How does biguanides work

A potential explanation for this came with a report that adenylate cyclase, which generates cAMP in response to the starvation hormone glucagon in mouse hepatocytes is like fructose-1,6-bisphosphatase inhibited by AMP. While controversies therefore remain, it seems certain that some of the acute effects of metformin on hepatic glucose production are AMPK-independent, with inhibition of fructose-1,6-bisphosphatase by AMP being one likely explanation. However, a major long-term, clinically relevant effect of metformin is to enhance hepatic insulin sensitivity and mouse studies suggest that this is mediated by AMPK.

Consistent with the prediction that this would enhance fat synthesis and reduce fat oxidation, these mice although not obese had elevated diacylglycerol and triacylglycerol levels in liver and muscle.

Consistent with this steatosis, the mice were hyperglycaemic, hyperinsulinaemic, glucose intolerant and insulin resistant, even on a normal chow diet. When controls were placed on a high-fat diet for 6 weeks they became just as hyperglycaemic and glucose intolerant as the knock-in mice. However, while the metabolic measures of the high-fat fed control mice substantially improved after 6 weeks of treatment with metformin, those of the knock-in mice were unaffected [ 34 ].

These intriguing results suggest that metformin enhances insulin sensitivity, at least in mice, by phosphorylation of ACC1 and ACC2 as shown in Fig. It has been known for some time that the intestines may be a target organ for metformin [ 5 , 35 ], with metformin increasing anaerobic glucose metabolism in enterocytes, resulting in reduced net glucose uptake and increased lactate delivery to the liver.

Several recent studies have led to a renewed interest in the gut as a major site of action of metformin and three lines of evidence highlight that the liver may not be as important for metformin action in individuals with type 2 diabetes as commonly assumed. First, the glucose-lowering effect of metformin can only partially be explained by a reduction in EGP, suggesting other glucose-lowering mechanisms for metformin [ 13 ].

Second, genetic studies in humans have established that loss-of-function variants in SLC22A1 the gene encoding OCT1 , which reduce hepatic uptake of metformin [ 36 ], do not impact upon the efficacy of metformin to lower HbA 1c in individuals with type 2 diabetes [ 37 , 38 ]. Third, a delayed-release metformin that is largely retained in the gut, with minimal systemic absorption, is as effective at lowering blood glucose as the standard immediate-release formulation in individuals with type 2 diabetes [ 39 ].

There are a number of putative mechanisms for how metformin could impact on glucose metabolism via actions on the intestines reviewed in [ 40 ]. As already mentioned, metformin increases glucose utilisation by the gut; an effect that is apparent in PET imaging, where metformin-treated patients show considerable intestinal fluorodeoxyglucose FDG uptake, especially in the colon.

A recent study in mice established that colonic FDG uptake was not increased after 48 h of metformin treatment, but was increased after 30 days of treatment, an effect that persisted despite 48 h of metformin washout [ 41 ]. The increase in FDG uptake was paralleled by an increase in AMPK phosphorylation and, like the FDG uptake, this effect was only seen in colonic enterocytes where luminal glucose was almost absent, suggesting that metformin increases colonic uptake and metabolism of systemic glucose.

Metformin may also impact on glucose metabolism by increasing glucagon-like peptide-1 GLP-1 secretion, an effect that is described for both immediate-release [ 42 ] and delayed-release [ 43 ] metformin. 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.

It may even help with weight loss and lowering cholesterol. Metformin can cause nausea, upset stomach, and diarrhea, particularly when you first start taking it.

It should always be taken with food to reduce the risk of gastrointestinal issues. Over time, metformin may blocdk vitamin B12 absorption in the body. Ask your healthcare provider whether B12 vitamin supplements are right for you. People with severe kidney impairment or heart failure should not take metformin since in rare cases it can cause lactic acidosis. The risk is very low—around one in 30, people taking metformin—but the condition can be fatal. While metformin is generally well tolerated and has a good safety profile, if you combine this medication with others such as insulin or sulfonylureas, you'll need to work with your healthcare provider to be especially careful about side effects such as low blood sugar.

Report any changes or unusual symptoms to your health care provider right away when you're combining metformin with other medications. We know healthy eating is key to help manage diabetes, but that doesn't make it easy.

Our free nutrition guide is here to help. Sign up and receive your free copy! American Diabetes Association. Diabetes Care.

Doyle-Delgado K et al. Pharmacologic approaches to glycemic treatment of type 2 diabetes: Synopsis of the American Diabetes Association's standards of medical care in diabetes clinical guideline. Ann Intern Med Sep 1; [e-pub]. MedlinePlus, U. National Library of Medicine. US FDA. FDA drug safety communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function.

Your Privacy Rights. To change or withdraw your consent choices for VerywellHealth. At any time, you can update your settings through the "EU Privacy" link at the bottom of any page. These choices will be signaled globally to our partners and will not affect browsing data. Biguanides should not be used in women who have Type 1 diabetes or metabolic acidosis.

Premenopausal women who have insulin resistance and are not ovulating may resume ovulation on biguanide therapy.

Appropriate contraception should be considered in these cases. Biguanides are not recommended for routine use during pregnancy. Metformin is known to pass through the placenta and expose the fetus to therapeutic concentrations of the drug. In gestational diabetic mothers, metformin is a second-line treatment. Insulin is always the preferred agent, but in mothers who can not or refuse to administer insulin, metformin is the second choice agent to control blood sugars during pregnancy.

Biguanides do cross into the breastmilk. However, clinical trials have shown no effects on growth, motor, and social development in early life. Hypoglycemia , or low blood sugar , is a possibility, and the risks should be carefully considered before administering metformin to a breastfeeding mother. Biguanides are approved in certain pediatric populations for limited purposes. For the treatment of Type 2 diabetes , children 10 years of age and older can use immediate-release metformin or the metformin oral solution.

Children should not use the extended-release formulations of metformin. In off-label use, metformin is sometimes used to delay puberty and early menses in girls as young as 6 years of age. Seniors can take biguanides. Kidney and liver function should be monitored to determine the safety and any necessary dose adjustments. You should not take biguanides if you have ever had a hypersensitivity reaction to biguanides or metformin.

Biguanides are contraindicated in patients with metabolic acidosis. Metabolic acidosis is a risk factor for lactic acidosis. This can lead to metformin accumulation in the bloodstream, a toxicity that can be fatal. Kidney function should be screened prior to initiating therapy by obtaining the estimated glomerular filtration rate eGFR. This should be repeated annually, and therapy in a patient with an eGFR of less than 45 should be monitored closely. If the eGFR is less than 30, biguanides should not be used.

Gastrointestinal side effects such as nausea, vomiting, and diarrhea are common during the initial stages of treatment with biguanides. Benefits 1. Reduce risk of heart disease In addition to lower blood glucose, Binguinides lower the risk of heart disease because it helps lower bad cholesterol levels in the blood. Unlikely to cause low blood glucose When used by itself, biguanides are unlikely to cause low blood sugars.

Possible weight loss Biguanides may help with weight loss. Possible Side Effects 1. Vitamin deficiency Long-term use may be associated with vitamin B12 deficiency in the body.