6,864
Views
36
CrossRef citations to date
0
Altmetric
Review

Metformin as a potential therapeutic for neurological disease: mobilizing AMPK to repair the nervous system

, , &
Pages 45-63 | Received 13 Sep 2020, Accepted 04 Nov 2020, Published online: 04 Dec 2020

References

  • Pernicova I, Korbonits M. Metformin–mode of action and clinical implications for diabetes and cancer. Nat Rev Endocrinol. 2014;10:143–156.
  • Montvida O, Shaw J, Atherton JJ, et al. Long-term trends in antidiabetes drug usage in the U.S.: real-world evidence in patients newly diagnosed with type 2 diabetes. Diabetes Care. 2018;41:69–78.
  • Evans M, Morgan AR, Yousef Z. What next after metformin? Thinking beyond glycaemia: are SGLT2 inhibitors the answer? Diabetes Ther. 2019;10:1719–1731.
  • Lipscombe L, Booth G, Butalia S, et al. Pharmacologic glycemic management of type 2 diabetes in adults. Can J Diabetes. 2018;42 Suppl 1:S88–S103.
  • American Diabetes Association. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2019. Diabetes Care. 2019;42:S90–S102.
  • Buse JB, Wexler DJ, Tsapas A, et al. 2019 update to: management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2020;63:221–228.
  • Out M, Kooy A, Lehert P, et al. Long-term treatment with metformin in type 2 diabetes and methylmalonic acid: post hoc analysis of a randomized controlled 4.3year trial. J Diabetes Complications. 2018;32:171–178.
  • DePalo VA, Mailer K, Yoburn D, et al. Lactic acidosis associated with metformin use in treatment of type 2 diabetes mellitus. Geriatrics. 2005;60:36–41.
  • Donnan K, Segar L. SGLT2 inhibitors and metformin: dual antihyperglycemic therapy and the risk of metabolic acidosis in type 2 diabetes. Eur J Pharmacol. 2019;846:23–29.
  • Frid A, Sterner GN, Londahl M, et al. Novel assay of metformin levels in patients with type 2 diabetes and varying levels of renal function: clinical recommendations. Diabetes Care. 2010;33:1291–1293.
  • Shaw JS, Wilmot RL, Kilpatrick ES. Establishing pragmatic estimated GFR thresholds to guide metformin prescribing. Diabet Med. 2007;24:1160–1163.
  • Moin T, Schmittdiel JA, Flory JH, et al. Review of metformin use for type 2 diabetes prevention. Am J Prev Med. 2018;55:565–574.
  • Diabetes Prevention Program Research Group. The diabetes prevention program (DPP): description of lifestyle intervention. Diabetes Care. 2002;25:2165–2171.
  • UKPDS. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK prospective diabetes study (UKPDS) Group. Lancet. 1998;352:854–865.
  • Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–1589.
  • Panagiotopoulos C, Hadjiyannakis S, Henderson M. Type 2 diabetes in children and adolescents. Can J Diabetes. 2018;42 Suppl 1:S247–S54.
  • Jones KL, Arslanian S, Peterokova VA, et al. Effect of metformin in pediatric patients with type 2 diabetes: a randomized controlled trial. Diabetes Care. 2002;25:89–94.
  • Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–2559.
  • Meneilly GS, Knip A, Miller DB, et al. Diabetes in Older People. Can J Diabetes. 2018;42 Suppl 1:S283–S95.
  • Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1996;81:4059–4067.
  • Hundal RS, Krssak M, Dufour S, et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000;49:2063–2069.
  • Stumvoll M, Nurjhan N, Perriello G, et al. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333:550–554.
  • Luo T, Nocon A, Fry J, et al. AMPK Activation by metformin suppresses abnormal extracellular matrix remodeling in adipose tissue and ameliorates insulin resistance in obesity. Diabetes. 2016;65:2295–2310.
  • Liang X, Giacomini KM. Transporters involved in metformin pharmacokinetics and treatment response. J Pharm Sci. 2017;106:2245–2250.
  • Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13:251–262.
  • Canto C, Auwerx J. PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure. Curr Opin Lipidol. 2009;20:98–105.
  • Canto C, Auwerx J. AMP-activated protein kinase and its downstream transcriptional pathways. Cell Mol Life Sci. 2010;67:3407–3423.
  • Feige JN, Auwerx J. Transcriptional coregulators in the control of energy homeostasis. Trends Cell Biol. 2007;17:292–301.
  • Foretz M, Guigas B, Bertrand L, et al. Metformin: from mechanisms of action to therapies. Cell Metab. 2014;20:953–966.
  • Vial G, Detaille D, Guigas B. Role of mitochondria in the mechanism(s) of action of metformin. Front Endocrinol (Lausanne). 2019;10:294.
  • Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr. 2011;93:884S–90.
  • Hu Y, Chen H, Zhang L, et al. The AMPK-MFN2 axis regulates MAM dynamics and autophagy induced by energy stresses. Autophagy. 2020;1-15.
  • Zhou G, Myers R, Li Y, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Investig. 2001;108:1167–1174.
  • Shaw RJ, Lamia KA, Vasquez D, et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science. 2005;310:1642–1646.
  • Foretz M, Hebrard S, Leclerc J, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010;120:2355–2369.
  • Owen MR, Doran E, Halestrao AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348:607–614.
  • El-Mir MY, Nogueira V, Fontaine E, et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem. 2000;275:223–228.
  • Bridges HR, Jones AJ, Pollak MN, et al. Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J. 2014;462:475–487.
  • Alshawi A, Agius L. Low metformin causes a more oxidized mitochondrial NADH/NAD redox state in hepatocytes and inhibits gluconeogenesis by a redox-independent mechanism. J Biol Chem. 2019;294:2839–2853.
  • Bailey CJ, Mynett KJ, Page T. Importance of the intestine as a site of metformin-stimulated glucose utilization. Br J Pharmacol. 1994;112:671–675.
  • McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia. 2016;59:426–435.
  • Walker J, Jijon HB, Diaz H, et al. 5-aminoimidazole-4-carboxamide riboside (AICAR) enhances GLUT2-dependent jejunal glucose transport: a possible role for AMPK. Biochem J. 2005;385:485–491.
  • Ouyang J, Parakhia RA, Ochs RS. Metformin activates AMP kinase through inhibition of AMP deaminase. J Biol Chem. 2011;286:1–11.
  • Boyle JG, Logan PJ, Jones GC, et al. AMP-activated protein kinase is activated in adipose tissue of individuals with type 2 diabetes treated with metformin: a randomised glycaemia-controlled crossover study. Diabetologia. 2011;54:1799–1809.
  • Moreno-Navarrete JM, Ortega FJ, Rodriguez-Hermosa JI, et al. OCT1 Expression in adipocytes could contribute to increased metformin action in obese subjects. Diabetes. 2011;60:168–176.
  • Karise I, Bargut TC, Del Sol M, et al. Metformin enhances mitochondrial biogenesis and thermogenesis in brown adipocytes of mice. Biomed Pharmacother. 2019;111:1156–1165.
  • Breining P, Jensen JB, Sundelin EI, et al. Metformin targets brown adipose tissue in vivo and reduces oxygen consumption in vitro. Diabetes Obes Metab. 2018;20:2264–2273.
  • Chiang MC, Cheng YC, Chen SJ, et al. Metformin activation of AMPK-dependent pathways is neuroprotective in human neural stem cells against Amyloid-beta-induced mitochondrial dysfunction. Exp Cell Res. 2016;347:322–331.
  • Inyang KE, Szabo-Pardi T, Wentworth E, et al. The antidiabetic drug metformin prevents and reverses neuropathic pain and spinal cord microglial activation in male but not female mice. Pharmacol Res. 2019;139:1–16.
  • Chung MM, Nicol CJ, Cheng YC, et al. Metformin activation of AMPK suppresses AGE-induced inflammatory response in hNSCs. Exp Cell Res. 2017;352:75–83.
  • Wang S, Kobayashi K, Kogure Y, et al. Negative regulation of TRPA1 by AMPK in primary sensory neurons as a potential mechanism of painful diabetic neuropathy. Diabetes. 2018;67:98–109.
  • Chau-Van C, Gamba M, Salvi R, et al. Metformin inhibits adenosine 5ʹ-monophosphate-activated kinase activation and prevents increases in neuropeptide Y expression in cultured hypothalamic neurons. Endocrinology. 2007;148:507–511.
  • El-Mir MY, Detaille D, RV G, et al. Neuroprotective role of antidiabetic drug metformin against apoptotic cell death in primary cortical neurons. J Mol Neurosci. 2008;34:77–87.
  • Kulkarni SS, Canto C. The molecular targets of resveratrol. Biochim Biophys Acta. 2015;1852:1114–1123.
  • Baur JA, Pearson KJ, Price NL, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444:337–342.
  • Bonnefont-Rousselot D. Resveratrol and cardiovascular diseases. Nutrients. 2016;8:250.
  • Roy Chowdhury SK, Smith DR, Saleh A, et al. Impaired adenosine monophosphate-activated protein kinase signalling in dorsal root ganglia neurons is linked to mitochondrial dysfunction and peripheral neuropathy in diabetes. Brain. 2012;135:1751–1766.
  • Zang M, Xu S, Maitland-Toolan KA, et al. Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice. Diabetes. 2006;55:2180–2191.
  • Suchankova G, Nelson LE, Gerhart-Hines Z, et al. Concurrent regulation of AMP-activated protein kinase and SIRT1 in mammalian cells. Biochem Biophys Res Commun. 2009;378:836–841.
  • *Dasgupta B, Milbrandt J. Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci U S A. 2007;104:7217–7222.
  • Breen DM, Sanli T, Giacca A, et al. Stimulation of muscle cell glucose uptake by resveratrol through sirtuins and AMPK. Biochem Biophys Res Commun. 2008;374:117–122.
  • Price NL, Gomes AP, Ling AJ, et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 2012;15:675–690.
  • Gantois I, Popic J, Khoutorsky A, et al. Metformin for treatment of fragile X syndrome and other neurological disorders. Annu Rev Med. 2019;70:167–181.
  • Lipton JO, Sahin M. The neurology of mTOR. Neuron. 2014;84:275–291.
  • Christie KJ, Webber CA, Martinez JA, et al. PTEN inhibition to facilitate intrinsic regenerative outgrowth of adult peripheral axons. J Neurosci. 2010;30:9306–9315.
  • Park KK, Liu K, Hu Y, et al. Promoting axon regeneration in the adult CNS by modulation of the PTEN/mTOR pathway. Science. 2008;322:963–966.
  • Aghanoori MR, Smith DR, Shariati-Ievari S, et al. Insulin-like growth factor-1 activates AMPK to augment mitochondrial function and correct neuronal metabolism in sensory neurons in type 1 diabetes. Mol Metab. 2019;20:149–165.
  • Koley S, Rozenbaum M, Fainzilber M, et al. Translating regeneration: local protein synthesis in the neuronal injury response. Neurosci Res. 2019;139:26–36.
  • Rotermund C, Machetanz G, Fitzgerald JC. The therapeutic potential of metformin in neurodegenerative diseases. Front Endocrinol (Lausanne). 2018;9:400.
  • Riching AS, Major JL, Londono P, et al. The brain-heart axis: alzheimer’s, diabetes, and hypertension. ACS Pharmacol Transl Sci. 2020;3:21–28.
  • Wahl D, Solon-Biet SM, Cogger VC, et al. Aging, lifestyle and dementia. Neurobiol Dis. 2019;130:104481.
  • Markowicz-Piasecka M, Sikora J, Szydlowska A, et al. Metformin - a future therapy for neurodegenerative diseases: theme: drug discovery, development and delivery in alzheimer’s disease guest editor: davide brambilla. Pharm Res. 2017;34:2614–2627.
  • Torres-Odio S, Key J, Hoepken HH, et al. Progression of pathology in PINK1-deficient mouse brain from splicing via ubiquitination, ER stress, and mitophagy changes to neuroinflammation. J Neuroinflammation. 2017;14:154.
  • Curry DW, Stutz B, Andrews ZB, et al. Targeting AMPK signaling as a neuroprotective strategy in Parkinson’s disease. J Parkinsons Dis. 2018;8:161–181.
  • Zheng B, Liao Z, Locascio JJ, et al. PGC-1alpha, a potential therapeutic target for early intervention in Parkinson’s disease. Sci Transl Med. 2010;2:52ra73.
  • Lu M, Su C, Qiao C, et al. Metformin prevents dopaminergic neuron death in MPTP/P-induced mouse model of Parkinson’s disease via autophagy and mitochondrial ROS clearance. Int J Neuropsychopharmacol. 2016;19:1–11.
  • Katila N, Bhurtel S, Shadfar S, et al. Metformin lowers alpha-synuclein phosphorylation and upregulates neurotrophic factor in the MPTP mouse model of Parkinson’s disease. Neuropharmacology. 2017;125:396–407.
  • Patil SP, Jain PD, Ghumatkar PJ, et al. Neuroprotective effect of metformin in MPTP-induced Parkinson’s disease in mice. Neuroscience. 2014;277:747–754.
  • Bayliss JA, Lemus MB, Santos VV, et al. Metformin prevents nigrostriatal dopamine degeneration independent of AMPK activation in dopamine neurons. PLoS One. 2016;11:e0159381.
  • Dias V, Junn E, Mouradian MM. The role of oxidative stress in Parkinson’s disease. J Parkinsons Dis. 2013;3:461–491.
  • Fitzgerald JC, Zimprich A, Carvajal Berrio DA, et al. Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson’s disease. Brain. 2017;140:2444–2459.
  • Ryu YK, Park HY, Go J, et al. Metformin inhibits the development of L-DOPA-induced dyskinesia in a murine model of Parkinson’s disease. Mol Neurobiol. 2018;55:5715–5726.
  • Schulte J, Littleton JT. The biological function of the Huntingtin protein and its relevance to Huntington’s Disease pathology. Curr Trends Neurol. 2011;5:65–78.
  • Bence NF, Sampat RM, Kopito RR. Impairment of the ubiquitin-proteasome system by protein aggregation. Science. 2001;292:1552–1555.
  • Steffan JS, Kazantsev A, Spasic-Boskovic O, et al. The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci U S A. 2000;97:6763–6768.
  • Hervas D, Fornes-Ferrer V, Gomez-Escribano AP, et al. Metformin intake associates with better cognitive function in patients with Huntington’s disease. PLoS One. 2017;12:e0179283.
  • Parker JA, Connolly JB, Wellington C, et al. Expanded polyglutamines in Caenorhabditis elegans cause axonal abnormalities and severe dysfunction of PLM mechanosensory neurons without cell death. Proc Natl Acad Sci U S A. 2001;98:13318–13323.
  • Vazquez-Manrique RP, Farina F, Cambon K, et al. AMPK activation protects from neuronal dysfunction and vulnerability across nematode, cellular and mouse models of Huntington’s disease. Hum Mol Genet. 2016;25:1043–1058.
  • Arnoux I, Willam M, Griesche N, et al. Metformin reverses early cortical network dysfunction and behavior changes in Huntington’s disease. Elife. 2018;7:e38744.
  • Ju TC, Chen HM, Lin JT, et al. Nuclear translocation of AMPK-alpha1 potentiates striatal neurodegeneration in Huntington’s disease. J Cell Biol. 2011;194:209–227.
  • Antel JP, Lin YH, Cui QL, et al. Immunology of oligodendrocyte precursor cells in vivo and in vitro. J Neuroimmunol. 2019;331:28–35.
  • Ludwin SK, Rao V, Moore CS, et al. Astrocytes in multiple sclerosis. Mult Scler. 2016;22:1114–1124.
  • Largani SHH, Borhani-Haghighi M, Pasbakhsh P, et al. Oligoprotective effect of metformin through the AMPK-dependent on restoration of mitochondrial hemostasis in the cuprizone-induced multiple sclerosis model. J Mol Histol. 2019;50:263–271.
  • Smirnova LP, Krotenko NV, Grishko EV, et al. State of antioxidant system in patients with multiple sclerosis during therapy. Biomed Khim. 2011;57:661–670.
  • Paintlia AS, Paintlia MK, Mohan S, et al. AMP-activated protein kinase signaling protects oligodendrocytes that restore central nervous system functions in an experimental autoimmune encephalomyelitis model. Am J Pathol. 2013;183:526–541.
  • Collaborators GMaCoD. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 2016;388:1459–1544.
  • Wang S, Zhai H, Wei L, et al. Socioeconomic status predicts the risk of stroke death: a systematic review and meta-analysis. Prev Med Rep. 2020;19:101124.
  • Leech T, Chattipakorn N, Chattipakorn SC. The beneficial roles of metformin on the brain with cerebral ischaemia/reperfusion injury. Pharmacol Res. 2019;146:104261.
  • Xia CY, Zhang S, Gao Y, et al. Selective modulation of microglia polarization to M2 phenotype for stroke treatment. Int Immunopharmacol. 2015;25:377–382.
  • Jin Q, Cheng J, Liu Y, et al. Improvement of functional recovery by chronic metformin treatment is associated with enhanced alternative activation of microglia/macrophages and increased angiogenesis and neurogenesis following experimental stroke. Brain Behav Immun. 2014;40:131–142.
  • Zhu J, Liu K, Huang K, et al. Metformin improves neurologic outcome via AMP-activated protein kinase-mediated autophagy activation in a rat model of cardiac arrest and resuscitation. J Am Heart Assoc. 2018;7:e008389.
  • Nandini HS, Paudel YN, Krishna KL. Envisioning the neuroprotective effect of Metformin in experimental epilepsy: a portrait of molecular crosstalk. Life Sci. 2019;233:116686.
  • Citraro R, Leo A, Constanti A, et al. mTOR pathway inhibition as a new therapeutic strategy in epilepsy and epileptogenesis. Pharmacol Res. 2016;107:333–343.
  • Yang Y, Zhu B, Zheng F, et al. Chronic metformin treatment facilitates seizure termination. Biochem Biophys Res Commun. 2017;484:450–455.
  • Shaw RJ. LKB1 and AMP-activated protein kinase control of mTOR signalling and growth. Acta Physiol (Oxf). 2009;196:65–80.
  • Mehrabi S, Sanadgol N, Barati M, et al. Evaluation of metformin effects in the chronic phase of spontaneous seizures in pilocarpine model of temporal lobe epilepsy. Metab Brain Dis. 2018;33:107–114.
  • Zeyghami MA, Hesam E, Khadivar P, et al. Effects of atorvastatin and metformin on development of pentylenetetrazole-induced seizure in mice. Heliyon. 2020;6:e03761.
  • Heinrich C, Lahteinen S, Suzuki F, et al. Increase in BDNF-mediated TrkB signaling promotes epileptogenesis in a mouse model of mesial temporal lobe epilepsy. Neurobiol Dis. 2011;42:35–47.
  • Bennett GJ, Doyle T, Salvemini D. Mitotoxicity in distal symmetrical sensory peripheral neuropathies. Nat Rev Neurol. 2014;10:326–336.
  • Cashman CR, Hoke A. Mechanisms of distal axonal degeneration in peripheral neuropathies. Neurosci Lett. 2015;596:33–50.
  • Chowdhury SK, Smith DR, Fernyhough P. The role of aberrant mitochondrial bioenergetics in diabetic neuropathy. Neurobiol Dis. 2013;51:56–65.
  • Trecarichi A, Flatters SJL. Mitochondrial dysfunction in the pathogenesis of chemotherapy-induced peripheral neuropathy. Int Rev Neurobiol. 2019;145:83–126.
  • Bernstein BW, Bamburg JR. Actin-ATP hydrolysis is a major energy drain for neurons. J Neurosci. 2003;23:1–6.
  • Harris JJ, Jolivet R, Attwell D. Synaptic energy use and supply. Neuron. 2012;75:762–777.
  • Li Z, Okamoto K, Hayashi Y, et al. The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell. 2004;119:873–887.
  • Wang SS, Shultz JR, Burish MJ, et al. Functional trade-offs in white matter axonal scaling. J Neurosci. 2008;28:4047–4056.
  • Chen H, Chan DC. Critical dependence of neurons on mitochondrial dynamics. Curr Opin Cell Biol. 2006;18:453–459.
  • Breathnach AS. Electron microscopy of cutaneous nerves and receptors. J Invest Dermatol. 1977;69:8–26.
  • Liu L, Tian D, Liu C, et al. Metformin enhances functional recovery of peripheral nerve in rats with sciatic nerve crush injury. Med Sci Monit. 2019;25:10067–10076.
  • Piermarini E, Cartelli D, Pastore A, et al. Frataxin silencing alters microtubule stability in motor neurons: implications for Friedreich’s ataxia. Hum Mol Genet. 2016;25:4288–4301.
  • Huber K, Patel P, Zhang L, et al. 2-[(1-methylpropyl)dithio]-1H-imidazole inhibits tubulin polymerization through cysteine oxidation. Mol Cancer Ther. 2008;7:143–151.
  • Wang H, Zheng Z, Han W, et al. Metformin promotes axon regeneration after spinal cord injury through inhibiting oxidative stress and stabilizing microtubule. Oxid Med Cell Longev. 2020;2020:1–20.
  • Pereira JA, Lebrun-Julien F, Suter U. Molecular mechanisms regulating myelination in the peripheral nervous system. Trends Neurosci. 2012;35:123–134.
  • Dunlop EA, Tee AR. mTOR and autophagy: a dynamic relationship governed by nutrients and energy. Semin Cell Dev Biol. 2014;36:121–129.
  • Ma J, Liu J, Yu H, et al. Effect of metformin on Schwann cells under hypoxia condition. Int J Clin Exp Pathol. 2015;8:6748–6755.
  • Calcutt NA, Smith DR, Frizzi K, et al. Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy. J Clin Invest. 2017;127:608–622.
  • Brand MD, Nicholls DG. Assessing mitochondrial dysfunction in cells. Biochem J. 2011;435:297–312.
  • Puigserver P, Wu Z, Park CW, et al. A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998;92:829–839.
  • Fernyhough P. Mitochondrial dysfunction in diabetic neuropathy: a series of unfortunate metabolic events. Curr Diab Rep. 2015;15:89.
  • Baron R, Binder A, Wasner G. Neuropathic pain: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol. 2010;9:807–819.
  • Price TJ, Das V, Dussor G. Adenosine monophosphate-activated protein kinase (AMPK) activators for the prevention, treatment and potential reversal of pathological pain. Curr Drug Targets. 2016;17:908–920.
  • Bastianetto S, Menard C, Quirion R. Neuroprotective action of resveratrol. Biochim Biophys Acta. 2015;1852:1195–1201.
  • Xu M, Cheng Z, Ding Z, et al. Resveratrol enhances IL-4 receptor-mediated anti-inflammatory effects in spinal cord and attenuates neuropathic pain following sciatic nerve injury. Mol Pain. 2018;14:1–11.
  • Yang YJ, Hu L, Xia YP, et al. Resveratrol suppresses glial activation and alleviates trigeminal neuralgia via activation of AMPK. J Neuroinflammation. 2016;13:84.
  • Sharma S, Kulkarni SK, Chopra K. Effect of resveratrol, a polyphenolic phytoalexin, on thermal hyperalgesia in a mouse model of diabetic neuropathic pain. Fundam Clin Pharmacol. 2007;21:89–94.
  • Das V, Kroin JS, Moric M, et al. AMP-activated protein kinase (AMPK) activator drugs reduce mechanical allodynia in a mouse model of low back pain. Reg Anesth Pain Med. 2019;44:1010–1014.
  • Liu Y, Li J, Li H, et al. AMP-activated protein kinase activation in dorsal root ganglion suppresses mTOR/p70S6K signaling and alleviates painful radiculopathies in lumbar disc herniation rat model. Spine (Phila Pa 1976). 2019;44:E865–E72.
  • Melemedjian OK, Khoutorsky A, Sorge RE, et al. mTORC1 inhibition induces pain via IRS-1-dependent feedback activation of ERK. Pain. 2013;154:1080–1091.
  • Melemedjian OK, Asiedu MN, Tillu DV, et al. Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain. Mol Pain. 2011;7:70.
  • Augusto PSA, Braga AV, Rodrigues FF, et al. Metformin antinociceptive effect in models of nociceptive and neuropathic pain is partially mediated by activation of opioidergic mechanisms. Eur J Pharmacol. 2019;858:172497.
  • Das V, Kroin JS, Moric M, et al. Antihyperalgesia effect of AMP-activated protein kinase (AMPK) activators in a mouse model of postoperative pain. Reg Anesth Pain Med. 2019;44:781–786.
  • Ma J, Kavelaars A, Dougherty PM, et al. Beyond symptomatic relief for chemotherapy-induced peripheral neuropathy: targeting the source. Cancer. 2018;124:2289–2298.
  • Inyang KE, McDougal TA, Ramirez ED, et al. Alleviation of paclitaxel-induced mechanical hypersensitivity and hyperalgesic priming with AMPK activators in male and female mice. Neurobiol Pain. 2019;6:100037.
  • Mao-Ying QL, Kavelaars A, Krukowski K, et al. The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model. PLoS One. 2014;9:e100701.
  • Pereira AF, Pereira LMS, Silva CMP, et al. Metformin reduces c-Fos and ATF3 expression in the dorsal root ganglia and protects against oxaliplatin-induced peripheral sensory neuropathy in mice. Neurosci Lett. 2019;709:134378.
  • Ludman T, Melemedjian OK. Bortezomib and metformin opposingly regulate the expression of hypoxia-inducible factor alpha and the consequent development of chemotherapy-induced painful peripheral neuropathy. Mol Pain. 2019;15:1–13.
  • Bhadri N, Sanji T, Madakasira Guggilla H, et al. Amelioration of behavioural, biochemical, and neurophysiological deficits by combination of monosodium glutamate with resveratrol/alpha-lipoic acid/coenzyme Q10 in rat model of cisplatin-induced peripheral neuropathy. ScientificWorldJournal. 2013;2013:565813.
  • Selvarajah D, Kar D, Khunti K, et al. Diabetic peripheral neuropathy: advances in diagnosis and strategies for screening and early intervention. Lancet Diabetes Endocrinol. 2019;7:938–948.
  • Tesfaye S, Selvarajah D. Advances in the epidemiology, pathogenesis and management of diabetic peripheral neuropathy. Diabetes Metab Res Rev. 2012;28 Suppl 1:8–14.
  • Vinik AI, Nevoret ML, Casellini C, et al. Diabetic neuropathy. Endocrinol Metab Clin North Am. 2013;42:747–787.
  • Pop-Busui R, Boulton AJ, Feldman EL, et al. Diabetic neuropathy: a position statement by the american diabetes association. Diabetes Care. 2017;40:136–154.
  • Abbott CA, Malik RA, van Ross ER, et al. Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K.. Diabetes Care. 2011;34:2220–2224. .
  • Partanen J, Niskanen L, Lehtinen J, et al. Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333:89–94.
  • Liu X, Xu Y, An M, et al. The risk factors for diabetic peripheral neuropathy: a meta-analysis. PLoS One. 2019;14:e0212574.
  • Ward JD, Fisher DJ, Barnes CG, et al. Improvement in nerve conduction following treatment in newly diagnosed diabetics. Lancet. 1971;297:428–431.
  • Pop-Busui R, Martin C. Neuropathy in the DCCT/EDIC-what was done then and what we would do better now. Int Rev Neurobiol. 2016;127:9–25.
  • Guo X, Tao X, Tong Q, et al. Impaired AMPK-CGRP signaling in the central nervous system contributes to enhanced neuropathic pain in highfat dietinduced obese rats, with or without nerve injury. Mol Med Rep. 2019;20:1279–1287.
  • Tanaka Y, Uchino H, Shimizu T, et al. Effect of metformin on advanced glycation endproduct formation and peripheral nerve function in streptozotocin-induced diabetic rats. Eur J Pharmacol. 1999;376:17–22.
  • Ma J, Yu H, Liu J, et al. Metformin attenuates hyperalgesia and allodynia in rats with painful diabetic neuropathy induced by streptozotocin. Eur J Pharmacol. 2015;764:599–606.
  • Lin JY, Huang XL, Chen J, et al. Stereological study on the number of synapses in the rat spinal dorsal horn with painful diabetic neuropathy induced by streptozotocin. Neuroreport. 2017;28:319–324.
  • Lin JY, He YN, Zhu N, et al. Metformin attenuates increase of synaptic number in the rat spinal dorsal horn with painful diabetic neuropathy induced by type 2 diabetes: a stereological study. Neurochem Res. 2018;43:2232–2239.
  • Los DB, Oliveira WH, Duarte-Silva E, et al. Preventive role of metformin on peripheral neuropathy induced by diabetes. Int Immunopharmacol. 2019;74:105672.
  • Kim SH, Park TS, Jin HY. Metformin preserves peripheral nerve damage with comparable effects to alpha lipoic acid in streptozotocin/high-fat diet induced diabetic rats. Diabetes Metab J. 2020. DOI:10.4093/dmj.2019.0190
  • Wile DJ, Toth C. Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes Care. 2010;33:156–161.
  • Ciric D, Martinovic T, Petricevic S, et al. Metformin exacerbates and simvastatin attenuates myelin damage in high fat diet-fed C57BL/6 J mice. Neuropathology. 2018;38:468–474.
  • Gupta K, Jain A, Rohatgi A. An observational study of vitamin b12 levels and peripheral neuropathy profile in patients of diabetes mellitus on metformin therapy. Diabetes Metab Syndr. 2018;12:51–58.
  • Miller JW. Proton pump inhibitors, H2-receptor antagonists, metformin, and vitamin B-12 deficiency: clinical implications. Adv Nutr. 2018;9:511S–8S.
  • Ozturk E, Arslan AKK, Yerer MB, et al. Resveratrol and diabetes: a critical review of clinical studies. Biomed Pharmacother. 2017;95:230–234.
  • Brasnyo P, Molnar GA, Mohas M, et al. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetic patients. Br J Nutr. 2011;106:383–389.
  • Seyyedebrahimi S, Khodabandehloo H, Nasli Esfahani E, et al. The effects of resveratrol on markers of oxidative stress in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled clinical trial. Acta Diabetol. 2018;55:341–353.
  • Timmers S, de Ligt M, Phielix E, et al. Resveratrol as add-on therapy in subjects with well-controlled type 2 diabetes: a randomized controlled trial. Diabetes Care. 2016;39:2211–2217.
  • Kumar A, Kaundal RK, Iyer S, et al. Effects of resveratrol on nerve functions, oxidative stress and DNA fragmentation in experimental diabetic neuropathy. Life Sci. 2007;80:1236–1244.
  • Kumar A, Sharma SS. NF-kappaB inhibitory action of resveratrol: a probable mechanism of neuroprotection in experimental diabetic neuropathy. Biochem Biophys Res Commun. 2010;394:360–365.
  • Yang W, Cai X, Wu H, et al. Associations between metformin use and vitamin B12 levels, anemia, and neuropathy in patients with diabetes: a meta-analysis. J Diabetes. 2019;11:729–743.
  • Stabler SP. Vitamin B12Deficiency. N Engl J Med. 2013;368:149–160.
  • Ahmed MA, Muntingh GL, Rheeder P. Perspectives on peripheral neuropathy as a consequence of metformin-induced vitamin B12 deficiency in T2DM. Int J Endocrinol. 2017;2017:2452853.
  • Adams JF, Clark JS, Ireland JT, et al. Malabsorption of vitamin B12 and intrinsic factor secretion during biguanide therapy. Diabetologia. 1983;24:16–18.
  • Bauman WA, Shaw S, Jayatilleke E, et al. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care. 2000;23:1227–1231.
  • Scarpello JHB, Hodgson E, Howlett HCS. Effect of metformin on bile salt circulation and intestinal motility in Type 2 diabetes mellitus. Diabetic Med. 1998;15:651–656.
  • Alvarez M, Sierra OR, Saavedra G, et al. Vitamin B12 deficiency and diabetic neuropathy in patients taking metformin: a cross-sectional study. Endocr Connect. 2019;8:1324–1329.
  • de Jager J, Kooy A, Lehert P, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010;340:c2181.
  • Kim J, Kundu M, Viollet B, et al. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13:132–141.
  • Campbell JM, Stephenson MD, de Courten B, et al. Metformin use associated with reduced risk of dementia in patients with diabetes: a systematic review and meta-analysis. J Alzheimers Dis. 2018;65:1225–1236.