Anti-Inflammatory Effects of Metformin Irrespective of Diabetes Status

Cameron, Amy R.; Morrison, Vicky L.; Levin, Daniel L.; Mohan, Mohapradeep; Forteath, Calum; Beall, Craig; McNeilly, Alison D.; Balfour, David J.K.; Savinko, Terhi; Wong, Aaron; Viollet, Benoı̂t; Sakamoto, Kei; Fagerholm, Susanna C.; Foretz, Marc; Lang, Chim C.; Rena, Graham

doi:10.1161/circresaha.116.308445

Cited by 549 publications

(472 citation statements)

References 58 publications

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“…HGP was measured, essentially as previously described,25 using mouse primary hepatocytes. Viable cells were allowed to settle for 4‐6 hours before serum starvation in M199 media containing dexamethasone (100 nM).…”

Section: Methodsmentioning

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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Section: Methodsmentioning

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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“…и соавт. (2016), продемонстрировав в эксперименте на молекулярном уровне противовоспалительные эффекты метформина, заключили, что у пациентов с кардиоваскулярными за-болеваниями необходимо интенсифицировать прове-дение исследований в этом направлении, независимо от наличия СД [51]. Chang S.H.…”

Section: диагностика контроль лечение Diagnosis Control Treatmentunclassified

Multidimensional effects of metformin in patients with type 2 diabetes

Ruyatkina¹,

Ruyatkin²

2017

Diabetes mellitus

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Диагностика, контроль, лечение Diagnosis, control, treatment современных алгоритмах антигипергликемизи-рующей терапии при сахарном диабете 2 типа (СД2) метформин занимает лидирующие по-зиции [1]. Этому предшествовала своеобразная драма в конце XX в., когда стало ясно, что разные группы са-хароснижающих препаратов могут противоположно влиять на риск сердечно-сосудистых событий (ССС). Так, вследствие негативного влияния на него первая ге-нерация производных сульфонилмочевины (СМ) ушла из клинической практики, тогда как для препаратов второй генерации такие эффекты не были характерны, что убедительно продемонстрировано в UKPDS, так же, как и для глимепирида -производного СМ третьей гене-рации [2]. На основании данных о повышении сердечно-сосудистого риска из медицинской практики ушли бигуаниды [3]

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“…15 AMPK activation by statins and metformin has been proposed to contribute to the pleiotropic effects of this compound class. 6 In addition, pharmacological interventions that include aspirin, 5-aminoimidazole-4-carboxamide riboside, thiazolidinediones, and the phytochemicals berberine, quercetin, and resveratrol have the ability to activate AMPK signaling by raising the (AMP+ADP)/ATP ratio as a consequence of mitochondrial electron transport and glycolysis inhibition.…”

Section: Clinical Significancementioning

confidence: 99%