Metformin mechanism of action -
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GFRAL is the receptor for GDF15 and the ligand promotes weight loss in mice and nonhuman primates. Gerstein HC, Pare G, Hess S, et al. Growth differentiation factor 15 as a novel biomarker for metformin. Download references. The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.
Department of Physiology and Pathophysiology, Jerry M. Wallace School of Osteopathic Medicine, Campbell University SOM, Buies Creek, NC, USA.
Department of Biology, College of Arts and Sciences, University of North Carolina, Greensboro, NC, USA. Department of Pharmacology, Jerry M. Wallace School of Osteopathic Medicine, Campbell University, Buies Creek, NC, USA. Geisinger Commonwealth School of Medicine, Scranton, PA, USA.
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Overview Metformin 1,1-dimethylbiguanide structure in Fig. Chemical structure of metformin 1,2-dimethylbiguanide. Full size image.
Novel molecular targets involved in glycemic control Inhibition of hepatic gluconeogenesis is a major action of metformin in lowering blood glucose. AMPK activation How metformin activates AMPK remains unclear. MicroRNA modulation, another AMPK-independent mechanism The evolutionarily conserved transcription factor hepatocyte nuclear factor 4 alpha HNF4α plays an important role in promoting hepatic glucose production and regulating energy balance [ 13 ].
Novel molecular targets involved in cardiovascular protection Extensive studies in animal models suggested an important role for metformin in protecting against diverse cardiovascular disorders, including atherosclerosis, hypertension, myocardial ischemic injury, and heart failure reviewed in [ 2 ] , as well as cardiovascular toxicity induced by drugs and environmental pollutants [ 19 , 20 ].
Novel molecular targets involved in anticancer activities Direct and indirect mechanisms Numerous studies in animal models and multiple cohort studies in humans show an anticancer activity for metformin reviewed in [ 2 , 3 ].
Anti-inflammation The anti-inflammatory activities of metformin have been observed in various animal models and human subjects [ 58 , 59 , 60 ]. Antiaging activity Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to developing chronic diseases, such as cardiovascular disorders, neurodegenerative diseases, and some types of cancers, among others.
Weight control and energy balance It is well established that metformin treatment is associated with weight loss in diabetic and non-diabetic people [ 70 , 71 , 72 ]. Conclusion and perspectives In conclusion, multiple novel molecular targets of metformin action have been discovered over the past few years Fig.
Boosting GLP-1 by Natural Products Chapter © Data availability Not applicable since this is a review article. Abbreviations AMPK: Adenosine monophosphate-activated kinase ERAD: Endoplasmic reticulum-associated protein degradation GDF Growth differentiation factor 15 GPD2: Mitochondrial glycerolphosphate dehydrogenase HNF4α: Hepatocyte nuclear factor 4 alpha IL: Interleukin METC: Mitochondrial electron transport chain mtDNA: Mitochondrial DNA mTOR: Mammalian target of rapamycin ORAC: Calcium release-activated channel ox-mtDNA: Oxidized mitochondrial DNA PM: Particulate matter ROS: Reactive oxygen species.
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Article CAS PubMed Google Scholar Seneviratne A, Cave L, Hyde G, et al. In the longitudinal study UKPDS [ 3 ], it was found that taking metformin significantly reduces mortality from all causes.
Studies in non-diabetic rats has confirmed that metformin improves heart function and reduces the size of lesions after induction of myocardial infarction [ 24 ]. This beneficial effect is the result of a myocardial preconditioning induced by metformin with varying degrees of permanence. One fundamental effect of metformin is to induce metabolic adaptation of the myocardium in critical energy situations such as ischaemia.
In a rodent model of heart failure, metformin promotes metabolic adaptation in the heart by stimulating gradual consumption of glucose instead of fatty acids. This action appears to be dependent upon activation of AMPK, which contributes to stimulating glucose uptake and glycolysis activity to cope with oxygen deprivation [ 25 ].
Metformin has been found to have beneficial effects in diabetic patients with a history of heart failure, reducing both mortality and morbidity [ 26 ]. One of the mechanisms thought to be behind diabetic cardiomyopathy and heart failure is defective autophagy in the heart. Metformin restores autophagy in diabetic mice and prevents the formation of cardiac lesions.
AMPK must be activated, since metformin is ineffective in diabetic mice with defective AMPK activity in their hearts [ 27 ]. The cardioprotective effects of metformin stem from more than one mechanism and both macro- and microvascular systems are involved.
Metformin is known to exercise a protective effect on the vascular endothelium, both by decreasing the production of free radicals and by reducing the formation of glycated proteins, which cause oxidative stress and inflammation.
The first studies suggesting a possible role for metformin in oncology were published in [ 28 ]. Since then, many other observational epidemiological studies have confirmed that type 2 diabetic patients who have been taking metformin for several years are at lower risk of developing or dying from cancer [ 29 ].
A relationship has also been found between the dose of metformin or duration of treatment and the protection observed, giving further evidence of anticancer properties [ 28 ].
A wide variety of mechanisms has been described to explain its beneficial effects Figure 3 , as they are dependent upon the metabolic and molecular characteristics of each type of tumour. Figure 3. Several different modes of action have been suggested, due to the diversity of in vivo and in vitro cancer models studied.
At cell level, metformin inhibits the mTORC1 mammalian target of rapamycin complex 1 pathway via mechanisms dependent on AMPK activation by phosphorylation of TSC2 tuberous sclerosis complex 2 and raptor regulatory associated protein of mTOR. However, metformin is able to inhibit the mTORC1 pathway via AMPK-independent mechanisms, by inhibiting Rag GTPases and inducing REDD1 expression.
It is possible that the drug acts at the level of cell cycle regulation by inhibiting cyclin D1 expression. Metformin causes a reduction in neoplastic cell angiogenesis by lowering blood concentrations of PAI-1 plasminogen activator inhibitor-1 and VEGF vascular endothelial growth factor.
Inhibition of metastasis formation through decreased activity of the metalloproteinases MMP2 and -9 has also been described.
Several epidemiological studies have reported a strong link between type 2 diabetes and elevated risk of certain types of cancer, in particular colon, endometrium, rectum and breast cancer, compared with the incidence of these cancers in the non-diabetic population.
It is thought that compensatory hyperinsulinaemia and chronic hyperglycaemia, both characteristics of type 2 diabetes, are behind this link between diabetes and cancer.
Insulin is known to promote cell proliferation and increase blood levels of IGF1 insulin-like growth factor 1 , which acts as a growth factor in tumour development. It is also well established that glucose is the preferred energy substrate used by cells during proliferation and hyperglycaemia could therefore contribute to increasing the growth and survival of cancer cells.
The inhibition of tumour progression by metformin has been confirmed through studies of large numbers of mouse carcinogenesis models, as well as the observational epidemiological studies. In some models, the inhibition of tumour proliferation was directly linked to reduction in blood insulin and IGF1 levels by metformin Figure 3 and reduced activity of receptors with tyrosine kinase activity [ 30 ].
However, this effect was not observed in other models, suggesting a mode of action working independently of decreased blood insulin levels. Several clinical trials have suggested that metformin is able to procure a protective effect against cancer regardless of whether the patient has diabetes [ 31 ].
This finding has been supported by a large body of in vitro evidence demonstrating that the drug directly inhibits the proliferation of cancer cells [ 32 , 33 ].
It is important to point out that tumour cells have varying degrees of sensitivity to metformin and its antiproliferative effect is only observed at concentrations much higher mM than those used to treat diabetes plasma concentrations in the region of 10—40 μM.
Nonetheless, metformin does accumulate in some organs, such as the intestine and liver, allowing much higher intracellular concentrations than those in the plasma. Moreover, in a carcinogenesis model induced via the loss of the tumour suppressor PTEN phosphatase and tensin homolog , activation of AMPK by a direct activator A produces a reduction in tumour progression identical to that obtained with metformin [ 34 ].
AMPK directly phosphorylates the tumour suppressor TSC2 tuberous sclerosis complex 2 and the regulator protein raptor regulatory associated protein of mTOR , leading to rapid suppression of mTORC1 signalling pathway Figure 3. This inhibition of the mTORC1 pathway by metformin leads to decreased expression of EGF epidermal growth factor receptor and the oncoprotein HER2 erbB-2 in breast cancer lines.
A study of gene expression profiles in breast cancer tumours treated with metformin revealed a reduction in the expression of genes involved in mitosis progression.
The metabolism of cancer cells is essentially based on consuming glucose to produce energy, even when oxygen is present. This feature means that cancer cells preferentially use glycolysis in aerobic conditions Warburg effect [ 52 ] or aerobic glycolysis , as opposed to mitochondrial oxidative phosphorylation.
However, cancer cells use their mitochondria to produce some metabolites malate, citrate needed for the various biosynthetic pathways required for cell proliferation. By blocking the respiratory chain, metformin will therefore inhibit this adaptive metabolism and cause a major energy crisis.
For example, tumour cells with a loss of p53 function cannot cope with the metabolic changes imposed by metformin which require activation of p53 by AMPK and die from apoptosis [ 36 ].
Similarly, cancer cells that are deficient in LKB1 showing low AMPK activity are more sensitive to the ATP depletion imposed by metformin because of their inability to restore their energy balance via AMPK activation.
In these situations, metformin acts on cancer cells as a selective cytotoxic agent. Changes in the tumour microenvironment may also contribute to the beneficial effects of metformin. The possibility has also been raised that it may inhibit tumour angiogenesis via a reduction in blood levels of PAI-1 plasminogen activator inhibitor-1 and VEGF vascular endothelial growth factor Figure 3.
However, the opposite was found in a different study, reporting an increase in intratumoural microvascular density in tumour xenograft cells [ 31 ].
Metformin participates in the response to damaged DNA by selectively activating ATM ataxia telangiectasia mutated , but also by inhibiting reactive oxygen species production brought about through transformation by the oncogene Ras [ 38 ].
Metformin also contributes to preventing tumour development by controlling cancer stem cell ontogenesis, as it targets the epithelial-mesenchymal transition and differentiation in these cells [ 39 , 40 ]. This specific action of metformin on cancer stem cells has opened up new possibilities in cancer prevention, due to the resistance of these cells to chemotherapy.
It is significant that metformin treatment has been linked to a better response rate to chemotherapy for breast cancer [ 41 ]. This synergistic effect of metformin on the cytotoxicity of chemotherapy agents has been confirmed in vitro and has been found to be effective in reducing resistance to these drugs, which supports the potential use of metformin as a chemotherapy adjuvant [ 42 ].
Lastly, recent studies have suggested a role for metformin in inhibiting the invasive potential of cancer cells and the formation of metastasis by decreasing the activity of the metalloproteinases MMP2 and MMP9 [ 40 , 43 ] Figure 3. However, it is now important to identify which patients might benefit from its potential for preventing and treating cancer, by investigating biomarkers that will predict its therapeutic effect.
The sensitivity of cancer cells to metformin depends on the type of cancer, the presence of mutations for example for LKB1, p53 or OCT1 polymorphisms and the tumour environment. On the basis of the pharmacokinetic properties of phenformin membrane permeability, potent complex I inhibition , several authors have suggested that this drug previously taken off the market could be used as a much more effective antineoplastic agent than metformin [ 34 ].
Future studies will need to determine the optimal tolerable doses of both metformin and phenformin for the treatment of different cancers. Over one hundred phase II and III clinical trials are currently under way to assess the use of metformin in oncology 2.
Recent studies have opened up the prospect of possible therapeutic indications for metformin in the treatment of neurodegenerative diseases. Metformin induces dephosphorylation of tau by activating the protein phosphatase 2A PP2A , and thus slows the progression of the disease.
Another recent study also showed that metformin promotes neurogenesis and enhances hippocampus-dependent spatial memory formation and learning [ 48 ]. Metformin promotes phosphorylation of CBP CREB binding protein , a transcription coactivator with intrinsic histone acetyltransferase activity, via the protein kinase C PKC -ζ.
This stage is crucial for the differentiation of radial glial neuronal precursors and the formation of new neurons in the hippocampus. The protection afforded by metformin against diabetes, cardiovascular disease and cancer is similar to the anti-ageing effects of calorie restriction Figure 4.
There have been reports of metformin having properties that mimic calorie restriction and prolong the lifespan of the nematode Caenorhabditis elegans and rodents.
Figure 4. Summary of the principal effects of metformin. The principal antidiabetic effects of metformin occur in the liver, via inhibition of gluconeogenesis, and to a lesser extent in the intestine and muscle, leading to a reduction in hyperglycaemia and blood lipids and to increased insulin sensitivity.
These same improvements indirectly procure both cardiovascular protective and anticancer effects. Added to this, metformin directly reduces the risk of cardiovascular disease through actions that affect both macro- and microvascular systems and exerts a direct antitumoural effect on cancer cells.
Furthermore, metformin is thought to have a neuroprotective effect in neurodegenerative diseases. The beneficial effects of metformin are similar to those observed with calorie restriction, which help to prolong lifespan. Metformin can therefore be considered a calorie restriction mimetic with possible anti-ageing properties.
In non-diabetic mice, metformin mimics the effects of calorie restriction on the gene expression profile and prevents the onset of diabetes, cardiovascular disease and cancer [ 49 ]. It has recently been suggested that metformin indirectly increases the lifespan of nematodes by disrupting the metabolism of its accompanying microbe Escherichia coli [ 51 ].
At present, metformin is the most frequently used antidiabetic agent in the treatment of type 2 diabetes. Its success is due to various factors: efficacy, safety, good tolerability and low production cost. The drug also has the advantage of counteracting the cardiovascular complications associated with diabetes, by inducing myocardial preconditioning.
Another significant benefit of metformin is its demonstrated capacity to reduce the risk of tumour development by controlling cell differentiation and proliferation. New therapeutic indications may also be found for the drug in the treatment of neurodegenerative diseases.
This old drug may well have more surprises in store. The authors declare that they have no interests associated with the information published in this article.
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Data correspond to usage on the plateform after The current usage metrics is available hours after online publication and is updated daily on week days. Free Access. Issue Med Sci Paris. Effect on longevity: metformin as an elixir of life? Conclusion Declaration of interests References List of figures.
Bailey C, Campbell I. Metformin: the gold standard; a scientific handbook Chichester, UK: Wiley, p. Du nouveau dans les antidiabétiques. La NN diméthylamino guanyl guanidine N. Maroc Med ; — Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes UKPDS Lancet ; — Metformin and lactic acidosis: cause or coincidence?
A review of case reports. J Intern Med ; — Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes.
Obes Res ; 6: 47— Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med ; 6: — Metformin might influence tumourigenesis, both indirectly, through the systemic reduction of insulin levels, and directly, via the induction of energetic stress; however, these effects require further investigation.
Here, we discuss the updated understanding of the antigluconeogenic action of metformin in the liver and the implications of the discoveries of metformin targets for the treatment of diabetes mellitus and cancer.
Abstract Metformin has been the mainstay of therapy for diabetes mellitus for many years; however, the mechanistic aspects of metformin action remained ill-defined. Publication types Research Support, Non-U.
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Metformin exerts its prevailing, glucose-lowering effect by inhibiting hepatic gluconeogenesis and opposing the action of glucagon. The inhibition of mitochondrial complex I results in defective cAMP and protein kinase A signalling in response to glucagon.
Stimulation of 5'-AMP-activated protein kinase, although dispensable for the glucose-lowering effect of metformin, confers insulin sensitivity, mainly by modulating lipid metabolism. Metformin might influence tumourigenesis, both indirectly, through the systemic reduction of insulin levels, and directly, via the induction of energetic stress; however, these effects require further investigation.
Here, we discuss the updated understanding of the antigluconeogenic action of metformin in the liver and the implications of the discoveries of metformin targets for the treatment of diabetes mellitus and cancer. Abstract Metformin has been the mainstay of therapy for diabetes mellitus for many years; however, the mechanistic aspects of metformin action remained ill-defined.
Publication types Research Support, Non-U. Gov't Review. Substances Glucagon Metformin AMP-Activated Protein Kinases.
: Metformin mechanism of action| Publication types | elegans and D. Twenty-five years of mTOR: uncovering the link from nutrients to growth. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Article CAS PubMed PubMed Central Google Scholar Vasamsetti SB, Karnewar S, Kanugula AK, Thatipalli AR, Kumar JM, Kotamraju S. Regular insulin. The demonstration is clear and straightforward, and the results may have a great impact not only on our understanding of metformin mechanism in humans but also on future metformin therapy in clinic, for example, using gut-released metformin Met DR instead of the current formulation Met XR. |
| Frontiers | Molecular Mechanisms of Metformin for Diabetes and Cancer Treatment | Stimulation of 5'-AMP-activated protein kinase, although dispensable for the glucose-lowering effect of metformin, confers insulin sensitivity, mainly by modulating lipid metabolism. Metformin might influence tumourigenesis, both indirectly, through the systemic reduction of insulin levels, and directly, via the induction of energetic stress; however, these effects require further investigation. Here, we discuss the updated understanding of the antigluconeogenic action of metformin in the liver and the implications of the discoveries of metformin targets for the treatment of diabetes mellitus and cancer. Abstract Metformin has been the mainstay of therapy for diabetes mellitus for many years; however, the mechanistic aspects of metformin action remained ill-defined. Sterne J. Blood sugar-lowering effect of 1,1-dimethylbiguanide. Knaani Z , Klajman A. 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| Mechanisms of Action of Metformin | IntechOpen | Metformin mechanism of action between malate-aspartate Metformin mechanism of action and citric acid cycle in jechanism heart mitochondria. Inside the cell metformin inhibits Metformjn respiratory-chain complex 1, resulting Metformib reduced ATP mchanism and increased AMP. However, despite initially lower birth weight, children exposed to metformin during pregnancy had accelerated growth after birth, and were heavier by mid-childhood than those exposed to insulin during pregnancy. Effect on longevity: metformin as an elixir of life? Archived from the original on 8 June Brain Plasticity. |
| Molecular mechanisms of action of metformin: latest advances and therapeutic implications | Impact of intermediate hyperglycemia and diabetes on immune dysfunction in tuberculosis. Metformin-associated lactate production may also take place in the large intestine, which could potentially contribute to lactic acidosis in those with risk factors. Drug Saf. In this mini-review, we discuss the latest cutting-edge research discoveries on novel molecular targets of metformin in glycemic control, cardiovascular protection, cancer intervention, anti-inflammation, antiaging, and weight control. a , Following putative transporter-mediated internalization in various immune cell subsets, metformin inhibits the mitochondrial respiratory chain complex I and can modulate cell-specific inflammatory processes by both AMP-activated protein kinase AMPK -independent and AMPK-dependent mechanisms. Gin H , Messerchmitt C , Brottier E , Aubertin J. |
| Mechanisms of Action of Metformin | Two studies showed that portal infusions of insulin in dogs reduced HGP; however, suppression of HGP tracked very closely with peripheral insulin levels rather than portal insulin , Further evidence for indirect regulation of gluconeogenesis came from studies reporting increased glycerol turnover and gluconeogenesis from glycerol in type 2 diabetic patients compared with healthy controls , Additionally, infusion of acetate and glycerol to maintain intrahepatic acetyl-CoA concentration and glycerol turnover respectively in awake rodents is sufficient to prevent insulin suppression of hepatic gluconeogenesis, indicating that regulation of WAT lipolysis by insulin indirectly regulates hepatic gluconeogenesis and maintains euglycemia One proposed mechanism of action for metformin is inhibition of GPD2, leading to reduced hepatic gluconeogenesis in a substrate-specific, redox-dependent manner. This is supported by the observation that acute metformin treatment increases plasma glycerol and hepatic glycerolphosphate G3P concentrations in rodents, indicating reduced gluconeogenesis from glycerol 48 , At clinically relevant concentrations, metformin is shown to inhibit GPD2, leading to increased cytosolic redox state and decreasing gluconeogenesis from redox-dependent substrates. Redox balance is maintained by the continuous function of 2 redox shuttles: the malate-aspartate shuttle and the α-glycerophosphate shuttle. Perturbation of this balance of reducing equivalents can directly impact gluconeogenesis from redox-dependent substrates. This regulatory mechanism is especially pertinent in the context of obesity and T2D due to dysregulated WAT lipolysis and increased glycerol supply to the liver , , Therefore, inhibition of gluconeogenesis from glycerol may disproportionately benefit individuals with poorly controlled T2D with dysregulated WAT lipolysis. Importantly, this substrate-specific effect that is observed with metformin treatment is not predicted by any other proposed mechanisms of metformin action 48 , Furthermore, this substrate-specific effect of metformin to inhibit gluconeogenesis would also explain why hypoglycemia is rarely observed in patients taking metformin given that other substrates eg, alanine and other amino acids are still able to contribute to gluconeogenesis. This proposed mechanism of action will be discussed further below. This hypothesis emerged in the early s when 2 groups reported robust inhibition of complex I following metformin treatment in vitro 57 , These data are consistent with previous studies performed more than 50 years ago demonstrating that phenformin and other guanides inhibit complex I activity Complex I is the site of NADH contribution to the mitochondrial proton gradient and, given the energetic cost of gluconeogenesis, its inhibition was linked to decreased HGP. Several mechanisms by which complex I inhibition leads to suppression of gluconeogenesis are proposed, including altered hepatic energy charge and AMPK activation 98 , , However, the physiological relevance of these mechanisms has been contested due to the supra-pharmacological millimolar concentrations typically used in these studies 48 , 50 , Additionally, these studies are challenged by conflicting data showing that metformin does not alter hepatic energy charge and does not require AMPK activation to exert its therapeutic effects in vivo 59 , In this section, we review the studies related to complex I inhibition by metformin. Proposed mechanisms of metformin action. Complex I inhibition top panel. Inhibition of complex I is central to several proposed mechanisms of metformin action. Following complex I inhibition, AMPK is activated by increased AMP levels, leading to inhibition of CRTC2 and preventing formation of the CREB-CBP-CRTC2 complex orange boxes. AMPK also phosphorylates and inhibits ACC1 and 2, which promotes fat oxidation and decreases lipogenesis purple boxes. Additionally, increased AMP is proposed to inhibit hepatic gluconeogenesis independently of AMPK. High AMP prevents glucagon-stimulated production of cAMP and therefore antagonizes hepatic glucagon action pink boxes. AMP also allosterically inhibits FBP1, which directly inhibits the gluconeogenic pathway blue boxes. Increased cytosolic redox bottom panel. Metformin inhibition of GPD2 is the only proposed mechanism that is independent of Complex I inhibition and produces substrate-selective inhibition of gluconeogenesis. Abbreviations: ACC, acetyl-CoA carboxylase; AMPK, adenosine monophosphate—activated protein kinase; CBP, CREB-binding protein; CREB, cAMP-responsive element-binding protein 1; CRTC2, CREB-regulated transcription co-activator 2; DHAP, dihydroxyacetone phosphate; FBP, fructose 1,6-bisphosphatase; FDP, fructose 1,6-diphosphate; G3P, glycerolphosphate; GLP-1, glucagon-like peptide-1; GPD, glycerolphosphate dehydrogenase; LDH, lactate dehydrogenase; OCT1, organic cation transporter 1. Complex I inhibition at millimolar concentrations of metformin is well-established, and metformin is proposed to alter hepatic adenine nucleotide energy charge due to decreased electron transport chain activity 58 , Specifically, reduced electron transport chain activity decreases the cellular [ATP]:[ADP] and [ATP]:[AMP] ratios, which may potentially mediate the antidiabetic effects of metformin. One study reported that increased hepatic AMP concentrations following metformin treatment allosterically inhibits adenylyl cyclase, decreasing intracellular cAMP production and antagonizing hepatic glucagon action However, we and others have not observed an effect of metformin on cAMP levels at clinically relevant concentrations of metformin 50 , 59 , Moreover, a trial of metformin in individuals with prediabetes showed that metformin did not suppress glucagon-dependent HGP, demonstrating that this mechanism for metformin action does not appear to be relevant to humans It should be noted that Miller et al propose an additional mechanism, in which AMP directly inhibits gluconeogenesis through allosteric inhibition of fructose 1,6-biphosphatase In support of this mechanism, a recent study reported that expression of a mutant fructose 1,6-bisphosphatase enzyme that is not regulated by AMP abrogated the glucose-lowering effect of metformin in vivo Thus, further investigation is needed to determine the clinical significance of this mechanism. Whether clinically relevant concentrations of metformin alter hepatocellular adenine nucleotide levels is also unresolved. As discussed earlier, one of the main challenges in interpreting these studies as well as other studies that have implicated complex I as the major therapeutic target of metformin is the supra-pharmacological doses of metformin utilized in many studies , 63 , , Tables 1 , 2. Initial studies indicated that, in vitro, the K 0. Subsequent studies have observed complex I inhibition only in the presence of 2 mM to 10 mM and, similarly, altered hepatic energy charge is not observed at clinically relevant concentrations, which are in the micromolar range 58 , 59 , Furthermore, studies in lean and rat models of T2D report no change in hepatic [ATP]:[ADP] or [ATP]:[AMP] ratios following acute or chronic metformin treatment 48 , In addition to complex I inhibition, one of the most frequently invoked mechanisms of metformin action is AMPK activation due to complex I inhibition. This occurs during times of metabolic stress, such as prolonged starvation and intense exercise , The proposed beneficial metabolic effects of AMPK activation are two-fold: transcriptional downregulation of gluconeogenic genes reduces HGP, and phosphorylation of acetyl-CoA carboxylase 1 ACC1 and ACC2, which reduces lipogenesis and promotes hepatic mitochondrial oxidation, respectively , resulting in reductions in hepatic diacylglycerol content and improved hepatic insulin sensitivity , , Although there is disagreement in the literature regarding hepatic energy charge as a mechanism of metformin action, metformin is shown to activate AMPK-Thr phosphorylation independently of changes in adenine nucleotides 48 , , However, it is unlikely that metformin directly binds to and activates AMPK because metformin has no effect on the activity of purified AMPK In the search for a new mechanism of AMPK activation, LKB1 was identified in the early s as an upstream kinase responsible for phosphorylating and activating AMPK and was implicated as a major target of metformin action , Activation of this pathway induces disassembly of the CREB-CBP-CRTC2 complex which transcriptionally regulates gluconeogenic gene expression 91 , In support of this mechanism, liver-specific LKB1 knockout mice presented with hyperglycemia, inactivation of AMPK, and transcriptional upregulation of gluconeogenesis. However, conflicting data were reported by Foretz et al, demonstrating that LKB1 knockout hepatocytes were surprisingly responsive to metformin therapy, and liver-specific deletion of AMPK was insufficient to suppress metformin action The notable discrepancies between these studies may be due to variation in metformin dosage, route of administration intraperitoneal versus intragastric , and diet composition regular chow versus high fat. ACC1 and ACC2 are major downstream targets of AMPK activation that are involved with the regulation of lipid metabolism. Specifically, ACC1 and ACC2 catalyze the production of malonyl-CoA, a precursor for de novo lipogenesis and a regulator of mitochondrial fat oxidation Thus, phosphorylation and inhibition of ACC1 and ACC2 by AMPK decreases hepatic lipogenesis and increases hepatic fat oxidation respectively , leading to reduced hepatic lipid accumulation and improved insulin sensitivity. In an elegant study using ACC double knock-in DKI mice that are insensitive to AMPK inhibition, Fullerton et al showed that AMPK inhibition of ACC is necessary for the therapeutic actions of chronic metformin treatment in mice fed a high-fat diet Interestingly, the authors show that these mice were in fact responsive to acute metformin treatment. This is consistent with a later study using the same ACC DKI mouse model, which showed no genotype differences in response to acute metformin treatment following high-fat feeding 48 , suggesting an ACC-independent mechanism. Indeed, multiple groups have shown that both pharmacological inhibition of hepatic ACC and activation of AMPK independently reverse hepatic steatosis and restore hepatic insulin sensitivity in rodents, nonhuman primates, and humans In contrast, metformin is unable to reverse hepatic steatosis or improve liver function in the absence of weight loss in nondiabetic patients Taken together, these data suggest that hepatic ACC inhibition is not a major target of metformin action in humans. In summary, there is competing evidence both in support of and in opposition to an AMPK-dependent mechanism of action for therapeutic doses of metformin. A more recently proposed mechanism of action of metformin is increased cytosolic redox due to inhibition of hepatic GPD2 activity Fig. In the liver, glycerol is phosphorylated to G3P and converted to DHAP by GPD2. Thus, GPD2 is necessary for glycerol entry into the gluconeogenic pathway. GPD2 is also a redox-dependent enzyme that is a key component of the α-glycerophosphate shuttle, 1 of the 2 major redox shuttles the second being the malate-aspartate shuttle. Importantly, GPD2 inhibition reduces gluconeogenesis from redox-dependent substrates only glycerol and lactate , which differentiates this mechanism from what would be expected with complex I inhibition as well as all other proposed mechanisms for metformin action. This substrate selectivity for metformin inhibition of hepatic gluconeogenesis has been demonstrated both in vitro and in vivo 48 , Contrary to these findings, Calza et al did not report any changes in gluconeogenesis from lactate in response to metformin in the perfused rat liver and Alshawi et al did not observe significant inhibition of GPD2 by metformin However, in contrast to these 2 studies, several other groups have independently reported an inhibitory effect of metformin and phenformin on GPD2 activity at clinically relevant μM concentrations 50 , Metformin inhibition of GPD2 activity is further supported by studies showing increased hepatocellular G3P and glycerol concentrations following metformin treatment in vitro and in vivo, which is consistent with inhibition of GPD2 activity 50 , GPD2 is widely expressed throughout the body; however, expression levels vary notably between tissues A recent report from MacDonald et al questioned the proposed GPD2-dependent mechanism of metformin action in the liver, in part due to the high level of pancreatic GPD2 expression However, this conclusion fails to consider the tissue distribution of metformin. As discussed earlier, metformin primarily accumulates in the liver, kidney, and small intestine due to the expression profile of the OCT1, OCT3, and MATE1 transporters, which are required for metformin uptake 64 , 65 , , Indeed, metformin treatment was recently shown to alter redox balance in the kidney in addition to the liver 48 , , consistent with GPD2 inhibition in tissues in which metformin accumulates It has also been suggested that metformin inhibits the malate-aspartate shuttle; however, this mechanism is challenged by the absence of an effect of metformin on malate dehydrogenase or aspartate aminotransferase 50 , As described in the preceding sections, glycerol turnover is increased in individuals with T2D due to insulin resistance and inflammation in WAT, which in turn leads to increased contributions of glycerol to gluconeogenesis by a substrate-push mechanism , , There is also evidence to suggest that metformin can alter redox balance even when rates of the glycerophosphate shuttle do not exceed that of the malate-aspartate shuttle Data obtained from GPD2 knockout mice and patients with GPD2 mutations or deficiency have provided insight to the metabolic consequences of GPD2 inhibition 50 , Most striking is the observation that GPD2 knockout mice are protected from diet-induced hyperglycemia independent of glucose-stimulated insulin secretion Perturbation of the glycerophosphate shuttle also inhibits gluconeogenesis from glycerol, leading to impaired lipid and amino acid metabolism in mice. The clinical relevance of these changes is demonstrated by the association between low GPD2 expression and hepatic steatosis in patients with and without NAFLD, potentially indicating reduced gluconeogenesis from glycerol In the following sections, we summarize the evidence for a direct versus indirect mechanism of inhibition, in addition to the redox-dependency of this mechanism. Metformin is shown to decrease hepatic gluconeogenesis from redox-dependent substrates through inhibition of GPD2 activity; however, it is unclear whether metformin directly or indirectly inhibits GPD2 48 , Importantly, metformin inhibition of GPD2 exhibits noncompetitive kinetics with a K i of ~50µM, which is in stark contrast with the millimolar concentrations required to inhibit complex I activity. Supporting a direct interaction between metformin and GPD2, independent studies using intact mitochondria, mitochondrial lysates, and isolated enzyme assays with immunoprecipitated GPD2, biguanides are shown to inhibit GPD2 activity in vitro 50 , , , although other groups have not observed an inhibitory effect Several alternative hypotheses in support of an indirect mechanism of GPD2 inhibition have also been postulated. It is likely that metformin has many additional effects and may in fact alter the activity of several complexes of the electron transport chain, which in turn indirectly leads to inhibition of GPD2. Metformin and other guanides have consistently been shown to bind metal ions, such as copper and iron, possibly by acting as a Schiff base, which is consistent with reports that metformin interacts with heme or cytochrome c directly Indeed, downstream inhibition of the electron transport chain is shown to backlog the entire electron transport chain, providing a potential link between metformin interaction with downstream complexes and indirect inhibition of GPD2 , GPD2 is also calcium-dependent and is therefore sensitive to changes in local calcium concentrations; however, there is little evidence to support a role for metformin in calcium homeostasis Further investigation is necessary to determine whether metformin and other guanides interact with copper and iron contained in the electron transport chain, which in turn results in inhibition of GPD2 by an indirect mechanism leading to an increase in the cytosolic redox state. Metformin-metal interactions might also explain the pleotropic effects of metformin on mitochondrial function and other metabolic processes. The observation that metformin selectively inhibits gluconeogenesis from redox-dependent substrates lactate and glycerol , but not redox-independent substrates pyruvate, DHAP, alanine strongly indicates a redox-dependent mechanism of action 37 , , Several groups have shown that biguanide treatment increases the cytosolic redox state in a variety of tissues, consistent with inhibition of the glycerophosphate shuttle 48 , , , , , , , Metformin-induced increases in the cytosolic redox state will reduce lactate conversion to pyruvate due to the dependency of lactate dehydrogenase activity on the cytosolic redox state and it will reduce glycerol conversion to glucose due to inhibition of GPD2 activity. Isotopically labeled tracer studies have independently confirmed that metformin reduces gluconeogenesis from lactate and glycerol, while gluconeogenesis from alanine remains unaltered 37 , 48 , Importantly this substrate-selective inhibition of gluconeogenesis cannot be explained by any of the previously described proposed mechanisms of metformin action, including complex I inhibition, AMPK activation, fructose 1,6-bisphosphatase inhibition, or CREB inhibition. In comparison with other pharmacologic interventions for T2D, metformin treatment rarely causes hypoglycemia Yet, this remains an area of active investigation. Here, we have highlighted several characteristics of metformin action that are consistent with a redox-dependent mechanism of action on hepatic gluconeogenesis at therapeutically relevant μM concentrations. Furthermore, we described key features of metformin treatment that are inconsistent with clinically meaningful complex I inhibition, including the millimolar concentrations required to observe complex I inhibition, and the substrate selectivity of metformin inhibition of gluconeogenesis. Many of the postulated mechanisms of metformin action, including AMPK activation and altered energy charge, are dependent on significant complex I inhibition. Therefore, although these pathways may play a role in the pleiotropic effects of metformin, they are likely dispensable for the glucose-lowering effect of metformin in patients with poorly controlled T2D. In recent years, the utility of metformin has been expanded beyond the first-line treatment for T2D, and it has the potential to enter the realms of aging, cancer, and cardiovascular disease. Thus, the quest to identify a clear mechanism of metformin action is pertinent to the development of new therapeutic strategies and alleviating these chronic illnesses. Financial Support: This work was supported by grants from the United States Public Health Service R01 DK, R01 DK, R01 DK, R01 DK, RC2 DK, P30 DK, and GM Disclosure Summary: G. serves on the scientific advisory boards for Merck, AstraZeneca, iMBP, and Janssen Research and Development and receives investigator-initiated support from Gilead Sciences, Merck, and AstraZeneca. He is also a Scientific Co-Founder of TLC. Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. Diabetes Care. King P , Peacock I , Donnelly R. The UK prospective diabetes study UKPDS : clinical and therapeutic implications for type 2 diabetes. Br J Clin Pharmacol. Google Scholar. DeFronzo RA , Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. 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Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. Metformin might influence tumourigenesis, both indirectly, through the systemic reduction of insulin levels, and directly, via the induction of energetic stress; however, these effects require further investigation. Here, we discuss the updated understanding of the antigluconeogenic action of metformin in the liver and the implications of the discoveries of metformin targets for the treatment of diabetes mellitus and cancer. Abstract Metformin has been the mainstay of therapy for diabetes mellitus for many years; however, the mechanistic aspects of metformin action remained ill-defined. Publication types Research Support, Non-U. Show pagesource. Old revisions. Recent Changes. Metformin Trade Names: Glucophage, Glucophage XR ®. decreases the liver's production of glucose via activation of AMP-activated protein kinase AMPK see Figure. at very high doses it may increase the removal of glucose from muscle, the liver, and other body tissues where it is stored. a FIRST LINE drug in the treatment of type II diabetes except when contraindicated - see below. it has been shown to reduce the risk of cardiovascular events and macrovascular disease Kooy et al, ; Wexler, not as an FDA approved indication in obese type 1 diabetics as an adjunct to insulin not as monotherapy to reduce weight and to better control hemoglobin A1C levels. IMPORTANT Contraindications :. chronic cardiopulmonary dysfunction congestive heart failure, emphysema - conditions that predispose patients to tissue anoxia, which increases the risk of lactic acidosis. Previous guidelines had contraindications based upon serum creatinine levels vs estimated GFR:. liver disease because of increased risk of lactic acidosis. There isn't a fixed dosage regimen for metformin. It can be given in divided doses with meals, or as an extended-release formulation Glucophage XR ® that is generally given once daily with the evening meal. Rare : dose-related incidence of lactic acidosis. Vitamin B12 deficiency. In rare patients, Vit B12 deficiency may result in peripheral neuropathy and megaloblastic anemia. Taking a daily multivitamin may protect against Vit B12 deficiency McCulloch, Most patients with type 2 diabetes, as well as those with prediabetes are overweight or obese. Metformin has been found to produce a more significant degree of weight loss in patients with polycystic ovary syndrome PCOS , a complex endocrine disorder with symptoms including diabetes, obesity, infertility and heart disease Li et al, metformin can result in lactic acidosis due to its effect to block gluconeogenesis, which can impair the hepatic metabolism of lactic acid. Anderson K et al : Is metformin effective for reducing weight in obese or overweight adolescents?. DOI: |
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