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A spotlight on underlying the mechanism of AMPK in diabetes complications

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Abstract

Objective

Type 2 diabetes (T2D) is one of the centenarian metabolic disorders and is considered as a stellar and leading health issue worldwide. According to the International Diabetes Federation (IDF) Diabetes Atlas and National Diabetes Statistics, the number of diabetic patients will increase at an exponential rate from 463 to 700 million by the year 2045. Thus, there is a great need for therapies targeting functions that can help in maintaining the homeostasis of glucose levels and improving insulin sensitivity. 5′ adenosine monophosphate-activated protein kinase (AMPK) activation, by various direct and indirect factors, might help to overcome the hurdles (like insulin resistance) associated with the conventional approach.

Materials and results

A thorough review and analysis was conducted using various database including MEDLINE and EMBASE databases, with Google scholar using various keywords. This extensive review concluded that various drugs (plant-based, synthetic indirect/direct activators) are available, showing tremendous potential in maintaining the homeostasis of glucose and lipid metabolism, without causing insulin resistance, and improving insulin sensitivity. Moreover, these drugs have an effect against diabetes and are therapeutically beneficial in the treatment of diabetes-associated complications (neuropathy and nephropathy) via mechanism involving inhibition of nuclear translocation of SMAD4 (SMAD family member) expression and association with peripheral nociceptive neurons mediated by AMPK.

Conclusion

From the available information, it may be concluded that various indirect/direct activators show tremendous potential in maintaining the homeostasis of glucose and lipid metabolism, without resulting in insulin resistance, and may improve insulin sensitivity, as well. Therefore, in a nut shell, it may be concluded that the regulation of APMK functions by various direct/indirect activators may bring promising results. These activators may emerge as a novel therapy in diabetes and its associated complications.

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References

  1. IDF DIABETES ATLAS. 9th ed. (2019). https://diabetesatlas.org/data/en/world/. Accessed 22 Mar

  2. Gupta A, Behl T, Sehgal A, Bhatia S, Jaglan D, Bungau S. Therapeutic potential of Nrf-2 pathway in the treatment of diabetic neuropathy and nephropathy. Mol Biol Rep. 2021;22:1–4.

    Google Scholar 

  3. CDC. U.S. Department of Health and Human Service. Center for Disease Control and Prevention. National Diabetes Statistics Report, 2020. https://www.cdc.gov/diabetes/library/features/diabetes-stat-report.html; https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Accessed 28 Jul

  4. Gupta A, Behl T, Sehgal A, Bhardwaj S, Singh S, Sharma N, Hafeez A. Exploring the recent molecular targets for diabetes and associated complications. Mol Biol Rep. 2021;24:1–7.

    Google Scholar 

  5. Gupta A, Behl T, Panichayupakaranan P. A review of phytochemistry and pharmacology profile of Juglans regia. Obes Med. 2019;16: 100142. https://doi.org/10.1016/j.obmed.2019.100142.

    Article  Google Scholar 

  6. Behl T, Kaur I, Kotwani A. Implication of oxidative stress in progression of diabetic retinopathy. Surv Ophthalmol. 2016;61:187–96. https://doi.org/10.1016/j.survophthal.2015.06.001.

    Article  PubMed  Google Scholar 

  7. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman B, American Diabetes Association; European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32:193–203. https://doi.org/10.2337/dc08-9025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Gupta A, Behl T, Sachdeva M. Key milestones in the diabetes research: a comprehensive update. Obes Med. 2020;17: 100183. https://doi.org/10.1016/j.obmed.2020.100183.

    Article  Google Scholar 

  9. Mihaylova MM, Shaw RJ. The AMP-activated protein kinase (AMPK) signaling pathway coordinates cell growth, autophagy, & metabolism. Nat Cell Biol. 2011;13:1016–23. https://doi.org/10.1038/ncb2329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hardie DG, Ross FA, Hawley SA. AMPK—a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol. 2012;13:251–62. https://doi.org/10.1038/nrm3311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Popa AR, Bungau S, Vesa CM, Bondar AC, Pantis C, Maghiar O, Dimulescu IA, Cseppento DCN, Rus M. Evaluating the efficacy of the treatment with benfotiamine and alpha-lipoic acid in distal symmetric painful diabetic polyneuropathy. Rev Chim. 2019;70:3108–14.

    Article  CAS  Google Scholar 

  12. Vesa CM, Popa L, Popa AR, Rus M, Zaha AA, Bungau S, Tit DM, Aron RAC, Zaha DC. Current data regarding the relationship between type 2 diabetes mellitus and cardiovascular risk factors. Diagnostics. 2020. https://doi.org/10.3390/diagnostics10050314.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ford RJ, Fullerton MD, Pinkosky SL, Day EA, Scott JW, Oakhill JS, Bujak AL, Smith BK, Crane JD, Blumer RM, et al. Metformin and salicylate synergistically activate liver AMPK, inhibit lipogenesis and improve insulin sensitivity. Biochem J. 2015;468:125–32. https://doi.org/10.1042/bj20150125.

    Article  CAS  PubMed  Google Scholar 

  14. Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: from mechanisms of action to therapies. Cell Metab. 2014;20:953–66. https://doi.org/10.1016/j.cmet.2014.09.018.

    Article  CAS  PubMed  Google Scholar 

  15. Greenfield JR, Chisholm DJ, Department of Endocrinology. Thiazolidinediones—mechanisms of action. Aust Prescr. 2004;27:67–70. https://doi.org/10.18773/austprescr.2004.059.

    Article  Google Scholar 

  16. Hardie DG. AMPK: a key regulator of energy balance in the single cell and the whole organism. Int J Obes (Lond). 2008;32:S7–12. https://doi.org/10.1038/ijo.2008.116.

    Article  CAS  Google Scholar 

  17. Garcia D, Shaw RJ. AMPK: mechanisms of cellular energy sensing and restoration of metabolic balance. Mol Cell. 2017;66:789–800. https://doi.org/10.1016/j.molcel.2017.05.032.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kazgan N, Williams T, Forsberg LJ, Brenman JE. Identification of a nuclear export signal in the catalytic subunit of AMP-activated protein kinase. Mol Biol Cell. 2010;21:3433–42. https://doi.org/10.1091/mbc.E10-04-0347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shrikanth CB, Nandini CD. AMPK in microvascular complications of diabetes and the beneficial effects of AMPK activators from plants. Phytomedicine. 2020;73: 152808. https://doi.org/10.1016/j.phymed.2018.12.031.

    Article  CAS  PubMed  Google Scholar 

  20. Scott JW, Hawley SA, Green KA, Anis M, Stewart G, Scullion GA, Norman DG, Hardie DG. CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations. J Clin Invest. 2004;113:274–84. https://doi.org/10.1172/jci200419874.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ruderman N, Prentki M. AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat Rev Drug Discov. 2004;3:340–51. https://doi.org/10.1038/nrd1344.

    Article  CAS  PubMed  Google Scholar 

  22. Ruderman NB, Carling D, Prentki M, Cacicedo JM. AMPK, insulin resistance, and the metabolic syndrome. J Clin Invest. 2013;123:2764–72. https://doi.org/10.1172/jci67227.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hardie DG, Carling D, Sim ATR. The AMP-activated protein kinase: a multisubstrate regulator of lipid metabolism. Trends Biochem Sci. 1989;14:20–3. https://doi.org/10.1016/0968-0004(89)90084-4.

    Article  CAS  Google Scholar 

  24. Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, Hardie DG. Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem. 1996;271:27879–87. https://doi.org/10.1074/jbc.271.44.27879.

    Article  CAS  PubMed  Google Scholar 

  25. Jeon SM. Regulation and function of AMPK in physiology and diseases. Exp Mol Med. 2016;48: e245. https://doi.org/10.1038/emm.2016.81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. O’Neill LA, Hardie DG. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature. 2013;493:346–55. https://doi.org/10.1038/nature11862.

    Article  CAS  PubMed  Google Scholar 

  27. O’Neill HM, Holloway GP, Steinberg GR. AMPK regulation of fatty acid metabolism and mitochondrial biogenesis: implications for obesity. Mol Cell Endocrinol. 2013;366:135–51. https://doi.org/10.1016/j.mce.2012.06.019.

    Article  CAS  PubMed  Google Scholar 

  28. Li W, Saud SM, Young MR, Chen G, Hua B. Targeting AMPK for cancer prevention and treatment. Oncotarget. 2015;6:7365–78. https://doi.org/10.18632/oncotarget.3629.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Chen W, Lu Y, Chen G, Huang S. Molecular evidence of cryptotanshinone for treatment and prevention of human cancer. Anti-Cancer Agents Med Chem. 2013;13(7):979–87. https://doi.org/10.2174/18715206113139990115 (PMID: 23272908; PMCID: PMC3625674).

    Article  CAS  Google Scholar 

  30. Deng S, Wong CK, Lai HC, Wong AS. Ginsenoside-Rb1 targets chemotherapy-resistant ovarian cancer stem cells via simultaneous inhibition of Wnt/β-catenin signaling and epithelial-to-mesenchymal transition. Oncotarget. 2017;8(16):25897. https://doi.org/10.18632/oncotarget.13071 (PMCID:PMC5432225).

    Article  PubMed  Google Scholar 

  31. Chavez JA, Roach WG, Keller SR, Lane WS, Lienhard GE. Inhibition of GLUT4 translocation by Tbc1d1, a Rab GTPase-activating protein abundant in skeletal muscle, is partially relieved by AMP-activated protein kinase activation. J Biol Chem. 2008;283:9187–95. https://doi.org/10.1074/jbc.M708934200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chen S, Murphy J, Toth R, Campbell DG, Morrice NA, Mackintosh C. Complementary regulation of TBC1D1 and AS160 by growth factors, insulin and AMPK activators. Biochem J. 2008;409:449–59. https://doi.org/10.1042/BJ20071114.

    Article  CAS  PubMed  Google Scholar 

  33. Cool B, Zinker B, Chiou W, Kifle L, Cao N, Perham M, Dickinson R, Adler A, Gagne G, Iyengar R, et al. Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome. Cell Metab. 2006;3:403–16. https://doi.org/10.1016/j.cmet.2006.05.005.

    Article  CAS  PubMed  Google Scholar 

  34. Birkenfeld AL, Shulman GI. Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology. 2014;59:713–23. https://doi.org/10.1002/hep.26672.

    Article  PubMed  Google Scholar 

  35. Fogarty S, Hardie DG. Development of protein kinase activators: AMPK as a target in metabolic disorders and cancer. Biochim Biophys Acta. 2010;1804:581–91. https://doi.org/10.1016/j.bbapap.2009.09.012.

    Article  CAS  PubMed  Google Scholar 

  36. Sharpe LJ, Brown AJ. Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). J Biol Chem. 2013;288:18707–15. https://doi.org/10.1074/jbc.R113.479808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yang X, Mudgett J, Bou-About G, Champy MF, Jacobs H, Monassier L, Pavlovic G, Sorg T, Herault Y, Petit-Demoulière B, et al. Physiological expression of AMPKγ2RG mutation causes Wolff-Parkinson-White syndrome and induces kidney injury in mice. J Biol Chem. 2016;291:23428–39. https://doi.org/10.1074/jbc.M116.738591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Shirwany NA, Zou MH. AMPK in cardiovascular health and disease. Acta Pharmacol Sin. 2010;31:1075–84. https://doi.org/10.1038/aps.2010.139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Coelho M, Oliveira T, Fernandes R. Biochemistry of adipose tissue: an endocrine organ. Arch Med Sci. 2013;9:191–200. https://doi.org/10.5114/aoms.2013.33181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Resta N, Pierannunzio D, Lenato GM, Stella A, Capocaccia R, Bagnulo R, Lastella P, Susca FC, Bozzao C, Loconte DC, et al. Cancer risk associated with STK11/LKB1 germline mutations in Peutz-Jeghers syndrome patients: results of an Italian multicenter study. Dig Liver Dis. 2013;45:606–11. https://doi.org/10.1016/j.dld.2012.12.018.

    Article  CAS  PubMed  Google Scholar 

  41. Faubert B, Vincent EE, Poffenberger MC, Jones RG. The AMP-activated protein kinase (AMPK) and cancer: many faces of a metabolic regulator. Cancer Lett. 2015;356:165–70. https://doi.org/10.1016/j.canlet.2014.01.018.

    Article  CAS  PubMed  Google Scholar 

  42. Wang Z, Wang N, Liu P, Xie X. AMPK and cancer. In: Cordero MD, Viollet B, editors. AMP-activated protein kinase. Cham: Springer International Publishing; 2016. p. 203–26. https://doi.org/10.1007/978-3-319-43589-3_9.

    Chapter  Google Scholar 

  43. Hardie DG, Frenguelli BG. A neural protection racket: AMPK and the GABA(B) receptor. Neuron. 2007;53:159–62. https://doi.org/10.1016/j.neuron.2007.01.004.

    Article  CAS  PubMed  Google Scholar 

  44. Gailite I, Aerne BL, Tapon N. Differential control of Yorkie activity by LKB1/AMPK and the Hippo/Warts cascade in the central nervous system. Proc Natl Acad Sci USA. 2015;112:E5169–78. https://doi.org/10.1073/pnas.1505512112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Rosso P, Fioramonti M, Fracassi A, Marangoni M, Taglietti V, Siteni S, Segatto M. AMPK in the central nervous system: physiological roles and pathological implications. Res Rep Biol. 2016;7:1–13. https://doi.org/10.2147/RRB.S90858.

    Article  CAS  Google Scholar 

  46. Zhao J, Miyamoto S, You YH, Sharma K. AMP-activated protein kinase (AMPK) activation inhibits nuclear translocation of Smad4 in mesangial cells and diabetic kidneys. Am J Physiol-Renal Physiol. 2015;308(10):F1167–77.

    Article  CAS  Google Scholar 

  47. Asiedu MN, Dussor G, Price TJ. Targeting AMPK for the alleviation of pathological pain. In: AMP-activated protein kinase. Cham: Springer; 2016. p. 257–85.

    Chapter  Google Scholar 

  48. Popa AR, Fratila O, Rus M, Aron RAC, Vesa CM, Pantis C, Diaconu CC, Bratu O, Bungau S, Nemeth S. Risk factors for adiposity in the urban population and influence on the prevalence of overweight and obesity. Exp Ther Med. 2020;20:129–33. https://doi.org/10.3892/etm.2020.8662.

    Article  Google Scholar 

  49. Coughlan KA, Valentine RJ, Ruderman NB, Saha AK. Nutrient excess in AMPK downregulation and insulin resistance. J Endocrinol Diabetes Obes. 2013;1:1008.

    PubMed  PubMed Central  Google Scholar 

  50. Coughlan KA, Balon TW, Valentine RJ, Petrocelli R, Schultz V, Brandon A, Cooney GJ, Kraegen EW, Ruderman NB, Saha AK. Nutrient excess and AMPK downregulation in incubated skeletal muscle and muscle of glucose infused rats. PLoS ONE. 2015;10: e0127388. https://doi.org/10.1371/journal.pone.0127388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Saha AK, Xu XJ, Balon TW, Brandon A, Kraegen EW, Ruderman NB. Insulin resistance due to nutrient excess: is it a consequence of AMPK downregulation? Cell Cycle. 2011;10:3447–51. https://doi.org/10.4161/cc.10.20.17886.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wu Y, Song P, Xu J, Zhang M, Zou MH. Withdrawal: activation of protein phosphatase 2A by palmitate inhibits AMP-activated protein kinase. J Biol Chem. 2019;294:10741. https://doi.org/10.1074/jbc.W119.009747.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Valentine RJ, Coughlan KA, Ruderman NB, Saha AK. Insulin inhibits AMPK activity and phosphorylates AMPK Ser485/491 through Akt in hepatocytes, myotubes and incubated rat skeletal muscle. Arch Biochem Biophys. 2014;562:62–9. https://doi.org/10.1016/j.abb.2014.08.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Szendroedi J, Yoshimura T, Phielix E, Koliaki C, Marcucci M, Zhang D, Jelenik T, Müller J, Herder C, Nowotny P, et al. Role of diacylglycerol activation of PKCθ in lipid-induced muscle insulin resistance in humans. Proc Natl Acad Sci USA. 2014;111:9597–602. https://doi.org/10.1073/pnas.1409229111.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Blagosklonny MV. TOR-centric view on insulin resistance and diabetic complications: perspective for endocrinologists and gerontologists. Cell Death Dis. 2013;4: e964. https://doi.org/10.1038/cddis.2013.506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Lynch CJ, Adams SH. Branched-chain amino acids in metabolic signalling and insulin resistance. Nat Rev Endocrinol. 2014;10:723–36. https://doi.org/10.1038/nrendo.2014.171.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Steinberg GR, Kemp BE. AMPK in health and disease. Physiol Rev. 2009;89:1025–78. https://doi.org/10.1152/physrev.00011.2008.

    Article  CAS  PubMed  Google Scholar 

  58. Srivastava RAK, Pinkosky SL, Filippov S, Hanselman JC, Cramer CT, Newton RS. AMP-activated protein kinase: an emerging drug target to regulate imbalances in lipid and carbohydrate metabolism to treat cardio-metabolic diseases: thematic review series: new lipid and lipoprotein targets for the treatment of cardiometabolic diseases. J Lipid Res. 2012;53:2490–514. https://doi.org/10.1194/jlr.R025882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferré P, Birnbaum MJ, et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature. 2004;428:569–74. https://doi.org/10.1038/nature02440.

    Article  CAS  PubMed  Google Scholar 

  60. Liang Z, Li T, Jiang S, Xu J, Di W, Yang Z, Hu W, Yang Y. AMPK: a novel target for treating hepatic fibrosis. Oncotarget. 2017;8(37):62780.

    Article  Google Scholar 

  61. Glosse P, Föller M. AMP-activated protein kinase (AMPK)-dependent regulation of renal transport. Int J Mol Sci. 2018;19(11):3481.

    Article  Google Scholar 

  62. Kelley DE, Goodpaster BH, Storlien L. Muscle triglyceride and insulin resistance. Annu Rev Nutr. 2002;22:325–46. https://doi.org/10.1146/annurev.nutr.22.010402.102912.

    Article  CAS  PubMed  Google Scholar 

  63. Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science. 2005;307:384–7. https://doi.org/10.1126/science.1104343.

    Article  CAS  PubMed  Google Scholar 

  64. Munday MR, Campbell DG, Carling D, Hardie DG. Identification by amino acid sequencing of three major regulatory phosphorylation sites on rat acetyl-CoA carboxylase. Eur J Biochem. 1988;175:331–8. https://doi.org/10.1111/j.1432-1033.1988.tb14201.x.

    Article  CAS  PubMed  Google Scholar 

  65. Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115:577–90. https://doi.org/10.1016/s0092-8674(03)00929-2.

    Article  CAS  PubMed  Google Scholar 

  66. Clarke PR, Hardie DG. Regulation of HMG-CoA reductase: identification of the site phosphorylated by the AMP-activated protein kinase in vitro and in intact rat liver. EMBO J. 1990;9:2439–46. https://doi.org/10.1002/j.1460-2075.1990.tb07420.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Jäger S, Handschin C, St-Pierre J, Spiegelman BM. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc Natl Acad Sci USA. 2007;104:12017–22. https://doi.org/10.1073/pnas.0705070104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Zong H, Ren JM, Young LH, Pypaert M, Mu J, Birnbaum MJ, Shulman GI. AMP kinase is required for mitochondrial biogenesis in skeletal muscle in response to chronic energy deprivation. Proc Natl Acad Sci USA. 2002;99:15983–7. https://doi.org/10.1073/pnas.252625599.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Patade GR, Marita AR. Metformin: a journey from countryside to the bedside. J Obes Metab Res. 2014;1(2):127.

    Article  Google Scholar 

  70. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167–74. https://doi.org/10.1172/JCI13505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348:607–14.

    Article  CAS  Google Scholar 

  72. Hawley SA, Ross FA, Chevtzoff C, Green KA, Evans A, Fogarty S, Towler MC, Brown LJ, Ogunbayo OA, Evans AM, et al. Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab. 2010;11:554–65. https://doi.org/10.1016/j.cmet.2010.04.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Foretz M, Hébrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, Sakamoto K, Andreelli F, Viollet B. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010;120:2355–69. https://doi.org/10.1172/jci40671.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Fryer LG, Parbu-Patel A, Carling D. The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem. 2002;277:25226–32. https://doi.org/10.1074/jbc.M202489200.

    Article  CAS  PubMed  Google Scholar 

  75. LeBrasseur NK, Kelly M, Tsao TS, Farmer SR, Saha AK, Ruderman NB, Tomas E. Thiazolidinediones can rapidly activate AMP-activated protein kinase in mammalian tissues. Am J Physiol Endocrinol Metab. 2006;291:E175–81. https://doi.org/10.1152/ajpendo.00453.2005.

    Article  CAS  PubMed  Google Scholar 

  76. Saha AK, Avilucea PR, Ye JM, Assifi MM, Kraegen EW, Ruderman NB. Pioglitazone treatment activates AMP-activated protein kinase in rat liver and adipose tissue in vivo. Biochem Biophys Res Commun. 2004;314:580–5. https://doi.org/10.1016/j.bbrc.2003.12.120.

    Article  CAS  PubMed  Google Scholar 

  77. Brunmair B, Staniek K, Gras F, Scharf N, Althaym A, Clara R, Roden M, Gnaiger E, Nohl H, Waldhäusl W, et al. Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes. 2004;53:1052–9. https://doi.org/10.2337/diabetes.53.4.1052.

    Article  CAS  PubMed  Google Scholar 

  78. Bungau S, Abdel-Daim MM, Tit DM, Ghanem E, Sato S, Maruyama-Inoue M, Yamane S, Kadonosono K. Health benefits of polyphenols and carotenoids in age-related eye diseases. Oxid Med Cell Longev. 2019. https://doi.org/10.1155/2019/9783429.

    Article  PubMed  PubMed Central  Google Scholar 

  79. AlBasher G, Abdel-Daim MM, Almeer R, Ibrahim KA, Hamza RZ, Bungau S, Aleya L. Synergistic antioxidant effects of resveratrol and curcumin against fipronil-triggered oxidative damage in male albino rats. Environ Sci Pollut Res. 2020;27:6505–14. https://doi.org/10.1007/s11356-019-07344-8.

    Article  CAS  Google Scholar 

  80. Ahn J, Lee H, Kim S, Park J, Ha T. The anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathways. Biochem Biophys Res Commun. 2008;373:545–9. https://doi.org/10.1016/j.bbrc.2008.06.077.

    Article  CAS  PubMed  Google Scholar 

  81. Lee YS, Kim WS, Kim KH, Yoon MJ, Cho HJ, Shen Y, Ye JM, Lee CH, Oh WK, Kim CT, et al. Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes. 2006;55:2256–64. https://doi.org/10.2337/db06-0006.

    Article  CAS  PubMed  Google Scholar 

  82. Bungau SG, Popa V-C. Between religion and science some aspects concerning illness and healing in antiquity. Transylv Rev. 2015;24:3–18.

    Google Scholar 

  83. Hwang JT, Kwon DY, Yoon SH. AMP-activated protein kinase: a potential target for the diseases prevention by natural occurring polyphenols. N Biotechnol. 2009;26:17–22. https://doi.org/10.1016/j.nbt.2009.03.005.

    Article  CAS  PubMed  Google Scholar 

  84. Lin YC, Hung CM, Tsai JC, Lee JC, Chen YL, Wei CW, Kao JY, Way TD. Hispidulin potently inhibits human glioblastoma multiforme cells through activation of AMP-activated protein kinase (AMPK). J Agric Food Chem. 2010;58:9511–7. https://doi.org/10.1021/jf1019533.

    Article  CAS  PubMed  Google Scholar 

  85. Turner N, Li JY, Gosby A, To SW, Cheng Z, Miyoshi H, Taketo MM, Cooney GJ, Kraegen EW, James DE, et al. Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes. 2008;57:1414–8. https://doi.org/10.2337/db07-1552.

    Article  CAS  PubMed  Google Scholar 

  86. Glevitzky I, Dumitrel GA, Glevitzky M, Pasca B, Otrisal P, Bungau S, Cioca G, Pantis C, Popa M. Statistical analysis of the relationship between antioxidant activity and the structure of flavonoid compounds. Rev Chim. 2019;70:3103–7.

    Article  CAS  Google Scholar 

  87. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006;444:337–42. https://doi.org/10.1038/nature05354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Park CE, Kim MJ, Lee JH, Min BI, Bae H, Choe W, Kim SS, Ha J. Resveratrol stimulates glucose transport in C2C12 myotubes by activating AMP-activated protein kinase. Exp Mol Med. 2007;39:222–9. https://doi.org/10.1038/emm.2007.25.

    Article  CAS  PubMed  Google Scholar 

  89. Kim T, Davis J, Zhang AJ, He X, Mathews ST. Curcumin activates AMPK and suppresses gluconeogenic gene expression in hepatoma cells. Biochem Biophys Res Commun. 2009;388:377–82. https://doi.org/10.1016/j.bbrc.2009.08.018.

    Article  CAS  PubMed  Google Scholar 

  90. Gledhill JR, Montgomery MG, Leslie AG, Walker JE. Mechanism of inhibition of bovine F1-ATPase by resveratrol and related polyphenols. Proc Natl Acad Sci USA. 2007;104:13632–7. https://doi.org/10.1073/pnas.0706290104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zheng J, Ramirez VD. Inhibition of mitochondrial proton F0F1-ATPase/ATP synthase by polyphenolic phytochemicals. Br J Pharmacol. 2000;130:1115–23. https://doi.org/10.1038/sj.bjp.0703397.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. de la Luz C-G, Olivares-Vicente M, Herranz-López M, Arraez-Roman D, Fernández-Arroyo S, Micol V, Segura-Carretero A. Bioassay-guided purification of Lippia citriodora polyphenols with AMPK modulatory activity. J Funct Foods. 2018;46:514–20. https://doi.org/10.1016/j.jff.2018.05.026.

    Article  CAS  Google Scholar 

  93. Olivares-Vicente M, Sánchez-Marzo N, Encinar JA, Cádiz-Gurrea MD, Lozano-Sánchez J, Segura-Carretero A, Arraez-Roman D, Riva C, Barrajón-Catalán E, Herranz-López M, Micol V. The potential synergistic modulation of AMPK by Lippia citriodora compounds as a target in metabolic disorders. Nutrients. 2019;11(12):2961. https://doi.org/10.3390/nu11122961.

    Article  PubMed Central  Google Scholar 

  94. Campbell NK, Fitzgerald HK, Fletcher JM, Dunne A. Plant-derived polyphenols modulate human dendritic cell metabolism and immune function via AMPK-dependent induction of heme oxygenase-1. Front Immunol. 2019;1(10):345. https://doi.org/10.3389/fimmu.2019.00345.

    Article  CAS  Google Scholar 

  95. Tan Y, Kim J, Cheng J, Ong M, Lao WG, Jin XL, Lin YG, Xiao L, Zhu XQ, Qu XQ. Green tea polyphenols ameliorate non-alcoholic fatty liver disease through upregulating AMPK activation in high fat fed Zucker fatty rats. World J Gastroenterol. 2017;23(21):3805. https://doi.org/10.3748/wjg.v23.i21.3805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Vlavcheski F, Naimi M, Murphy B, Hudlicky T, Tsiani E. Rosmarinic acid, a rosemary extract polyphenol, increases skeletal muscle cell glucose uptake and activates AMPK. Molecules. 2017;22(10):1669. https://doi.org/10.3390/molecules22101669.

    Article  CAS  PubMed Central  Google Scholar 

  97. Xiong R, Zhou XG, Tang Y, Wu JM, Sun YS, Teng JF, Pan R, Law BY, Zhao Y, Qiu WQ, Wang XL. Lychee seed polyphenol protects the blood–brain barrier through inhibiting Aβ (25–35)-induced NLRP3 inflammasome activation via the AMPK/mTOR/ULK1-mediated autophagy in bEnd. 3 cells and APP/PS1 mice. Phytother Res. 2020. https://doi.org/10.1002/ptr.6849.

    Article  PubMed  Google Scholar 

  98. Kim H, Krenek KA, Fang C, Minamoto Y, Markel ME, Suchodolski JS, Talcott ST, Mertens-Talcott SU. Polyphenolic derivatives from mango (Mangifera Indica L.) modulate fecal microbiome, short-chain fatty acids production and the HDAC1/AMPK/LC3 axis in rats with DSS-induced colitis. J Funct Foods. 2018;48:243–51. https://doi.org/10.1016/j.jff.2018.07.011.

    Article  CAS  Google Scholar 

  99. Wang Y, Li X, Guo Y, Chan L, Guan X. Alpha-lipoic acid increases energy expenditure by enhancing AMPK-PGC-1α signalling in the skeletal muscle of aged mice. Metabolism. 2010;59:967–76. https://doi.org/10.1016/j.metabol.2009.10.018.

    Article  CAS  PubMed  Google Scholar 

  100. Park KG, Min AK, Koh EH, Kim HS, Kim MO, Park HS, Kim YD, Yoon TS, Jang BK, Hwang JS, et al. Alpha-lipoic acid decreases hepatic lipogenesis through adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent pathways. Hepatology. 2008;48:1477–86. https://doi.org/10.1002/hep.22496.

    Article  CAS  PubMed  Google Scholar 

  101. Kim MS, Park JY, Namkoong C, Jang PG, Ryu JW, Song HS, Yun JY, Namgoong IS, Ha J, Park IS, et al. Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med. 2004;10:727–33. https://doi.org/10.1038/nm1061.

    Article  CAS  PubMed  Google Scholar 

  102. Lee WJ, Lee IK, Kim HS, Kim YM, Koh EH, Won JC, Han SM, Kim MS, Jo I, Oh GT, et al. Alpha-lipoic acid prevents endothelial dysfunction in obese rats via activation of AMP-activated protein kinase. Arterioscler Thromb Vasc Biol. 2005;25:2488–94. https://doi.org/10.1161/01.ATV.0000190667.33224.4c.

    Article  CAS  PubMed  Google Scholar 

  103. Lee Y, Naseem RH, Park BH, Garry DJ, Richardson JA, Schaffer JE, Unger RH. Alpha-lipoic acid prevents lipotoxic cardiomyopathy in acyl CoA-synthase transgenic mice. Biochem Biophys Res Commun. 2006;344:446–52. https://doi.org/10.1016/j.bbrc.2006.03.062.

    Article  CAS  PubMed  Google Scholar 

  104. Shen QW, Zhu MJ, Tong J, Ren J, Du M. Ca2+/calmodulin-dependent protein kinase kinase is involved in AMP-activated protein kinase activation by alpha-lipoic acid in C2C12 myotubes. Am J Physiol Cell Physiol. 2007;293:C1395–403. https://doi.org/10.1152/ajpcell.00115.2007.

    Article  CAS  PubMed  Google Scholar 

  105. Gruzman A, Shamni O, Ben Yakir M, Sandovski D, Elgart A, Alpert E, Cohen G, Hoffman A, Katzhendler Y, Cerasi E, et al. Novel D-xylose derivatives stimulate muscle glucose uptake by activating AMP-activated protein kinase alpha. J Med Chem. 2008;51:8096–108. https://doi.org/10.1021/jm8008713.

    Article  CAS  PubMed  Google Scholar 

  106. Kim E, Kim YS, Kim KM, Jung S, Yoo SH, Kim Y. D-Xylose as a sugar complement regulates blood glucose levels by suppressing phosphoenolpyruvate carboxylase (PEPCK) in streptozotocin-nicotinamide-induced diabetic rats and by enhancing glucose uptake in vitro. Nutr Res Pract. 2016;10:11–8. https://doi.org/10.4162/nrp.2016.10.1.11.

    Article  CAS  PubMed  Google Scholar 

  107. Kim J, Yang G, Kim Y, Kim J, Ha J. AMPK activators: mechanisms of action and physiological activities. Exp Mol Med. 2016;48: e224. https://doi.org/10.1038/emm.2016.16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, Wang Y, Wang Z, Si S, Pan H, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med. 2004;10:1344–51. https://doi.org/10.1038/nm1135.

    Article  CAS  PubMed  Google Scholar 

  109. Yin J, Gao Z, Liu D, Liu Z, Ye J. Berberine improves glucose metabolism through induction of glycolysis. Am J Physiol Endocrinol Metab. 2008;294:E148–56. https://doi.org/10.1152/ajpendo.00211.2007.

    Article  CAS  PubMed  Google Scholar 

  110. Mohanan P, Subramaniyam S, Mathiyalagan R, Yang DC. Molecular signaling of ginsenosides Rb1, Rg1, and Rg3 and their mode of actions. J Ginseng Res. 2018;42(2):123–32. https://doi.org/10.1016/j.jgr.2017.01.008.

    Article  PubMed  Google Scholar 

  111. Wang CCL, Galinkin JL, Hiatt WR. Toxicity of a novel therapeutic agent targeting mitochondrial complex I. Clin Pharmacol Ther. 2015;98:551–9. https://doi.org/10.1002/cpt.178.

    Article  CAS  Google Scholar 

  112. Guigas B, Sakamoto K, Taleux N, Reyna SM, Musi N, Viollet B, Hue L. Beyond AICA riboside: in search of new specific AMP-activated protein kinase activators. IUBMB Life. 2009;61:18–26. https://doi.org/10.1002/iub.135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Göransson O, McBride A, Hawley SA, Ross FA, Shpiro N, Foretz M, Viollet B, Hardie DG, Sakamoto K. Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase. J Biol Chem. 2007;282:32549–60. https://doi.org/10.1074/jbc.M706536200.

    Article  CAS  PubMed  Google Scholar 

  114. Xiao B, Sanders MJ, Carmena D, Bright NJ, Haire LF, Underwood E, Patel BR, Heath RB, Walker PA, Hallen S, et al. Structural basis of AMPK regulation by small molecule activators. Nat Commun. 2013. https://doi.org/10.1038/ncomms4017.

    Article  PubMed  Google Scholar 

  115. Reymond P, Farmer EE. Jasmonate and salicylate as global signals for defense gene expression. Curr Opin Plant Biol. 1998;1:404–11. https://doi.org/10.1016/s1369-5266(98)80264-1.

    Article  CAS  PubMed  Google Scholar 

  116. Valgimigli M. The remarkable story of a wonder drug, which now comes to an end in the primary prevention setting: say bye-bye to aspirin! Eur Heart J. 2019;40:618–20. https://doi.org/10.1093/eurheartj/ehy872.

    Article  PubMed  Google Scholar 

  117. Jeffreys D. Aspirin: the remarkable story of a wonder drug. 1st ed. USA: Bloomsbury; 2008.

    Google Scholar 

  118. Hawley SA, Fullerton MD, Ross FA, Schertzer JD, Chevtzoff C, Walker KJ, Peggie MW, Zibrova D, Green KA, Mustard KJ, et al. The ancient drug salicylate directly activates AMP-activated protein kinase. Science. 2012;336:918–22. https://doi.org/10.1126/science.1215327.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Fleischman A, Shoelson SE, Bernier R, Goldfine AB. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care. 2008;31:289–94. https://doi.org/10.2337/dc07-1338.

    Article  CAS  PubMed  Google Scholar 

  120. Goldfine AB, Conlin PR, Halperin F, Koska J, Permana P, Schwenke D, Shoelson SE, Reaven PD. A randomised trial of salsalate for insulin resistance and cardiovascular risk factors in persons with abnormal glucose tolerance. Diabetologia. 2013;56:714–23. https://doi.org/10.1007/s00125-012-2819-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Gómez-Galeno JE, Dang Q, Nguyen TH, Boyer SH, Grote MP, Sun Z, Chen M, Craigo WA, van Poelje PD, MacKenna DA, et al. A potent and selective AMPK activator that inhibits de novo lipogenesis. ACS Med Chem Lett. 2010;1:478–82. https://doi.org/10.1021/ml100143q.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Hunter R, Foretz M, Bultot L, Fullerton M, Deak M, Ross F, Hawley S, Shpiro N, Viollet B, Barron D, et al. Mechanism of action of compound-13: an α1-selective small molecule activator of AMPK. Chem Biol. 2014;21:866–79. https://doi.org/10.1016/j.chembiol.2014.05.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Mo Y, Zhu J, Jiang A, Zhao J, Ye L, Han B. Compound 13 activates AMPK-Nrf2 signaling to protect neuronal cells from oxygen glucose deprivation-reoxygenation. Aging (Albany NY). 2019;11:12032–42. https://doi.org/10.18632/aging.102534.

    Article  CAS  Google Scholar 

  124. Zadra G, Photopoulos C, Tyekucheva S, Heidari P, Weng QP, Fedele G, Liu H, Scaglia N, Priolo C, Sicinska E, et al. A novel direct activator of AMPK inhibits prostate cancer growth by blocking lipogenesis. EMBO Mol Med. 2014;6:519–38. https://doi.org/10.1002/emmm.201302734.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Yuan X, Cai C, Chen S, Chen S, Yu Z, Balk SP. Androgen receptor functions in castration-resistant prostate cancer and mechanisms of resistance to new agents targeting the androgen axis. Oncogene. 2014;33:2815–25. https://doi.org/10.1038/onc.2013.235.

    Article  CAS  PubMed  Google Scholar 

  126. Corton JM, Gillespie JG, Hawley SA, Hardie DG. 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem. 1995;229:558–65. https://doi.org/10.1111/j.1432-1033.1995.tb20498.x.

    Article  CAS  PubMed  Google Scholar 

  127. Sullivan JE, Carey F, Carling D, Beri RK. Characterisation of 5′-AMP-activated protein kinase in human liver using specific peptide substrates and the effects of 5′-AMP analogues on enzyme activity. Biochem Biophys Res Commun. 1994;200:1551–6. https://doi.org/10.1006/bbrc.1994.1627.

    Article  CAS  PubMed  Google Scholar 

  128. Bergeron R, Previs SF, Cline GW, Perret P, Russell RR, Young LH, Shulman GI. Effect of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside infusion on in vivo glucose and lipid metabolism in lean and obese Zucker rats. Diabetes. 2001;50:1076–82. https://doi.org/10.2337/diabetes.50.5.1076.

    Article  CAS  PubMed  Google Scholar 

  129. Buhl ES, Jessen N, Schmitz O, Pedersen SB, Pedersen O, Holman GD, Lund S. Chronic treatment with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside increases insulin-stimulated glucose uptake and GLUT4 translocation in rat skeletal muscles in a fiber type-specific manner. Diabetes. 2001;50:12–7. https://doi.org/10.2337/diabetes.50.1.12.

    Article  CAS  PubMed  Google Scholar 

  130. Esquejo RM, Salatto CT, Delmore J, Albuquerque B, Reyes A, Shi Y, Moccia R, Cokorinos E, Peloquin M, Monetti M, Barricklow J. Activation of liver AMPK with PF-06409577 corrects NAFLD and lowers cholesterol in rodent and primate preclinical models. EBioMedicine. 2018;31:122–32.

    Article  Google Scholar 

  131. Li XF, Liu XM, Huang DR, Cao HJ, Wang JY. PF-06409577 activates AMPK signalling to protect retinal pigment epithelium cells from UV radiation. Biochem Biophys Res Commun. 2018;501(1):293–9.

    Article  CAS  Google Scholar 

  132. Saltto CT, Miller RA, Cameron KO, Cokorinos E, Reyes A, Ward J, Calbrese MF, Kurumbail RG, Rajamohan F, Kalgutkar AS, et al. Selective activation of AMPK B1-containing isoforms improves kidney function in a rat model of diabetic nephropathy. J Pharmacol Exp Ther. 2017;361(2):303–11.

    Article  Google Scholar 

  133. Myers RW, Guan H-P, Ehrhart J, Petrov A, Prahalada S, Tozzo E, Yang X, Kurtz MM, Yang X, Trujillo M. Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy. Science. 2017;357(6350):507–11.

    Article  CAS  Google Scholar 

  134. Schiattarella GG, Hill JA, Erhart J, Petrov A, Prahalada S, Tozzo E, Yang X, Kurtz MM, Trujillo M, Trotter DG, Feng D. Systemic pan-AMPK activator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy. Science. 2017;357(6350):507–11.

    Article  Google Scholar 

  135. Cokorinos EC, Delmore J, Reyes AR, Albuquerque B, Kjøbsted R, Jørgensen NO, Tran JL, Jatkar A, Cialdea K, Esquejo RM, Meissen J. Activation of skeletal muscle AMPK promotes glucose disposal and glucose lowering in non-human primates and mice. Cell metab. 2017;25(5):1147–59.

    Article  CAS  Google Scholar 

  136. Sun G, You Y, Li H, Cheng Y, Qian M, Zhou X, Yuan H, Xu QL, Dai L, Wang P, Cheng K. Discovery of AdipoRon analogues as novel AMPK activators without inhibiting mitochondrial complex I. Eur J Med Chem. 2020;200: 112466.

    Article  CAS  Google Scholar 

  137. Schmoll D, Ziegler N, Viollet B, Foretz M, Even PC, Azzout-Marniche D, Nygaard Madsen A, Illemann M, Mandrup K, Feigh M, Czech J. Activation of adenosine monophosphate—activated protein kinase reduces the onset of diet-induced hepatocellular carcinoma in mice. Hepatol Commun. 2020;4(7):1056–72.

    Article  CAS  Google Scholar 

  138. Iglesias MA, Ye JM, Frangioudakis G, Saha AK, Tomas E, Ruderman NB, Cooney GJ, Kraegen EW. AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats. Diabetes. 2002;51:2886–94. https://doi.org/10.2337/diabetes.51.10.2886.

    Article  CAS  PubMed  Google Scholar 

  139. Olivier S, Foretz M, Viollet B. Promise and challenges for direct small molecule AMPK activators. Biochem Pharmacol. 2018;153:147–58. https://doi.org/10.1016/j.bcp.2018.01.049.

    Article  CAS  PubMed  Google Scholar 

  140. Drummond MJ, Dreyer HC, Fry CS, Glynn EL, Rasmussen BB. Nutritional and contractile regulation of human skeletal muscle protein synthesis and mTORC1 signaling. J Appl Physiol. 1985;2009(106):1374–84. https://doi.org/10.1152/japplphysiol.91397.2008.

    Article  CAS  Google Scholar 

  141. McKiernan SH, Colman RJ, Lopez M, Beasley T, Aiken JM, Anderson RM, Weindruch R. Caloric restriction delays aging-induced cellular phenotypes in rhesus monkey skeletal muscle. Exp Gerontol. 2011;46:23–9. https://doi.org/10.1016/j.exger.2010.09.011.

    Article  CAS  PubMed  Google Scholar 

  142. Lu Q, Li X, Liu J, Sun X, Rousselle T, Ren D, Tong N, Li J. AMPK is associated with the beneficial effects of antidiabetic agents on cardiovascular diseases. Biosci Rep. 2019;39: BSR20181995. https://doi.org/10.1042/bsr20181995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Singh M, Sharma R, Kumar A. Safety of SGLT2 inhibitors in patients with diabetes mellitus. Curr Drug Saf. 2019;14(2):87–93.

    Article  CAS  Google Scholar 

  144. Singh M, Kumar A. Risks associated with SGLT2 inhibitors: an overview. Curr Drug Saf. 2018;13(2):84–91.

    Article  CAS  Google Scholar 

  145. Mercken EM, Crosby SD, Lamming DW, JeBailey L, Krzysik-Walker S, Villareal D, Capri M, Franceschi C, Zhang Y, Becker K, et al. Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile. Aging Cell. 2013;12:645–51. https://doi.org/10.1111/acel.12088.

    Article  CAS  PubMed  Google Scholar 

  146. O’Brien AJ, Villani LA, Broadfield LA, Houde VP, Galic S, Blandino G, Kemp BE, Tsakiridis T, Muti P, Steinberg GR. Salicylate activates AMPK and synergizes with metformin to reduce the survival of prostate and lung cancer cells ex vivo through inhibition of de novo lipogenesis. Biochem J. 2015;469:177–87. https://doi.org/10.1042/BJ20150122.

    Article  CAS  PubMed  Google Scholar 

  147. Ducommun S, Ford RJ, Bultot L, Deak M, Bertrand L, Kemp BE, Steinberg GR, Sakamoto K. Enhanced activation of cellular AMPK by dual-small molecule treatment: AICAR and A769662. Am J Physiol Endocrinol Metab. 2014;306:E688–96. https://doi.org/10.1152/ajpendo.00672.2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Bultot L, Jensen TE, Lai YC, Madsen ALB, Collodet C, Kviklyte S, Deak M, Yavari A, Foretz M, Ghaffari S, et al. Benzimidazole derivative small-molecule 991 enhances AMPK activity and glucose uptake induced by AICAR or contraction in skeletal muscle. Am J Physiol Endocrinol Metab. 2016;311:E706–19. https://doi.org/10.1152/ajpendo.00237.2016.

    Article  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Chitkara College of Pharmacy, Chitkara University, Punjab, India

    Tapan Behl, Amit Gupta, Aayush Sehgal, Sanchay Sharma, Sukhbir Singh & Neelam Sharma

  2. Internal Medicine Department, Clinical Emergency Hospital of Bucharest, Bucharest, Romania

    Camelia Cristina Diaconu

  3. Department 5, ‘Carol Davila’ University of Medicine and Pharmacy, Bucharest, Romania

    Camelia Cristina Diaconu

  4. Department of Physics, University of Zabol, Zabol, Iran

    Abbas Rahdar

  5. Glocal School of Pharmacy, Glocal University, Mirzapur, Uttar Pradesh, India

    Abdul Hafeez

  6. Amity Institute of Pharmacy, Amity University, Haryana, India

    Saurabh Bhatia

  7. Natural and Medical Sciences Research Center, University of Nizwa, Nizwa, Oman

    Saurabh Bhatia & Ahmed Al-Harrasi

  8. Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania

    Simona Bungau

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All authors have equally contributed to this paper. All authors have read and agreed with the final form of this manuscript. Conceptualization: TB and AG; software: TB and OF; investigation: TB, AG, SB, OF, and CCD; writing—original draft preparation: TB, AG, and SB; writing—review and editing: TB, SB, and CCD; supervision: TB and SBU; proof read: SB and AAH.

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Behl, T., Gupta, A., Sehgal, A. et al. A spotlight on underlying the mechanism of AMPK in diabetes complications. Inflamm. Res. 70, 939–957 (2021). https://doi.org/10.1007/s00011-021-01488-5

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