The mechanisms of action of metformin.

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metformin 47 Title: DiabetologiaThe mechanisms of action of metformin Graham RenaD. Grahame HardieEwan R. PearsonPublication date (epub): 8/2017Publication date (pmc-release):
metformin 441 The mechanisms underlying these benefits are complex and still not fully understood. Physiologically, metformin has been shown to reduce hepatic glucose production, yet not all of its effects can be explained by
metformin 693 evidence of a key role for the gut. At the molecular level the findings vary depending on the doses of metformin used and duration of treatment, with clear differences between acute and chronic administration. Metformin
metformin 1148 mechanism involving the lysosome. In the last 10 years, we have moved from a simple picture, that metformin improves glycaemia by acting on the liver via AMPK activation, to a much more complex picture reflecting
metformin 2064 was found to be too toxic [[1], [2]]. At about the same time, two synthetic derivatives of galegine, metformin and phenformin, were first synthesised and tested, although they were not introduced to clinical use
metformin 2266 clinical use until the 1950s [[3]]. Chemically, galegine is an isoprenyl derivative of guanidine, while metformin and phenformin are biguanides containing two coupled molecules of guanidine with additional substitutions
metformin 2418 two coupled molecules of guanidine with additional substitutions (Fig. 1). Unlike most modern drugs, metformin is therefore derived from a natural product used in herbal medicine and was not designed to target a
metformin 2847 action remain much debated. In this brief review, we summarise the current evidence highlighting how metformin ’s benefits are likely to be caused by a variety of molecular mechanisms.Fig. 1Chemical structures
metformin 2970 are likely to be caused by a variety of molecular mechanisms.Fig. 1Chemical structures of galegine, metformin and phenformin. Metformin and phenformin are synthetic derivatives of galegine. Chemically, (a) galegine
metformin 3172 (a) galegine (also known as isoprenylguanidine), is an isoprenyl derivative of guanidine, while (b) metformin (dimethylbiguanide) and (c) phenformin (phenethylbiguanide) are biguanides containing two coupled molecules
metformin 3375 coupled molecules of guanidine with additional substitutionsFollowing oral dosing of immediate-release metformin in humans, approximately 70% of the dose is absorbed from the small intestine with the remainder passing
metformin 3641 [[4]]. Metformin is excreted in urine unchanged, with no metabolites reported. Plasma concentrations of metformin in humans are typically in the low micromolar range (e.g. 8–24 μmol/l) but are 30–300 times higher
metformin 3796 range (e.g. 8–24 μmol/l) but are 30–300 times higher in jejunal samples [[5]]. A recent [11C] metformin positron emission tomography (PET) study demonstrated that oral metformin becomes highly concentrated
metformin 3870 samples [[5]]. A recent [11C]metformin positron emission tomography (PET) study demonstrated that oral metformin becomes highly concentrated in the intestines, liver, kidneys and bladder (reflecting its route of elimination),
metformin 4132 [[6]]. In this study, the hepatic tissue:systemic blood activity was ~5 following oral dosing of the metformin tracer, demonstrating that much greater metformin concentrations are achieved in the liver than in the
metformin 4182 blood activity was ~5 following oral dosing of the metformin tracer, demonstrating that much greater metformin concentrations are achieved in the liver than in the plasma; extrapolating from systemic concentrations
metformin 4396 would estimate hepatic concentrations post-oral dose at ~50–100 μmol/l. In rats dosed with i.v. metformin , metformin accumulation was observed in the pancreas and adipose tissue at a concentration of approximately
metformin 4407 estimate hepatic concentrations post-oral dose at ~50–100 μmol/l. In rats dosed with i.v. metformin, metformin accumulation was observed in the pancreas and adipose tissue at a concentration of approximately half
metformin 4692 The human pharmacokinetic data point to the liver, kidney and intestines as the key target organs of metformin and in this review we will primarily focus on the liver and intestines, particularly when referring
metformin 4830 primarily focus on the liver and intestines, particularly when referring to the beneficial impact of metformin on metabolism and inflammation. Other mechanisms relating to potential cardiovascular benefits, cancer
metformin 5275 support this. First, in mice lacking the organic cation transporter 1 (OCT1), which take up little or no metformin into the liver [[11]], metformin was ineffective at improving blood glucose after high-fat feeding [[12]].
metformin 5308 the organic cation transporter 1 (OCT1), which take up little or no metformin into the liver [[11]], metformin was ineffective at improving blood glucose after high-fat feeding [[12]]. Second, tracer studies in
metformin 5435 at improving blood glucose after high-fat feeding [[12]]. Second, tracer studies in humans show that metformin lowers hepatic glucose production, with minimal impact on peripheral insulin-mediated glucose uptake.
metformin 5622 insulin-mediated glucose uptake. However, when only placebo-controlled studies were analysed, the impact of metformin on endogenous glucose production (EGP) was not significant unless concomitant drug-induced reductions
metformin 5914 summarised here, multiple studies in mouse hepatocytes and transgenic mice provide evidence for a role of metformin in reducing hepatic gluconeogenesis and/or insulin sensitivity.Metformin and the mitochondrial control
metformin 6417 within mitochondria to concentrations up to 1000-fold higher than in the extracellular medium, because metformin carries a positive charge and the membrane potentials across the plasma membrane and mitochondrial inner
metformin 6566 membrane potentials across the plasma membrane and mitochondrial inner membrane (positive outside) drive metformin into the cell and subsequently into the mitochondria (Fig. 2) [[14], [15]]. The most intensively studied
metformin 6705 subsequently into the mitochondria (Fig. 2) [[14], [15]]. The most intensively studied mitochondrial action of metformin is the inhibition of Complex I of the respiratory chain [[14], [16]], which suppresses ATP production.
metformin 6983 extracellular concentrations (mmol/l) required to observe rapid effects, although lower concentrations of metformin (50–100 μmol/l) do inhibit Complex I in rat hepatoma (H4IIE) cells after several hours; this delay
metformin 7131 I in rat hepatoma (H4IIE) cells after several hours; this delay was ascribed to the slow uptake of metformin by mitochondria [[14]], which has recently been observed experimentally [[15]]. In addition, some studies
metformin 7306 experimentally [[15]]. In addition, some studies do not detect any changes in cellular ADP:ATP ratios after metformin treatment, although they can be observed with phenformin [[17]]. In cells carrying out gluconeogenesis,
metformin 7668 besides ATP production, such as changes in the NAD+:NADH ratio, may also contribute to the effects of metformin on gluconeogenesis [[16]].Fig. 2The multiple mechanism via which metformin affects liver metabolism.
metformin 7743 contribute to the effects of metformin on gluconeogenesis [[16]].Fig. 2The multiple mechanism via which metformin affects liver metabolism. Note that the possible effect of metformin on mitochondrial glycerophosphate
metformin 7812 2The multiple mechanism via which metformin affects liver metabolism. Note that the possible effect of metformin on mitochondrial glycerophosphate dehydrogenase [[7]] has not been included. (1) Uptake of metformin
metformin 7913 metformin on mitochondrial glycerophosphate dehydrogenase [[7]] has not been included. (1) Uptake of metformin into hepatocytes is catalysed by the organic cation transporter-1 (OCT1) [[11]]. Being positively charged,
metformin 10569 oxaloacetate; PEP, phosphoenolpyruvate; 3PG, 3-phosphoglycerateRecently, an alternative mitochondrial target of metformin has been proposed [[7]]. EGP (primarily by the liver) was inhibited after just 1 h of i.v. administration
metformin 10689 proposed [[7]]. EGP (primarily by the liver) was inhibited after just 1 h of i.v. administration of metformin to rats and this was associated with an increase in the lactate:pyruvate ratio, suggesting a problem
metformin 11003 reducing equivalents from the cytoplasm into the mitochondrion for re-oxidation. In cell-free assays, metformin was found to inhibit mitochondrial glycerophosphate dehydrogenase (mGPD), a key component of this shuttle.
metformin 11290 oligonucleotides against mGPD, or a global mouse knockout, were found to lower EGP and abolish the effects of metformin on plasma glucose and EGP. However, as discussed by others, inhibition of the glycerophosphate shuttle
metformin 11721 becomes suppressed [[19]]. Thus, the relative contributions of inhibition of mGPD and Complex I in metformin ’s glucose-lowering effects need to be established, as does the possible role of its less well understood
metformin 11981 on interactions and oxidation of amino acid-bound copper ions [[21]–[23]].Molecular mechanisms for metformin -associated AMPK activationInhibition of mitochondrial function can also explain metformin’s ability
metformin 12071 mechanisms for metformin-associated AMPK activationInhibition of mitochondrial function can also explain metformin ’s ability to activate the cellular energy sensor AMP-activated protein kinase (AMPK). Once activated
metformin 12581 from synthesis of cellular nutrient stores to their breakdown, the idea that AMPK might be involved in metformin action was attractive and, in 2001, metformin was reported to activate AMPK in rat hepatocytes and rat
metformin 12627 their breakdown, the idea that AMPK might be involved in metformin action was attractive and, in 2001, metformin was reported to activate AMPK in rat hepatocytes and rat liver in vivo [[26]]. Although high concentrations
metformin 12763 AMPK in rat hepatocytes and rat liver in vivo [[26]]. Although high concentrations (500 μmol/l) of metformin were required to observe AMPK activation after brief (1 h) treatment of cells, significant effects
metformin 12950 cells, significant effects were observed after incubation for much longer periods with just 20 μmol/l metformin , more compatible with concentrations of the drug found in the portal vein. Supporting the idea that
metformin 13157 that biguanides acted by increasing cellular AMP:ATP/ADP:ATP ratios, AMPK was not activated by either metformin or phenformin in cells expressing an AMPK mutant that is insensitive to changes in AMP or ADP [[17]].
metformin 13357 ADP [[17]]. However, AMPK can also be activated by glucose starvation, and by low concentrations of metformin , by a different mechanism involving the formation of a complex with the proteins Axin and late endosomal/lysosomal
metformin 13587 adaptor, MAPK and mTOR activator 1 (LAMTOR1; Fig. 2), the latter being a lysosomal protein [[27]]. Thus, metformin might also activate AMPK by a mechanism involving the lysosome, rather than the mitochondrion.AMPK-dependent
metformin 13734 mechanism involving the lysosome, rather than the mitochondrion.AMPK-dependent and -independent effects of metformin on hepatic gluconeogenesisThe first pharmacological activator of AMPK to be developed was 5-aminoimidazole-4-carboxamide
metformin 14315 2) [[29]] initially supported the idea that AMPK activation might be responsible for the ability of metformin to inhibit hepatic glucose production. However, an important caveat is that ZMP also modulates other
metformin 14610 gluconeogenesis that is allosterically inhibited by both AMP and ZMP [[30]]. Tellingly, acute treatment with metformin or AICAR inhibited glucose production equally well in hepatocytes from control mice or mice lacking
metformin 14769 well in hepatocytes from control mice or mice lacking both AMPK catalytic subunits in the liver, while metformin acutely improved glucose tolerance in both mouse strains [[31]]. Metformin did increase cellular AMP:ATP
metformin 15034 inhibition of the respiratory chain. It seems likely that the acute inhibition of glucose production by metformin or AICAR was due to inhibition of fructose-1,6-bisphosphatase by AMP or ZMP, respectively. However,
metformin 15220 respectively. However, expression of mRNAs encoding G6Pase and PEPCK was also reduced by AICAR and metformin in both control and AMPK-null hepatocytes. A potential explanation for this came with a report that
metformin 15704 gluconeogenic enzymes [[32]]. More recently, another group has proposed an AMPK-dependent mechanism by which metformin reduces cAMP [[33]]: treatment of mouse hepatocytes with a more specific AMPK activator reduced glucagon-induced
metformin 16095 breakdown (Fig. 2).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
metformin 16299 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. AMPK
metformin 17368 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
metformin 17468 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.
metformin 17693 phosphorylation is abolished by AMPK knockout [[31]], the long-term insulin-sensitising effects of metformin appear to be mediated entirely by AMPK.Metformin and the intestinesIt has been known for some time that
metformin 17848 AMPK.Metformin and the intestinesIt 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
metformin 17876 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
metformin 18121 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
metformin 18212 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 18324 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
metformin 18438 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
metformin 18606 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 HbA1c in individuals with type 2 diabetes
metformin 18659 encoding OCT1), which reduce hepatic uptake of metformin [[36]], do not impact upon the efficacy of metformin to lower HbA1c in individuals with type 2 diabetes [[37], [38]]. Third, a delayed-release metformin
metformin 18759 metformin to lower HbA1c 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
metformin 19021 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 19140 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
metformin 19241 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.
metformin 19447 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 19557 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,
metformin 19796 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
metformin 20061 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
metformin 20120 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
metformin 20200 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
metformin 20466 (gut–brain–liver crosstalk, Fig. 3) [[44]]. A final potential gut-mediated mechanism of action of metformin involves alteration of the intestinal microbiome (Fig. 3), which is outlined below in relation to inflammation;
metformin 20675 inflammation; how this contributes to the glucose-lowering and gastrointestinal (GI) side effects of metformin is unknown.Fig. 3Actions of metformin on metabolism and inflammation. Responses to metformin in the
metformin 20713 the glucose-lowering and gastrointestinal (GI) side effects of metformin is unknown.Fig. 3Actions of metformin on metabolism and inflammation. Responses to metformin in the blood, liver and intestines are shown
metformin 20768 effects of metformin is unknown.Fig. 3Actions of metformin on metabolism and inflammation. Responses to metformin in the blood, liver and intestines are shown schematically. In the blood, in observational studies,
metformin 21091 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
metformin 21389 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
metformin 21462 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
metformin 21579 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
metformin 21936 associated with GI side effects (20–30% of patients) [[45]] with severe side effects resulting in metformin discontinuation in ~5% of patients. The mechanism by which metformin causes GI side effects remains
metformin 22005 severe side effects resulting in metformin discontinuation in ~5% of patients. The mechanism by which metformin causes GI side effects remains uncertain. However, there are a number of putative mechanisms; the side
metformin 22173 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
metformin 22266 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
metformin 22324 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
metformin 22701 increased luminal serotonin. Genetic studies have identified a key role for OCT1 and SERT in mediating metformin intolerance [[47], [48]]. A third potential mechanism of intolerance may be due to the impact of metformin
metformin 22808 metformin intolerance [[47], [48]]. 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 22921 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.
metformin 23092 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)
metformin 23265 drugs (such as proton pump inhibitors) are avoided in individuals experiencing GI side effects with metformin use [[47]].Inflammation, ageing and the impact of the microbiomeIn the nematode worm, Caenorhabditis
metformin 23385 [[47]].Inflammation, ageing and the impact of the microbiomeIn the nematode worm, Caenorhabditis elegans, metformin lengthens lifespan through effects on intestinal microbial growth [[49]]. Consistent with this interesting
metformin 23513 through effects on intestinal microbial growth [[49]]. Consistent with this interesting concept of metformin ’s ability to affect host metabolism indirectly, metformin expanded the gut population of Akkermansia
metformin 23573 Consistent with this interesting concept of metformin’s ability to affect host metabolism indirectly, metformin expanded the gut population of Akkermansia spp. in animal studies, which was linked to reduced adipose
metformin 23798 inflammation and suppressed postprandial hyperglycaemia [[50]]. More recent studies in humans found that metformin -dependent increases in Escherichia spp. and decreases in Intestinibacter spp. were the most consistently
metformin 24102 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
metformin 24525 [53]], as well as suppressing proinflammatory cytokines from these macrophages. Consistent with this, metformin suppresses the neutrophil to lymphocyte ratio (NLR) in type 2 diabetes (Fig. 3). NLR is a marker of
metformin 24751 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,
metformin 24909 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
metformin 25120 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 25502 with AMPK-dependent and -independent mechanisms identified [[57]].Insights from genetic studies of metformin action in humansRecently, genome-wide association studies have been undertaken to assess genetic contributions
metformin 25649 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
metformin 25796 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
metformin 25962 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
metformin 26098 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
metformin 26613 and other tissues [[60]]. 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
metformin 26866 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
metformin 27064 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
metformin 27594 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
metformin 27703 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
metformin 27827 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
metformin 28013 enable a more robust appreciation of the key mechanisms that are active in long-term treatment with metformin in humans.Electronic supplementary materialESM Downloadable slideset(PPTX 499 kb
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lactic acidosis 1747 phenformin (the latter withdrawn from diabetes treatment in most countries because of side effects of lactic acidosis ) are derived from galegine, a natural product from the plant Galega officinalis, used in herbal medicine

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