoms considerably. Because the ketogenic does not only facilitate weight loss but also lowers insulin, it is not surprising that it can benefit women with PCOS. In one study, women dropped weight by an average of 12% and reduced fasting insulin levels by 54%.
Metformin and exercise
Metformin and exercise are both known to increase insulin sensitivity of muscle cells. So you would expect that both in combination potentiate this effect, correct? On the contrary actually! One study showed that Metformin can reverse the insulin-sensitizing effect on muscle cells usually seen after aerobic exercise. They suggest this occurs due to decreased mitochondrial respiration; less oxygen can be used by these organelles to supply energy to the cell (ATP).
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What are Metformin side effects?
Metformin is taken up by the gut and is known to cause nausea, diarrhea and an upset stomach, probably by interfering with gut bacteria. Lowering the dose usually helps to eliminate this unpleasant effect.
A quite severe adverse effect of metformin is that it reduces the uptake of vitamin B12. Because vitamin B12 stores can last for a long time, metformin does not cause an immediate deficiency. When metformin is taken over many years, it can, however, lead to a deficiency in this crucial vitamin, which can cause irreversible damage in sensory and motor nerves, known as neuropathy. Since diabetes itself is a common cause of neuropathy, the danger is high that a vitamin B12 deficiency is not recognized and the nerve damage progresses. When taking metformin over the long term, vitamin B12 levels should be monitored, the diet skewed to a high intake of vitamin B12 and if necessary, supplemented.
Metformin can also cause a medical condition called lactic acidosis. Lactic acidosis is the result of too much lactic acid production, which lets the blood pH drop. This condition is, however, very rare and occurs only in < 10 cases per 100,000 patient years.
Metformin is supplied as a tablet. The starting dose is usually 2 x 500 mg per day, taken with meals. The dose is then slowly increased by 500 mg per week or 850 mg every two weeks, up to a maximum dose of 2550 mg per day. When taking more than 2000 mg per day, the dose should be divided by three and given three times per day together with meals.
A slow increase in dose helps to prevent digestive distress, but these side effects can still be dose limiting. If a dose increase worsens the side effects, the previous dose should be maintained for 2-4 weeks until tolerance has developed.
If you have a hard time tolerating metformin, you can try extended-release tablets. They are taken only once a day and then slowly release the agent over several hours.
After starting to take metformin, you might wonder how long it takes to see an effect. It is fast-acting medication, but because you usually start with a very low dose, which is slowly increased, it will take a few weeks or more before you can measure differences in blood sugar.
Metformin is well known for its anti-diabetic properties, and more and more benefits are emerging. It has been associated with decreased risk for certain cancers, may increase lifespan, is marginally helpful to lower body weight and can improve the symptoms of PCOS. Its insulin-lowering and -sensitizing effects seem to be mostly responsible for health benefits. However, insulin sensitivity can also be enhanced by low carb or ketogenic diet, without the side effects that come with drug treatment. While Metformin is a useful treatment for the discussed conditions, it is much more powerful when combined with a healthy lifestyle.
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Written by Raphael Sirtoli, MSc, Ph.D. (candidate)
Raphael Sirtoli has an MSc in Molecular Biology and is a Ph.D. candidate in Neuroscience at the Behavioral n’ Molecular Lab in Portugal. His understanding of metabolism, nutrition and clinical medicine is the base upon which Nutrita’s knowledge derives from. He loves open scientific debate, Crossfit, football, hiking, and cold water immersion.
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