Biochemical and clinical relevance of alpha lipoic acid: antioxidant and anti-inflammatory activity, molecular pathways and therapeutic potential

Inflammation Research

Volumn 66, Issue 11, 2017, Pages 947-959

  Tibullo, Daniele ^a   Li Volti, Giovanni ^a   Giallongo, Cesarina ^a   Grasso, Sonia ^a   Tomassoni, Daniele ^b   Anfuso, Carmelina Daniela ^a   Lupo, Gabriella ^a   Amenta, Francesco ^b   Avola, Roberto ^a   Bramanti, Vincenzo ^a,c  

^a UNIVERSITY OF CATANIA   (Italy)

^b UNIVERSITY OF CAMERINO   (Italy)

^c Hospital Villa Sofia   (Italy)

Author keywords

Alpha lipoic acid; Antioxidant; Chelation; Free radical scavenger; Glutathione; Inflammation; Therapeutic potential

Indexed keywords

ADENOSINE KINASE; COPPER; GLUTATHIONE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INSULIN RECEPTOR; PHOSPHATASE; PROTEIN KINASE; REACTIVE NITROGEN SPECIES; REACTIVE OXYGEN METABOLITE; THIOCTIC ACID; ZINC; ANTIINFLAMMATORY AGENT; ANTIOXIDANT;

AKT SIGNALING; ALZHEIMER DISEASE; ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; BIOCHEMICAL COMPOSITION; CHELATION; DIABETIC NEUROPATHY; DRUG EFFECT; HUMAN; INSULIN SIGNALING; IRON CHELATION; MALIGNANT NEOPLASM; NONHUMAN; OXIDATIVE STRESS; PROTEIN INTERACTION; REVIEW; SIGNAL TRANSDUCTION; ANIMAL;

ANIMALS; ANTI-INFLAMMATORY AGENTS; ANTIOXIDANTS; HUMANS; SIGNAL TRANSDUCTION; THIOCTIC ACID;

EID: 85021842306     PISSN: 10233830     EISSN: 1420908X     Source Type: Journal    
DOI: 10.1007/s00011-017-1079-6     Document Type: Review

References (91)

1. Abdul HM, Butterfield DA. Involvement of PI3K/PKG/ERK1/2 signaling pathways in cortical neurons to trigger protection by cotreatment of acetyl-L-carnitine and alpha-lipoic acid against HNE-mediated oxidative stress and neurotoxicity: implications for Alzheimer’s disease. Free Radic Biol Med. 2007;42(3):371–84.
2. Al Abdan M. Alfa-lipoic acid controls tumor growth and modulates hepatic redox state in Ehrlich-ascites-carcinoma-bearing mice. Sci World J. 2012;2012:509838.
3. Ametov AS, Barinov A, Dyck PJ, Hermann R, Kozlova N, Litchy WJ, Low PA, Nehrdich D, Novosadova M, O’Brien PC, Reljanovic M, Samigullin R, Schuette K, Strokov I, Tritschler HJ, Wessel K, Yakhno N, Ziegler D, S. T. S. Group. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care. 2003;26(3):770–776.
4. Bierhaus A, Chevion S, Chevion M, Hofmann M, Quehenberger P, Illmer T, Luther T, Berentshtein E, Tritschler H, Muller M, Wahl P, Ziegler R, Nawroth PP. Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Diabetes. 1997;46(9):1481–90.
5. Bo L, Dawson TM, Wesselingh S, Mork S, Choi S, Kong PA, Hanley D, Trapp BD. Induction of nitric oxide synthase in demyelinating regions of multiple sclerosis brains. Ann Neurol. 1994;36(5):778–86.
6. Bramanti V, Tomassoni D, Bronzi D, Grasso S, Curro M, Avitabile M, Li Volsi G, Renis M, Ientile R, Amenta F, Avola R. Alpha-lipoic acid modulates GFAP, vimentin, nestin, cyclin D1 and MAP-kinase expression in astroglial cell cultures. Neurochem Res. 2010;35(12):2070–7.
7. Chang MY, Gwon TM, Lee HS, Lee JH, Oh SH, Kim SJ, Park MH. The effect of systemic lipoic acid on hearing preservation after cochlear implantation via the round window approach: a guinea pig model. Eur J Pharmacol. 2017;799:67–72.
8. Cho KJ, Moon HE, Moini H, Packer L, Yoon DY, Chung AS. Alpha-lipoic acid inhibits adipocyte differentiation by regulating pro-adipogenic transcription factors via mitogen-activated protein kinase pathways. J Biol Chem. 2003;278(37):34823–33.
9. Cromheeke KM, Kockx MM, De Meyer GR, Bosmans JM, Bult H, Beelaerts WJ, Vrints CJ, Herman AG. Inducible nitric oxide synthase colocalizes with signs of lipid oxidation/peroxidation in human atherosclerotic plaques. Cardiovasc Res. 1999;43(3):744–54.
10. Diesel B, Kulhanek-Heinze S, Holtje M, Brandt B, Holtje HD, Vollmar AM, Kiemer AK. Alpha-lipoic acid as a directly binding activator of the insulin receptor: protection from hepatocyte apoptosis. Biochemistry. 2007;46(8):2146–55.
11. Duby JJ, Campbell RK, Setter SM, White JR, Rasmussen KA. Diabetic neuropathy: an intensive review. Am J Health Syst Pharm. 2004;61(2):160–173 (quiz 175–166).
12. Durand M, Mach N. Alpha lipoic acid and its antioxidant against cancer and diseases of central sensitization. Nutr Hosp. 2013;28(4):1031–8.
13. El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL, Roeder RG, Cooper ME, Brownlee M. Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med. 2008;205(10):2409–17.
14. Estrada DE, Ewart HS, Tsakiridis T, Volchuk A, Ramlal T, Tritschler H, Klip A. Stimulation of glucose uptake by the natural coenzyme alpha-lipoic acid/thioctic acid: participation of elements of the insulin signaling pathway. Diabetes. 1996;45(12):1798–804.
15. Evans JL, Goldfine ID. Alpha-lipoic acid: a multifunctional antioxidant that improves insulin sensitivity in patients with type 2 diabetes. Diabetes Technol Ther. 2000;2(3):401–13.
16. Feuerecker B, Pirsig S, Seidl C, Aichler M, Feuchtinger A, Bruchelt G, Senekowitsch-Schmidtke R. Lipoic acid inhibits cell proliferation of tumor cells in vitro and in vivo. Cancer Biol Ther. 2012;13(14):1425–35.
17. Gasic-Milenkovic J, Loske C, Munch G. Advanced glycation endproducts cause lipid peroxidation in the human neuronal cell line SH-SY5Y. J Alzheimers Dis. 2003;5(1):25–30.
18. Gerthoffer WT, Singer CA. MAPK regulation of gene expression in airway smooth muscle. Respir Physiol Neurobiol. 2003;137(2–3):237–50.
19. Ghibu S, Richard C, Vergely C, Zeller M, Cottin Y, Rochette L. Antioxidant properties of an endogenous thiol: alpha-lipoic acid, useful in the prevention of cardiovascular diseases. J Cardiovasc Pharmacol. 2009;54(5):391–8.
20. Golbidi S, Badran M, Laher I. Diabetes and alpha lipoic acid. Front Pharmacol. 2011;2:69.
21. Gomes MB, Negrato CA. Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetol Metab Syndr. 2014;6(1):80.
22. Grasso S, Bramanti V, Tomassoni D, Bronzi D, Malfa G, Traini E, Napoli M, Renis M, Amenta F, Avola R. Effect of lipoic acid and alpha-glyceryl-phosphoryl-choline on astroglial cell proliferation and differentiation in primary culture. J Neurosci Res. 2014;92(1):86–94.
23. Guais A, Baronzio G, Sanders E, Campion F, Mainini C, Fiorentini G, Montagnani F, Behzadi M, Schwartz L, Abolhassani M. Adding a combination of hydroxycitrate and lipoic acid (METABLOC) to chemotherapy improves effectiveness against tumor development: experimental results and case report. Invest New Drugs. 2012;30(1):200–11.
24. Hagen TM, Ingersoll RT, Lykkesfeldt J, Liu J, Wehr CM, Vinarsky V, Bartholomew JC, Ames AB. (R)-alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. FASEB J. 1999;13(2):411–8.
25. Hedges JC, Singer CA, Gerthoffer WT. Mitogen-activated protein kinases regulate cytokine gene expression in human airway myocytes. Am J Respir Cell Mol Biol. 2000;23(1):86–94.
26. Henriksen EJ, Jacob S, Streeper RS, Fogt DL, Hokama JY, Tritschler HJ. Stimulation by alpha-lipoic acid of glucose transport activity in skeletal muscle of lean and obese Zucker rats. Life Sci. 1997;61(8):805–12.
27. Hiller S, DeKroon R, Hamlett ED, Xu L, Osorio C, Robinette J, Winnik W, Simington S, Maeda N, Alzate O, Yi X. Alpha-lipoic acid supplementation protects enzymes from damage by nitrosative and oxidative stress. Biochim Biophys Acta. 2016;1860(1 Pt A):36–45.
28. Holmquist L, Stuchbury G, Berbaum K, Muscat S, Young S, Hager K, Engel J, Munch G. Lipoic acid as a novel treatment for Alzheimer’s disease and related dementias. Pharmacol Ther. 2007;113(1):154–64.
29. Jacob S, Henriksen EJ, Tritschler HJ, Augustin HJ, Dietze GJ. Improvement of insulin-stimulated glucose-disposal in type 2 diabetes after repeated parenteral administration of thioctic acid. Exp Clin Endocrinol Diabetes. 1996;104(3):284–8.
30. Jacob S, Ruus P, Hermann R, Tritschler HJ, Maerker E, Renn W, Augustin HJ, Dietze GJ, Rett K. Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Free Radic Biol Med. 1999;27(3–4):309–14.
31. Kates SA, Casale RA, Baguisi A, Beeuwkes R 3rd. Lipoic acid analogs with enhanced pharmacological activity. Bioorg Med Chem. 2014;22(1):505–12.
32. Khanna S, Roy S, Packer L, Sen CK. Cytokine-induced glucose uptake in skeletal muscle: redox regulation and the role of alpha-lipoic acid. Am J Physiol. 1999;276(5 Pt 2):R1327–33.
33. Kim JI, Cho SR, Lee CM, Park ES, Kim KN, Kim HC, Lee HY. Induction of ER stress-mediated apoptosis by alpha-lipoic acid in A549 cell lines. Korean J Thorac Cardiovasc Surg. 2012;45(1):1–10.
34. Kim MS, Park JY, Namkoong C, Jang PG, Ryu JW, Song HS, Yun JY, Namgoong IS, Ha J, Park IS, Lee IK, Viollet B, Youn JH, Lee HK, Lee KU. Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med. 2004;10(7):727–33.
35. Koh G, Yang EJ, Kim MK, Lee SA, Lee DH. Alpha-lipoic acid treatment reverses 2-deoxy-d-ribose-induced oxidative damage and suppression of insulin expression in pancreatic beta-cells. Biol Pharm Bull. 2013;36(10):1570–6.
36. Koprowski H, Zheng YM, Heber-Katz E, Fraser N, Rorke L, Fu ZF, Hanlon C, Dietzschold B. In vivo expression of inducible nitric oxide synthase in experimentally induced neurologic diseases. Proc Natl Acad Sci USA. 1993;90(7):3024–7.
37. Kwiecien B, Dudek M, Bilska-Wilkosz A, Knutelska J, Bednarski M, Kwiecien I, Zygmunt M, Iciek M, Sokolowska-Jezewicz M, Sapa J, Wlodek L. In vivo anti-inflammatory activity of lipoic acid derivatives in mice. Postepy Hig Med Dosw (Online). 2013;67:331–8.
38. Li Volti G, Salomone S, Sorrenti V, Mangiameli A, Urso V, Siarkos I, Galvano F, Salamone F. Effect of silibinin on endothelial dysfunction and ADMA levels in obese diabetic mice. Cardiovasc Diabetol. 2011;10:62.
39. Lovell MA, Markesbery WR. Oxidative damage in mild cognitive impairment and early Alzheimer’s disease. J Neurosci Res. 2007;85(14):3036–40.
40. Lovell MA, Xie C, Xiong S, Markesbery WR. Protection against amyloid beta peptide and iron/hydrogen peroxide toxicity by alpha lipoic acid. J Alzheimers Dis. 2003;5(3):229–39.
41. Mantovani G, Maccio A, Madeddu C, Mura L, Gramignano G, Lusso MR, Murgia V, Camboni P, Ferreli L, Mocci M, Massa E. The impact of different antioxidant agents alone or in combination on reactive oxygen species, antioxidant enzymes and cytokines in a series of advanced cancer patients at different sites: correlation with disease progression. Free Radic Res. 2003;37(2):213–23.
42. Merz PA, Wisniewski HM, Somerville RA, Bobin SA, Masters CL, Iqbal K. Ultrastructural morphology of amyloid fibrils from neuritic and amyloid plaques. Acta Neuropathol. 1983;60(1–2):113–24.
43. Michikoshi H, Nakamura T, Sakai K, Suzuki Y, Adachi E, Matsugo S, Matsumoto K. alpha-Lipoic acid-induced inhibition of proliferation and met phosphorylation in human non-small cell lung cancer cells. Cancer Lett. 2013;335(2):472–8.
44. Moini H, Tirosh O, Park YC, Cho KJ, Packer L. R-alpha-lipoic acid action on cell redox status, the insulin receptor, and glucose uptake in 3T3-L1 adipocytes. Arch Biochem Biophys. 2002;397(2):384–91.
45. Moura FA, de Andrade KQ, dos Santos JC, Goulart MO. Lipoic Acid: its antioxidant and anti-inflammatory role and clinical applications. Curr Top Med Chem. 2015;15(5):458–83.
46. Muller U, Krieglstein J. Prolonged pretreatment with alpha-lipoic acid protects cultured neurons against hypoxic, glutamate-, or iron-induced injury. J Cereb Blood Flow Metab. 1995;15(4):624–30.
47. Nagamatsu M, Nickander KK, Schmelzer JD, Raya A, Wittrock DA, Tritschler H, Low PA. Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care. 1995;18(8):1160–7.
48. Newsholme P, Rebelato E, Abdulkader F, Krause M, Carpinelli A, Curi R. Reactive oxygen and nitrogen species generation, antioxidant defenses, and beta-cell function: a critical role for amino acids. J Endocrinol. 2012;214(1):11–20.
49. Nickander KK, McPhee BR, Low PA, Tritschler H. Alpha-lipoic acid: antioxidant potency against lipid peroxidation of neural tissues in vitro and implications for diabetic neuropathy. Free Radic Biol Med. 1996;21(5):631–9.
50. Ou P, Tritschler HJ, Wolff SP. Thioctic (lipoic) acid: a therapeutic metal-chelating antioxidant? Biochem Pharmacol. 1995;50(1):123–6.
51. Packer L. alpha-Lipoic acid: a metabolic antioxidant which regulates NF-kappa B signal transduction and protects against oxidative injury. Drug Metab Rev. 1998;30(2):245–75.
52. Packer L, Kraemer K, Rimbach G. Molecular aspects of lipoic acid in the prevention of diabetes complications. Nutrition. 2001;17(10):888–95.
53. Packer L, Tritschler HJ, Wessel K. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med. 1997;22(1–2):359–78.
54. Palmer RM, Smith RE. Commentary on viewpoint article by AH Henderson, MJ Lewis, AM Shah, and JA Smith (April, pp 305–308). Cardiovasc Res. 1992;26(6):638.
55. Patrick L. Mercury toxicity and antioxidants: part 1: role of glutathione and alpha-lipoic acid in the treatment of mercury toxicity. Altern Med Rev. 2002;7(6):456–71.
56. Perez-Matos MC, Morales-Alvarez MC, Mendivil CO. Lipids: a suitable therapeutic target in diabetic neuropathy? J Diabetes Res. 2017;2017:6943851.
57. Pick U, Haramaki N, Constantinescu A, Handelman GJ, Tritschler HJ, Packer L. Glutathione reductase and lipoamide dehydrogenase have opposite stereospecificities for alpha-lipoic acid enantiomers. Biochem Biophys Res Commun. 1995;206(2):724–30.
58. Quinn JF, Bussiere JR, Hammond RS, Montine TJ, Henson E, Jones RE, Stackman RW Jr. Chronic dietary alpha-lipoic acid reduces deficits in hippocampal memory of aged Tg2576 mice. Neurobiol Aging. 2007;28(2):213–25.
59. Ramamurthy S, Ronnett G. AMP-activated protein kinase (AMPK) and energy-sensing in the brain. Exp Neurobiol. 2012;21(2):52–60.
60. Roman-Pintos LM, Villegas-Rivera G, Rodriguez-Carrizalez AD, Miranda-Diaz AG, Cardona-Munoz EG. Diabetic polyneuropathy in type 2 Diabetes Mellitus: inflammation, oxidative stress, and mitochondrial function. J Diabetes Res. 2016;2016:3425617.
61. Sacerdoti D, Colombrita C, Ghattas MH, Ismaeil EF, Scapagnini G, Bolognesi M, Li Volti G, Abraham NG. Heme oxygenase-1 transduction in endothelial cells causes downregulation of monocyte chemoattractant protein-1 and of genes involved in inflammation and growth. Cell Mol Biol (Noisy-le-grand). 2005;51(4):363–370.
62. Salinthone S, Yadav V, Bourdette DN, Carr DW. Lipoic acid: a novel therapeutic approach for multiple sclerosis and other chronic inflammatory diseases of the CNS. Endocr Metab Immune Disord Drug Targets. 2008;8(2):132–42.
63. Salomone F, Barbagallo I, Puzzo L, Piazza C, Li Volti G. Efficacy of adipose tissue-mesenchymal stem cell transplantation in rats with acetaminophen liver injury. Stem Cell Res. 2013;11(3):1037–44.
64. Shaw JE, Zimmet PZ, de Courten M, Dowse GK, Chitson P, Gareeboo H, Hemraj F, Fareed D, Tuomilehto J, Alberti KG. Impaired fasting glucose or impaired glucose tolerance. What best predicts future diabetes in Mauritius? Diabetes Care. 1999;22(3):399–402.
65. Shen QW, Zhu MJ, Tong J, Ren J, Du M. Ca2+/calmodulin-dependent protein kinase is involved in AMP-activated protein kinase activation by alpha-lipoic acid in C2C12 myotubes. Am J Physiol Cell Physiol. 2007;293(4):C1395–403.
66. Singer CA, Baker KJ, McCaffrey A, AuCoin DP, Dechert MA, Gerthoffer WT. p38 MAPK and NF-kappaB mediate COX-2 expression in human airway myocytes. Am J Physiol Lung Cell Mol Physiol. 2003;285(5):L1087–98.
67. Smith AR, Shenvi SV, Widlansky M, Suh JH, Hagen TM. Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Curr Med Chem. 2004;11(9):1135–46.
68. Smith AR, Visioli F, Frei B, Hagen TM. Lipoic acid significantly restores, in rats, the age-related decline in vasomotion. Br J Pharmacol. 2008;153(8):1615–22.
69. Steinberg GR, Kemp BE. AMPK in health and disease. Physiol Rev. 2009;89(3):1025–78.
70. Suh JH, Moreau R, Heath SH, Hagen TM. Dietary supplementation with (R)-alpha-lipoic acid reverses the age-related accumulation of iron and depletion of antioxidants in the rat cerebral cortex. Redox Rep. 2005;10(1):52–60.
71. Suh JH, Zhu BZ, deSzoeke E, Frei B, Hagen TM. Dihydrolipoic acid lowers the redox activity of transition metal ions but does not remove them from the active site of enzymes. Redox Rep. 2004;9(1):57–61.
72. Targonsky ED, Dai F, Koshkin V, Karaman GT, Gyulkhandanyan AV, Zhang Y, Chan CB, Wheeler MB. alpha-lipoic acid regulates AMP-activated protein kinase and inhibits insulin secretion from beta cells. Diabetologia. 2006;49(7):1587–98.
73. Tibullo D, Barbagallo I, Giallongo C, La Cava P, Parrinello N, Vanella L, Stagno F, Palumbo GA, Li Volti G, Di Raimondo F. Nuclear translocation of heme oxygenase-1 confers resistance to imatinib in chronic myeloid leukemia cells. Curr Pharm Des. 2013;19(15):2765–70.
74. Tibullo D, Giallongo C, Puglisi F, Tomassoni D, Camiolo G, Cristaldi M, Brundo MV, Anfuso CD, Lupo G, Stampone T, Li Volti G, Amenta F, Avola R, Bramanti V. Effect of lipoic acid on the biochemical mechanisms of resistance to Bortezomib in SH-SY5Y Neuroblastoma Cells. Mol Neurobiol. 2017.
75. Torella D, Leosco D, Indolfi C, Curcio A, Coppola C, Ellison GM, Russo VG, Torella M, Li Volti G, Rengo F, Chiariello M. Aging exacerbates negative remodeling and impairs endothelial regeneration after balloon injury. Am J Physiol Heart Circ Physiol. 2004;287(6):H2850–60.
76. Vallianou N, Evangelopoulos A, Koutalas P. Alpha-lipoic acid and diabetic neuropathy. Rev Diabet Stud. 2009;6(4):230–6.
77. van der Goes A, Brouwer J, Hoekstra K, Roos D, van den Berg TK, Dijkstra CD. Reactive oxygen species are required for the phagocytosis of myelin by macrophages. J Neuroimmunol. 1998;92(1–2):67–75.
78. Vinik AI, Park TS, Stansberry KB, Pittenger GL. Diabetic neuropathies. Diabetologia. 2000;43(8):957–73.
79. Wang Y, Li X, Guo Y, Chan L, Guan X. alpha-Lipoic acid increases energy expenditure by enhancing adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor-gamma coactivator-1alpha signaling in the skeletal muscle of aged mice. Metabolism. 2010;59(7):967–76.
80. Wenk GL. Neuropathologic changes in Alzheimer’s disease: potential targets for treatment. J Clin Psychiatry. 2006;67(Suppl 3):3–7 (quiz 23).
81. Winiarska K, Malinska D, Szymanski K, Dudziak M, Bryla J. Lipoic acid ameliorates oxidative stress and renal injury in alloxan diabetic rabbits. Biochimie. 2008;90(3):450–9.
82. Wong WS. Inhibitors of the tyrosine kinase signaling cascade for asthma. Curr Opin Pharmacol. 2005;5(3):264–71.
83. Xing ZG, Yu GD, Qin L, Jiang F, Zhao WH. Effects and mechanism of lipoic acid on beta-amyloid-intoxicated C6 glioma cells. Genet Mol Res. 2015;14(4):13880–8.
84. Yamamoto Y, Gaynor RB. Therapeutic potential of inhibition of the NF-kappaB pathway in the treatment of inflammation and cancer. J Clin Invest. 2001;107(2):135–42.
85. Yaworsky K, Somwar R, Ramlal T, Tritschler HJ, Klip A. Engagement of the insulin-sensitive pathway in the stimulation of glucose transport by alpha-lipoic acid in 3T3-L1 adipocytes. Diabetologia. 2000;43(3):294–303.
86. Ying Z, Kampfrath T, Sun Q, Parthasarathy S, Rajagopalan S. Evidence that alpha-lipoic acid inhibits NF-kappaB activation independent of its antioxidant function. Inflamm Res. 2011;60(3):219–25.
87. Zhang J, McCullough PA. Lipoic acid in the prevention of acute kidney injury. Nephron. 2016;134(3):133–40.
88. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167–74.
89. Ziegler D, Ametov A, Barinov A, Dyck PJ, Gurieva I, Low PA, Munzel U, Yakhno N, Raz I, Novosadova M, Maus J, Samigullin R. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care. 2006;29(11):2365–70.
90. Ziegler D, Hanefeld M, Ruhnau KJ, Hasche H, Lobisch M, Schutte K, Kerum G, Malessa R. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy. Diabetes Care. 1999;22(8):1296–301.
91. Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabet Med. 2004;21(2):114–21.