ALPHA-LIPOIC ACID IN TYPE 2 DIABETES MELLITUS: MECHANISMS, CLINICAL BENEFITS, AND IMPLEMENTATION IN THERAPY
DOI:
https://doi.org/10.22159/ajpcr.2024v17i12.51657Keywords:
Alpha Lipoic Acid, Type 2 Diabetes Mellitus, ALA, Diabetic Neuropathy, Antioxidant,, Anti-inflammatoryAbstract
Diabetes Mellitus (DM) encompasses a range of metabolic disorders marked by persistent high blood glucose levels. Type 2 Diabetes Mellitus (T2DM), the more common form of the disease is characterized by insulin resistance and partial insulin deficiency. The primary contributors to mortality and morbidity in diabetes are its vascular complications. Alpha-Lipoic Acid (ALA) is an antioxidant derived from caprylic acid and synthesized within the mitochondria. Extensive research shows that ALA aids in preventing and treating Diabetic Neuropathy (DN), lowers the risk of diabetes in at-risk individuals and is also beneficial for those with impaired glucose tolerance. Therefore, this review article aims to explore the different aspects of ALA and its beneficial effects on individuals with T2DM. A range of articles from databases such as Springer, Wiley, Web of Science, PubMed, Google Scholar, SCOPUS, Embase and Cochrane were examined. References from these articles were also analysed to broaden the search for pertinent reviews. Administering ALA in T2DM was found to have beneficial effects like anti-oxidant, anti-inflammatory, enhance glucose uptake, prevents diabetic neuropathy, neuroprotective, anti-obesity, cardio-protective, reno-protective, prevent diabetic retinopathy, anti-aging and improve metabolic parameters in Polycystic Ovary Syndrome (PCOS). Incorporating ALA into a comprehensive treatment plan, combined with lifestyle changes and standard therapies could improve patient outcome and enhance the quality of life for those managing T2DM and related conditions.
Downloads
References
Kosasih FR, Bonavida B. YY1-mediated Regulation of type 2 Diabetes Via Insulin. YY1 in the Control of the Pathogenesis and Drug Resistance of Cancer. Vol. 1. Netherlands: Elsevier; 2021. p. 271-87.
Thota S, Akbar A. Insulin. In: StatPearls. Treasure Island, FL: StatPearls; 2024.
Cole JB, Florez JC. Genetics of diabetes mellitus and diabetes complications. Nat Rev Nephrol. 2020;16(7):377-90. doi: 10.1038/ s41581-020-0278-5, PMID 32398868
Cho NH, Shaw JE, Karuranga S, Huang Y, Da Rocha Fernandes JD, Ohlrogge AW, et al. IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract. 2018;138:271-81. doi: 10.1016/j.diabres.2018.02.023, PMID 29496507
Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H, WHO Multinational Study Group. Mortality and causes of death in the WHO multinational study of vascular disease in diabetes. Diabetologia. 2001;44(Suppl 2):S14-21. doi: 10.1007/pl00002934, PMID 11587045
Da Rocha Fernandes J, Ogurtsova K, Linnenkamp U, Guariguata L, Seuring T, Zhang P, et al. IDF diabetes atlas estimates of 2014 global health expenditures on diabetes. Diabetes Res Clin Pract. 2016;117:48-54. doi: 10.1016/j.diabres.2016.04.016, PMID 27329022
Sloan G, Selvarajah D, Tesfaye S. Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy. Nat Rev Endocrinol. 2021;17(7):400-20. doi: 10.1038/s41574-021-00496-z, PMID 34050323
Malik RA, Andag-Silva A, Dejthevaporn C, Hakim M, Koh JS, Pinzon R, et al. Diagnosing peripheral neuropathy in South-East Asia: A focus on diabetic neuropathy. J Diabetes Investig. 2020;11(5):1097-3. doi: 10.1111/jdi.13269, PMID 32268012
Ziegler D, Papanas N, Vinik AI, Shaw JE. Epidemiology of polyneuropathy in diabetes and prediabetes. Handb Clin Neurol. 2014;126:3-22. doi: 10.1016/B978-0-444-53480-4.00001-1, PMID 25410210
Hsieh RY, Huang IC, Chen C, Sung JY. Effects of oral alpha-lipoic acid treatment on diabetic polyneuropathy: A meta-analysis and systematic review. Nutrients. 2023;15(16):3634. doi: 10.3390/nu15163634, PMID 37630823
Vallianou N, Evangelopoulos A, Koutalas P. Alpha-lipoic acid and diabetic neuropathy. Rev Diabet Stud. 2009;6(4):230-6. doi: 10.1900/ RDS.2009.6.230, PMID 20043035
Cutolo E, Reduzzi F. Acido tioctico inibisce l’insorgere del diabete da allossana nel ratto [Thioctic acid inhibition of development of alloxan diabetes in rats]. Boll Soc Ital Biol Sper. 1955;31(11-2):1532-3. PMID 13329205
Sladki E, Maldyk H, Prusinski A. Treatment of polyneuritic complications in diabetes with thioctic acid. Pol Tyg Lek. 1963;18:16-8. PMID 13989153
Klein W. Die Behandlung der Neuropathia diabetica mit oralen Gaben von alpha-Liponsäure [Treatment of diabetic neuropathy with oral alpha-lipoic acid (author’s transl)]. MMW Münch Med Wochenschr. 1975;117(22):957-8. PMID 807811
Fasipe B, Faria A, Laher I. Potential for novel therapeutic uses of alpha lipoic acid. Curr Med Chem. 2023;30(35):3942-54. doi: 10.2174/0929 867329666221006115329, PMID 36201272
Faust A, Burkart V, Ulrich H, Weischer CH, Kolb H. Effect of lipoic acid on cyclophosphamide-induced diabetes and insulitis in non-obese diabetic mice. Int J Immunopharmacol. 1994;16(1):61-6. doi: 10.1016/0192-0561(94)90119-8, PMID 8150556
Al-Mosawi A. The use of alpha-lipoic acid supplementation in diabetes: The available evidence. Int J Clin Med Edu Res. 2022;2(1):4-7.
Banday MZ, Sameer AS, Nissar S. Pathophysiology of diabetes: An overview. Avicenna J Med. 2020;10(4):174-88. doi: 10.4103/ajm. ajm_53_20, PMID 33437689
Medscape.com. Type 2 Diabetes Mellitus Guidelines; 2024. Available from: https://emedicine.medscape.com/article/117853- guidelines?form=fpf
Kesavadev J, Jawad F, Deeb A, Coetzee A, Ansari MA, Shrestha D, et al. Pathophysiology of Type 2 Diabetes. In: The Diabetes Textbook. Cham: Springer International Publishing; 2023. p. 127-42.
Salehi B, Berkay Yılmaz Y, Antika G, Boyunegmez Tumer T, Fawzi Mahomoodally M, Lobine D, et al. Insights on the use of α-lipoic acid for therapeutic purposes. Biomolecules. 2019;9(8):356. doi: 10.3390/ biom9080356, PMID 31405030
Reed LJ. From lipoic acid to multi-enzyme complexes. Protein Sci. 1998;7(1):220-4. doi: 10.1002/pro.5560070125, PMID 9514279
Teichert J, Kern J, Tritschler HJ, Ulrich H, Preiss R. Investigations on the pharmacokinetics of alpha-lipoic acid in healthy volunteers. Int J Clin Pharmacol Ther. 1998;36(12):625-8. PMID 9876998
Carlson DA, Smith AR, Fischer SJ, Young KL, Packer L. The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)- lipoate to healthy human subjects. Altern Med Rev. 2007;12(4):343-51. PMID 18069903
Florenzo M, Cinzia N, Giorgio G, Valerio N, Piera DM. Human bioavailability and pharmacokinetic profile of different formulations delivering. Alpha Lipoic Acid. Open Access Sci Rep. 2012;1:1-6.
Akiba S, Matsugo S, Packer L, Konishi T. Assay of protein-bound lipoic acid in tissues by a new enzymatic method. Anal Biochem. 1998;258(2):299-304. doi: 10.1006/abio.1998.2615, PMID 9570844
Wollin SD, Jones PJ. Alpha-lipoic acid and cardiovascular disease. J Nutr. 2003;133(11):3327-30. doi: 10.1093/jn/133.11.3327, PMID 14608040
Brufani M. α-lipoic acid drug or supplement. An overview of pharmacokinetics, available formulations, and clinical evidence in diabetes complications. Prog Nutr. 2014;16:62-74.
Rochette L, Ghibu S, Muresan A, Vergely C. Alpha-lipoic acid: Molecular mechanisms and therapeutic potential in diabetes. Can J Physiol Pharmacol. 2015;93(12):1021-7. doi: 10.1139/cjpp-2014-0353, PMID 26406389
Zhang WJ, Frei B. Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in human aortic endothelial cells. FASEB J. 2001;15(13):2423-32. doi: 10.1096/fj.01- 0260com, PMID 11689467
He L, He T, Farrar S, Ji L, Liu T, Ma X. Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species. Cell Physiol Biochem. 2017;44(2):532-53. doi: 10.1159/000485089, PMID 29145191
Kehrer JP. The Haber-Weiss reaction and mechanisms of toxicity. Toxicology. 2000;149(1):43-50. doi: 10.1016/s0300-483x(00)00231-6, PMID 10963860
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. doi: 10.2174/15680266156 66150114161358, PMID 25620240
Liu Z, Guo J, Sun H, Huang Y, Zhao R, Yang X. α-lipoic acid attenuates LPS-induced liver injury by improving mitochondrial function in association with GR mitochondrial DNA occupancy. Biochimie. 2015;116:52-60. doi: 10.1016/j.biochi.2015.06.023, PMID 26133658
Estrada DE, Ewart HS, Tsakiridis T, Volchuk A, Ramlal T, Tritschler H, et al. 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. doi: 10.2337/ diab.45.12.1798, PMID 8922368
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. doi: 10.1007/s001250050047, PMID 10768090
Viana MD, Lauria PS, De Lima AA, Opretzka LC, Marcelino HR, Villarreal CF. Alpha-lipoic acid as an antioxidant strategy for managing neuropathic pain. Antioxidants (Basel). 2022;11(12):2420. doi: 10.3390/antiox11122420, PMID 36552628
Mijnhout GS, Kollen BJ, Alkhalaf A, Kleefstra N, Bilo HJ. Alpha lipoic Acid for symptomatic peripheral neuropathy in patients with diabetes: A meta-analysis of randomized controlled trials. Int J Endocrinol. 2012;2012:456279. doi: 10.1155/2012/456279, PMID 22331979
Xu Q, Pan J, Yu J, Liu X, Liu L, Zuo X, et al. Meta-analysis of methylcobalamin alone and in combination with lipoic acid in patients with diabetic peripheral neuropathy. Diabetes Res Clin Pract. 2013;101(2):99-105. doi: 10.1016/j.diabres.2013.03.033, PMID 23664235
Liu F, Zhang Y, Yang M, Liu B, Shen YD, Jia WP, et al. Curative effect of alpha-lipoic acid on peripheral neuropathy in type 2 diabetes: A clinical study. Zhonghua Yi Xue Za Zhi. 2007;87(38):2706-9. PMID 18167250
Sadeghiyan Galeshkalami NS, Abdollahi M, Najafi R, Baeeri M, Jamshidzade A, Falak R, et al. Alpha-lipoic acid and coenzyme Q10 combination ameliorates experimental diabetic neuropathy by modulating oxidative stress and apoptosis. Life Sci. 2019;216:101-10. doi: 10.1016/j.lfs.2018.10.055, PMID 30393023
Choi K, Kim J, Kim H, Kim KT, Kim HS, Kim JT, et al. Alpha-lipoic acid treatment is neurorestorative and promotes functional recovery after stroke in rats. J Neurol Sci. 2013;333:e195. doi: 10.1016/j. jns.2013.07.784
Wang Q, Lv C, Sun Y, Han X, Wang S, Mao Z, et al. The role ofalpha-lipoic acid in the pathomechanism of acute ischemic stroke. Cell Physiol Biochem. 2018;48(1):42-53. doi: 10.1159/000491661, PMID 29996116
Yan T, Zhang Z, Li D. NGF receptors and PI3K/AKT pathway involved in glucose fluctuation-induced damage to neurons and α-lipoic acid treatment. BMC Neurosci. 2020;21(1):38. doi: 10.1186/s12868-020- 00588-y, PMID 32943002
Namazi N, Larijani B, Azadbakht L. Alpha-lipoic acid supple ment in obesity treatment: A systematic review and meta-analysis of clinical trials. Clin Nutr. 2018;37(2):419-28. doi: 10.1016/j.clnu.2017.06.002, PMID 28629898
Koh EH, Lee WJ, Lee SA, Kim EH, Cho EH, Jeong E, et al. Effects of alpha-lipoic acid on body weight in obese subjects. Am J Med. 2011;124(1):85.e1-8. doi: 10.1016/j.amjmed.2010.08.005, PMID 21187189
Carbonelli MG, Di Renzo L, Bigioni M, Di Daniele N, De Lorenzo A, Fusco MA. Alpha-lipoic acid supplementation: A tool for obesity therapy? Curr Pharm Des. 2010;16(7):840-6. doi: 10.2174/138161210790883589, PMID 20388095
Lee KM, Park KG, Kim YD, Lee HJ, Kim HT, Cho WH, et al. Alpha-Lipoic acid inhibits fractalkine expression and prevents neointimal hyperplasia after balloon injury in rat carotid artery. Atherosclerosis. 2006;189(1):106-14. doi: 10.1016/j.atherosclerosis.2005.12.003, PMID 16413026
Kamimura D, Ishihara K, Hirano T. IL-6 signal transduction and its physiological roles: The signal orchestration model. Rev Physiol Biochem Pharmacol. 2003;149:1-38. doi: 10.1007/s10254-003-0012-2, PMID 12687404
Sola S, Mir MQ, Cheema FA, Khan-Merchant N, Menon RG, Parthasarathy S, et al. Irbesartan and lipoic acid improve endothelial function and reduce markers of inflammation in the metabolic syndrome: Results of the irbesartan and lipoic acid in Endothelial Dysfunction (ISLAND) study. Circulation. 2005;111(3):343-8. doi: 10.1161/01.CIR.0000153272.48711.B9, PMID 15655130
Duann P, Lin PH. Mitochondria damage and kidney disease. Adv Exp Med Biol. 2017;982:529-51. doi: 10.1007/978-3-319-55330-6_27, PMID 28551805
Song Y, Yu H, Sun Q, Pei F, Xia Q, Gao Z, et al. Grape seed proanthocyanidin extract targets p66Shc to regulate mitochondrial biogenesis and dynamics in diabetic kidney disease. Front Pharmacol. 2022;13:1035755. doi: 10.3389/fphar.2022.1035755, PMID 36686673
Cleveland KH, Schnellmann RG. Pharmacological targeting of mitochondria in diabetic kidney disease. Pharmacol Rev. 2023;75(2):250- 62. doi: 10.1124/pharmrev.122.000560, PMID 36781216
Mohandes S, Doke T, Hu H, Mukhi D, Dhillon P, Susztak K. Molecular pathways that drive diabetic kidney disease. J Clin Invest. 2023;133(4):e165654. doi: 10.1172/JCI165654, PMID 36787250
Zhang J, McCullough PA. Lipoic acid in the prevention of acute kidney injury. Nephron. 2016;134(3):133-40. doi: 10.1159/000448666, PMID 27603173
Zhang HF, Liu HM, Xiang JY, Zhou XC, Wang D, Chen RY, et al. Alpha lipoamide inhibits diabetic kidney fibrosis via improving mitochondrial function and regulating RXRα expression and activation. Acta Pharmacol Sin. 2023;44(5):1051-65. doi: 10.1038/s41401-022- 00997-1, PMID 36347997
Lim PS, Wei YH, Yu YL, Kho B. Enhanced oxidative stress in haemodialysis patients receiving intravenous iron therapy. Nephrol Dial Transplant. 1999;14(11):2680-7. doi: 10.1093/ndt/14.11.2680, PMID 10534512
Roob JM, Khoschsorur G, Tiran A, Horina JH, Holzer H, Winklhofer- Roob BM. Vitamin E attenuates oxidative stress induced by intravenous iron in patients on hemodialysis. J Am Soc Nephrol. 2000;11(3):539-49. doi: 10.1681/ASN.V113539, PMID 10703678.
Leehey DJ, Palubiak DJ, Chebrolu S, Agarwal R. Sodium ferric gluconate causes oxidative stress but not acute renal injury in patients with chronic kidney disease: A pilot study. Nephrol Dial Transplant. 2005;20(1):135-40. doi: 10.1093/ndt/gfh565, PMID 15522899
Lee SJ, Kang JG, Ryu OH, Kim CS, Ihm SH, Choi MG, et al. Effects of α-lipoic acid on transforming growth factor β1-p38 mitogen-activated protein kinase-fibronec tin pathway in diabetic nephropathy. Metabolism. 2009;58(5):616-23. doi: 10.1016/j.metabol.2008.12.006, PMID 19375583
Cavdar Z, Oktan MA, Ural C, Calisir M, Kocak A, Heybeli C, et al. Renoprotec tive effects of alpha lipoic acid on iron overload-induced kidney injury in rats by suppressing NADPH oxidase 4 and p38 MAPK signaling. Biol Trace Elem Res. 2020;193(2):483-93. doi: 10.1007/ s12011-019-01733-3, PMID 31025242
Gao WW, Chun SY, Kim BS, Ha YS, Lee JN, Lee EH, et al. Locally transplanted human urine-induced nephron progenitor cells contribute to renal repair in mice kidney with diabetic nephropathy. Biochem Biophys Res Commun. 2022;629:128-34. doi: 10.1016/j. bbrc.2022.09.015, PMID 36116375
Wu J, Li R, Li W, Ren M, Thangthaeng N, Sumien N, et al. Administration of 5-methoxyindole-2-carboxylic acid that potentially targets mitochondrial dihydrolipoamide dehydrogenase confers cerebral preconditioning against ischemic stroke injury. Free Radic Biol Med. 2017;113:244-54. doi: 10.1016/j.freeradbiomed.2017.10.008, PMID 29017857
Golbidi S, Badran M, Laher I. Diabetes and alpha lipoic Acid. Front Pharmacol. 2011;2:69. doi: 10.3389/fphar.2011.00069, PMID 22125537
Ghibu S, Craciun CE, Rusu R, Morgovan C, Mogosan C, Rochette L, et al. Impact of alpha-lipoic acid chronic discontinuous treatment in cardiometabolic disorders and oxidative stress induced by fructose intake in rats. Antioxidants (Basel). 2019 Dec 11;8(12):636. doi: 10.3390/antiox8120636, PMID 31835800
Prabhakar S, Starnes J, Shi S, Lonis B, Tran R. Diabetic nephropathy is associated with oxidative stress and decreased renal nitric oxide production. J Am Soc Nephrol. 2007;18(11):2945-52. doi: 10.1681/ ASN.2006080895, PMID 17928507
Fong DS, Aiello L, Gardner TW, King GL, Blankenship G, Cavallerano JD, et al. Retinopathy in diabetes. Diabetes Care. 2004;27(Suppl 1):S84-7. doi: 10.2337/diacare.27.2007.S84
Ajith TA. Alpha-lipoic acid: A possible pharmacological agent for treating dry eye disease and retinopathy in diabetes. Clin Exp Pharmacol Physiol. 2020;47(12):1883-90. doi: 10.1111/1440-1681.13373, PMID 32621549
Genazzani AD, Prati A, Marchini F, Petrillo T, Napolitano A, Simoncini T. Differential insulin response to oral glucose tolerance test (OGTT) in overweight/obese polycystic ovary syndrome patients undergoing to myo-inositol (MYO), alpha lipoic acid (ALA), or combination of both. Gynecol Endo crinol. 2019;35:1088-93.
Genazzani AD, Shefer K, Della Casa D, Prati A, Napolitano A, Manzo A, et al. Modulatory effects of alpha lipoic acid (ALA) administration on insulin sensitivity in obese PCOS patients. J Endocrinol Invest. 2018;41(5):583-90. doi: 10.1007/s40618-017-0782-z, PMID 29090431
Nobakht-Haghighi N, Rahimifard M, Baeeri M, Rezvanfar MA, Moini Nodeh S, Haghi-Aminjan H, et al. Regulation of aging and oxidative stress pathways in aged pancreatic islets using alpha-lipoic acid. Mol Cell Biochem. 2018;449(1-2):267-76. doi: 10.1007/s11010-018- 3363-3, PMID 29696608
Moffa S, Improta I, Rocchetti S, Mezza T, Giaccari A. Potential cause-effect relationship between insulin autoimmune syndrome and alpha lipoic acid: Two case reports. Nutrition. 2019;57:1-4. doi: 10.1016/j. nut.2018.04.010, PMID 30086435
Cremer DR, Rabeler R, Roberts A, Lynch B. Safety evaluation of α-lipoic acid (ALA). Regul Toxicol Pharmacol. 2006;46(1):29-41. doi: 10.1016/j.yrtph.2006.06.004, PMID 16904799
Jibril AT, Jayedi A, Shab-Bidar S. Efficacy and safety of oral alpha-lipoic acid supplementation for type 2 diabetes management: A systematic review and dose-response meta-analysis of randomized trials. Endocr Connect. 2022;11(10):e220322. doi: 10.1530/EC-22- 0322, PMID 36006850
Vigil M, Berkson BM, Garcia AP. Adverse effects of high doses of intravenous alpha lipoic Acid on liver mitochondria. Glob Adv Health Med. 2014;3(1):25-7. doi: 10.7453/gahmj.2013.011, PMID 24753992
Published
How to Cite
Issue
Section
Copyright (c) 2024 B DHARANI, STEPHY SEBASTIAN, SUBA A
This work is licensed under a Creative Commons Attribution 4.0 International License.
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.