How does metformin work

Low blood sugar may happen if you: take too much of some types of diabetes medicines eat meals irregularly or skip meals are fasting do not eat a healthy diet and are not getting enough nutrients change what you eat increase your physical activity without eating more to compensate drink alcohol, especially after skipping a meal take some other medicines or herbal medicines at the same time have a hormone disorder, such as hypothyroidism have kidney or liver problems To prevent hypoglycaemia, it's important to have regular meals, including breakfast.

Serious allergic reaction It's possible to have a serious allergic reaction anaphylaxis to metformin.

Information: You can report any suspected side effect using the Yellow Card safety scheme. Visit Yellow Card for further information. What to do about: feeling sick — take metformin with food to reduce the chances of feeling sick.

It may also help to slowly increase your dose over several weeks. Ask a pharmacist or your doctor for advice. Take small, frequent sips if you're being sick. Speak to a pharmacist if you have signs of dehydration, such as peeing less than usual or having dark, strong-smelling pee. Do not take any other medicines to treat diarrhoea or vomiting without speaking to a pharmacist or doctor.

It can help to eat and drink slowly and have smaller and more frequent meals. Putting a heat pad or covered hot water bottle on your stomach may also help. If you're in a lot of pain, speak to your pharmacist or doctor. If it helps, eat smaller meals more often than usual. Metformin is usually safe to take during pregnancy, either alone or in combination with insulin. Metformin and breastfeeding You can take metformin while you're breastfeeding.

Metformin passes into breast milk, but the amount is too small to affect your baby. Non-urgent advice: Tell your doctor if you're:.

There are some medicines that interfere with the way metformin works. If you're taking any of the following medicines, your blood sugar levels may need to be checked more often and your dose adjusted: steroid tablets, such as prednisolone tablets that make you pee more diuretics , such as furosemide medicines to treat heart problems and high blood pressure male and female hormones, such as testosterone, oestrogen and progesterone other diabetes medicines Some women might need a small adjustment in their metformin dose after starting contraceptive pills.

Mixing metformin with herbal remedies and supplements There's very little information about taking herbal remedies and supplements with metformin. Important: Medicine safety Tell your doctor or pharmacist if you're taking any other medicines, including herbal medicines, vitamins or supplements. How does metformin work in diabetes? Metformin reduces the amount of sugar your liver releases into your blood.

How does metformin work in PCOS? PCOS cannot be cured, but the symptoms can be managed. It'll normally be prescribed when other treatments, such as clomifene, have not worked. With treatment, most women with PCOS are able to get pregnant.

When will I feel better? This does not mean that metformin is not working, and it's important to keep taking it. How long will I take metformin for? Keep taking metformin tablets, unless your doctor tells you to stop. Can I take metformin for a long time? It also helps keep your cholesterol at a healthy level. Your doctor will check how well your kidneys work at least once a year. If your kidneys are not working properly, your doctor will tell you to stop taking metformin.

Your doctor may also check the vitamin B12 level in your blood. If you become deficient, this can be treated by taking vitamin B12 supplements.

Can I come off metformin? Do not stop taking metformin without talking to your doctor. If you stop taking metformin suddenly, you may reduce the control over your diabetes. Are there other diabetes medicines?

Metformin is usually the first choice of medicine prescribed to treat type 2 diabetes. If you feel sick after taking your metformin then try taking it with food. It's best to take it with food even if you don't have this side effect anyway. If you continue to feel sick then you might need to have your dose changed.

Speak with your doctor about how you're feeling to get an idea of what you can do. If you're being sick or have diarrhoea, then take lots of small sips of water. And if you have any signs of dehydration then speak to your doctor or pharmacist. If you have any signs of sickness or diarrhoea then your doctor might be able to prescribe sickness tablets. But it's also important that you don't take any sickness or diarrhoea tablets without speaking to someone first. Always speak to your doctor before making changes to your medication.

If you have stomach pain or no appetite, you should eat smaller meals more regularly. If you do have stomach pain you can use things like a hot water bottle or heat pads to help you. You can also have a metallic taste in your mouth as a result of the metformin.

Some people find chewing sugar-free gum gets rid of this taste. If you do feel overwhelmed by your medication then try talking to someone. Our helpline can support you with information and advice.

Some people are able to stop taking diabetes medication like metformin, by putting their diabetes into remission. This means that blood sugar levels are in the non-diabetes range without needing any medication. There are many ways people with diabetes have done this, but they mostly involve making changes to your diet and losing weight. Jon was diagnosed with type 2 in and was given metformin. But after learning more about his condition, Jon started to address his weight.

After a couple of months, he was able to gradually stop taking medication. You may have heard that metformin can help you lose weight. But there isn't a straight answer to whether it can. There have been studies on its effects on weight loss. But currently, it hasn't been approved for weight loss. That's because the makers of the drugs haven't put it forward for the research.

That means metformin isn't labelled as safe to use for weight loss. And although some people think that it makes you gain weight, putting on weight isn't a side-effect of metformin. While metformin is a drug that is used to treat diabetes, it can also be prescribed for other uses. That's because it can lower insulin and blood sugar levels.

Metformin helps correct this problem, and slows liver sugar production. Metformin also improves muscle insulin sensitivity. Insulin is needed to move sugar from the blood into the muscle cell where it can be used for energy.

Metformin helps get the sugar to its proper destination, into your cells. Metformin may help with weight loss. Although it is not a weight loss medication and the research does not indicate a big impact on weight loss, we DO know it is NOT associated with weight gain.

By contrast, some diabetes medications ARE associated with weight gain. Metformin may also provide some cardiovascular benefit. Research shows that metformin can reduce the risk of dying from heart disease, lower LDL cholesterol, plaque accumulation and weight.

A further intriguing gut-mediated mechanism for metformin action was identified in rats and involves a pathway linking duodenal metformin exposure to suppression of hepatic glucose production, via the nucleus tractus solitarius and vagal efferents, through AMPK and GLP-1 receptor activation gut—brain—liver crosstalk, Fig.

A final potential gut-mediated mechanism of action of metformin involves alteration of the intestinal microbiome Fig. Actions of metformin on metabolism and inflammation. Responses to metformin in the blood, liver and intestines are shown schematically.

In the blood, in observational studies, NLR is suppressed in humans with type 2 diabetes, whilst in randomised placebo-controlled trials, cytokines, including C-C motif chemokine 11 CCL11, also known as eotaxin-1 , are also shown to be suppressed with metformin treatment. Other results indicate effects of this drug on monocytes and macrophages, affecting monocyte differentiation into macrophages and proinflammatory proinflam cytokine secretion. In the intestines, gut metabolism, incretin GLP-1 secretion and the microbiome are modified upon metformin use.

Further, there is evidence for gut-mediated mechanism for metformin action via gut—brain—liver crosstalk, which indirectly regulates hepatic glucose output. In the liver, metformin decreases lipogenesis and gluconeogenesis, as a result of its impact on molecular signalling and on mitochondrial function. The mechanism by which metformin causes GI side effects remains uncertain. However, there are a number of putative mechanisms; the side effects may simply relate to the high concentration of metformin in intestinal enterocytes, potentially explaining why slow-release formulations of metformin, which disperse slowly and reduce local luminal metformin concentrations, reduce GI intolerance.

An alternative mechanism may involve serotonin, either as a result of stimulation of serotonin release from enterochromaffin cells [ 46 ], or by reducing serotonin transport via the serotonin transporter SERT , resulting in increased luminal serotonin.

A third potential mechanism of intolerance may be due to the impact of metformin on the intestinal microbiome see later. Further studies are required to establish the mechanisms for metformin intolerance as this may enable approaches to reduce or avoid the unpleasant side effects of this drug.

For example, the studies we report on the role of OCT1 in metformin intolerance would support an approach whereby OCT1-interacting drugs such as proton pump inhibitors are avoided in individuals experiencing GI side effects with metformin use [ 47 ].

In the nematode worm, Caenorhabditis elegans , metformin lengthens lifespan through effects on intestinal microbial growth [ 49 ]. More recent studies in humans found that metformin-dependent increases in Escherichia spp.

This recent work emphasises that microbiome changes in type 2 diabetes are predominantly associated with metformin, rather than type 2 diabetes itself, although their role as cause or consequence of therapeutic benefit requires further investigation. Consistent with this, metformin suppresses the neutrophil to lymphocyte ratio NLR in type 2 diabetes Fig.

NLR is a marker of inflammation that has recently been found to be a predictor of all-cause mortality and cardiac events. In addition, metformin suppresses several inflammatory cytokines in human plasma in individuals without diabetes [ 53 ].

Interestingly, one of the cytokines suppressed by metformin is C-C motif chemokine 11 CCL11 , which has previously been found to contribute to age-related cellular and tissue dysfunction. It is possible that recent observations, consistent with the ability of metformin to prolong mammalian lifespan [ 54 , 55 ], may, at least in part, be due to suppression of this cytokine.

Metformin may also control longevity through regulation of mammalian target of rapamycin mTOR signalling, which is observed in mammals and C. Recently, genome-wide association studies have been undertaken to assess genetic contributions to glycaemic responses to metformin. These offer a complementary route to mouse and cellular studies and have the advantage that they may reveal the mechanisms of action of metformin in humans with type 2 diabetes without making prior assumptions about these mechanisms.

These studies are covered in more detail in the pharmacogenetics of metformin review in this issue of Diabetologia [ 58 ], but we briefly mention here two investigations that identified novel targets for metformin action. The first study reported on a locus on chromosome 11 involving seven genes, one of which was the ataxia telangiectasia mutated gene ATM [ 59 ]; recessive mutations in this gene cause ataxia telangiectasia, a condition associated with fatty liver, insulin resistance and diabetes.

These genes were not previously thought to be involved in the mechanisms of metformin action, and clinical and mechanistic studies are ongoing to address the role of these genes in both the liver and the gut.

Metformin is a complex drug with multiple sites of action and multiple molecular mechanisms. Physiologically, metformin acts directly or indirectly on the liver to lower glucose production, and acts on the gut to increase glucose utilisation, increase GLP-1 and alter the microbiome. At the molecular level, metformin inhibits the mitochondrial respiratory chain in the liver, leading to activation of AMPK, enhancing insulin sensitivity via effects on fat metabolism and lowering cAMP, thus reducing the expression of gluconeogenic enzymes.

As cell and tissue responses are not only a product of dose, but also of treatment duration and model used, we suggest that the physiological relevance of the effects of metformin identified in cells is best validated through studies carried out in vivo, ideally in humans given metformin by the oral route. Further, pharmacogenetic studies in humans, and careful physiological validation of cell-based metformin studies, focusing on intestinal, hepatic and renal effects are warranted to enable a more robust appreciation of the key mechanisms that are active in long-term treatment with metformin in humans.

GR acknowledges current funding from the Cunningham Trust. The authors declare that there is no duality of interest associated with this manuscript. All authors were responsible for drafting the article and revising it critically for important intellectual content. All authors approved the version to be published. Electronic supplementary material. Grahame Hardie, Email: ku. Ewan R. Pearson, Email: ku. National Center for Biotechnology Information , U.

Published online Aug 3. Graham Rena , 1 D. Grahame Hardie , 2 and Ewan R. Pearson 1. Grahame Hardie. Author information Article notes Copyright and License information Disclaimer. Corresponding author. Received Mar 28; Accepted Apr This article has been cited by other articles in PMC. Abstract Metformin is a widely-used drug that results in clear benefits in relation to glucose metabolism and diabetes-related complications.