Molecular mechanism of action of metformin: old or new insights?

Rena, Graham; Pearson, Ewan R.; Sakamoto, Kei

doi:10.1007/s00125-013-2991-0

Cited by 406 publications

(328 citation statements)

References 87 publications

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“…Interestingly, activation of the AMPK pathway by another pharmacological drug (AICAR) in rat Sertoli cells stimulated lactate production (Galardo et al 2007). Under our conditions, the lactate production could be due to the role of metformin in inhibiting the respiratory chain complex 1, blocking mitochondrial activity (Leverve et al 2003) and promoting anaerobic respiration (Rena et al 2013). Bertoldo et al (2014a) remarked that mitochondrial activity of mouse spermatozoa is reduced after metformin incubation.…”

Section: Discussionmentioning

confidence: 77%

“…The main mechanism of action of metformin is not completely elucidated. However, it is known that one of its actions is to block the respiratory chain complex I and inhibit ATP synthesis in mitochondria (Rena et al 2013). This action increases the AMP/ATP ratio, which induces and activates indirectly the energy sensor called AMP-activated protein kinase (AMPK).…”

Section: Introductionmentioning

confidence: 99%

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The insulin sensitiser metformin regulates chicken Sertoli and germ cell populations

Faure¹,

Guibert²,

Alves³

et al. 2016

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Metformin, an insulin sensitiser from the biguanide family of molecules, is used for the treatment of insulin resistance in type 2 diabetes individuals. It increases peripheral glucose uptake and may reduce food intake. Based on the tight link between metabolism and fertility, we investigated the role of metformin on testicular function using in vitro culture of Sertoli cells and seminiferous tubules, complemented by in vivo data obtained following metformin administration to prepubertal chickens. In vitro, metformin treatment reduced Sertoli cell proliferation without inducing apoptosis and morphological changes. The metabolism of Sertoli cells was affected because lactate secretion by Sertoli cells increased approximately twofold and intracellular free ATP was negatively impacted. Two important pathways regulating proliferation and metabolism in Sertoli cells were assayed. Metformin exposure was not associated with an increased phosphorylation of AKT or ERK. There was a 90% reduction in the proportion of proliferating germ cells after a 96-h exposure of seminiferous tubule cultures to metformin. In vivo, 6-week-old chickens treated with metformin for 3 weeks exhibited reduced testicular weight and a 50% decrease in testosterone levels. The expression of a marker of undifferentiated germ cells was unchanged in contrast to the decrease in expression of 'protamine', a marker of differentiated germ cells. In conclusion, these results suggest that metformin affects the testicular energy content and the proliferative ability of Sertoli and germ cells.

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Section: Discussionmentioning

confidence: 77%

Section: Introductionmentioning

confidence: 99%

The insulin sensitiser metformin regulates chicken Sertoli and germ cell populations

Faure¹,

Guibert²,

Alves³

et al. 2016

Reproduction

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“…Inhibition of the mitochondrial respiratory chain complex 1 has been suggested as a primary molecular target [6]. Inhibition of mitochondrial respiration decreases the cellular energy charge.…”

Section: Introductionmentioning

confidence: 99%

“…Inhibition of mitochondrial respiration decreases the cellular energy charge. The concomitant increase in AMP levels activates AMP-activated protein kinase (AMPK), which leads to inhibition of glucose production by reducing the expression of gluconeogenic enzymes [6], but also inhibits adenylate cyclase causing reduced intracellular levels of cAMP [7]. The latter has been shown to abrogate activation of protein kinase A and by this mechanism antagonise glucagon-dependent glucose output in hepatocytes in mice [7].…”

Section: Introductionmentioning

confidence: 99%

Endogenous glucose production increases in response to metformin treatment in the glycogen-depleted state in humans: a randomised trial

et al. 2015

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Aims/hypothesis Metformin is believed to reduce glucose levels primarily by inhibiting hepatic glucose production. Recent data indicate that metformin antagonises glucagondependent glucose output, suggesting that compensatory mechanisms protect against hypoglycaemia. Here, we examined the effect of metformin on glucose metabolism in humans after a glycogen-depleting fast and the role of reducedfunction alleles in OCT1 (also known as SLC22A1). Methods In a randomised, crossover trial, healthy individuals with or without reduced-function alleles in OCT1 were fasted for 42 h twice, either with or without prior treatment with 1 g metformin twice daily. Participants were recruited from the Pharmacogenomics Biobank of the University of Southern Denmark. Treatment allocation was generated by the Good Clinical Practice Unit, Odense University Hospital, Denmark. Variables of whole-body glucose metabolism were assessed using [3-3 H]glucose, indirect calorimetry and measurement of substrates and counter-regulatory hormones. The primary outcome was endogenous glucose production (EGP). Results Thirty-seven individuals were randomised. Thirty-four completed the study (12 had none, 13 had one and nine had two reduced-function alleles in OCT1). Three were excluded from the analysis because of early dropout. Metformin significantly stimulated glucose disposal rates and non-oxidative glucose metabolism with no effect on glucose oxidation. This increase in glucose utilisation was explained by a concomitant increase in glycolytic flux and accompanied by increased EGP, most likely mediated by increased plasma lactate, glucagon and cortisol levels. There was no effect of reduced-function OCT1 alleles on any of these measures. All individuals completed the glycogendepleting fast without hypoglycaemia. Conclusions/interpretation Metformin stimulates glycolytic glucose utilisation and lactate production in the glycogendepleted state. This may trigger a rise in glucose counterregulatory hormones and subsequently an increase in EGP, which protects against hypoglycaemia.

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“…Metformin and AICAR both activate AMPK. Previous work, including experiments in which AMPK activity was genetically ablated, indicate that AMPK is not essential for regulation of HGP, although both drugs activate AMPK 13, 14, 15, 17, 18. In the current study, we used AMPK activation purely as a marker of drug entry into the cell.…”

Section: Resultsmentioning

confidence: 99%

Regulation of hepatic glucose production and AMPK by AICAR but not by metformin depends on drug uptake through the equilibrative nucleoside transporter 1 (ENT1)

Logie

Lees

Allwood

et al. 2018

Diabetes Obesity Metabolism

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AimRecently we have observed differences in the ability of metformin and AICAR to repress glucose production from hepatocytes using 8CPT‐cAMP. Previous results indicate that, in addition to activating protein kinase A, 8CPT‐modified cAMP analogues suppress the nitrobenzylthioinosine (NBMPR)‐sensitive equilibrative nucleoside transporter ENT1. We aimed to exploit 8CPT‐cAMP, 8CPT‐2‐Methyl‐O‐cAMP and NBMPR, which is highly selective for a high‐affinity binding‐site on ENT1, to investigate the role of ENT1 in the liver‐specific glucose‐lowering properties of AICAR and metformin.MethodsPrimary mouse hepatocytes were incubated with AICAR and metformin in combination with cAMP analogues, glucagon, forskolin and NBMPR. Hepatocyte glucose production (HGP) and AMPK signalling were measured, and a uridine uptake assay with supporting LC‐MS was used to investigate nucleoside depletion from medium by cells.ResultsAICAR and metformin increased AMPK pathway phosphorylation and decreased HGP induced by dibutyryl cAMP and glucagon. HGP was also induced by 8CPT‐cAMP, 8CPT‐2‐Methyl‐O‐cAMP and NBMPR; however, in each case this was resistant to suppression by AICAR but not by metformin. Cross‐validation of tracer and mass spectrometry studies indicates that 8CPT‐cAMP, 8CPT‐2‐Methyl‐O‐cAMP and NBMPR inhibited the effects of AICAR, at least in part, by impeding its uptake into hepatocytes.ConclusionsWe report for the first time that suppression of ENT1 induces HGP. ENT1 inhibition also impedes uptake and the effects of AICAR, but not metformin, on HGP. Further investigation of nucleoside transport may illuminate a better understanding of how metformin and AICAR each regulate HGP.

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Molecular mechanism of action of metformin: old or new insights?

Cited by 406 publications

References 87 publications

The insulin sensitiser metformin regulates chicken Sertoli and germ cell populations

The insulin sensitiser metformin regulates chicken Sertoli and germ cell populations

Endogenous glucose production increases in response to metformin treatment in the glycogen-depleted state in humans: a randomised trial

Regulation of hepatic glucose production and AMPK by AICAR but not by metformin depends on drug uptake through the equilibrative nucleoside transporter 1 (ENT1)

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