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Drug/Regimen
Metformin Preserves Peripheral Nerve Damage with Comparable Effects to Alpha Lipoic Acid in Streptozotocin/High-Fat Diet Induced Diabetic Rats
Sun Hee Kim, Tae Sun Park, Heung Yong Jin
Diabetes Metab J. 2020;44(6):842-853.   Published online May 28, 2020
DOI: https://doi.org/10.4093/dmj.2019.0190
  • 6,303 View
  • 178 Download
  • 12 Web of Science
  • 12 Crossref
AbstractAbstract PDFPubReader   ePub   
Background

Metformin is widely marketed medication for the treatment of diabetes, but its pharmacological effect on diabetic peripheral neuropathy remains unclear. In this study, the effect of metformin on peripheral nerves in diabetic rats was investigated using diverse neuronal parameters of nerve fibers.

Methods

Rats were assigned to one of four groups (n=7 to 10 per group): normal, diabetes mellitus (DM), DM+metformin (100 mg/kg), and DM+alpha lipoic acid (ALA, 100 mg/kg). DM was induced by streptozotocin/high-fat diet (STZ/HFD). After 12 weeks, the sensory thresholds to mechanical and heat stimuli were assessed. Repeated sensory tests, immunofluorescence microscopic comparison of peripheral nerves, and biochemical blood analysis were performed after 24 weeks.

Results

Both DM+metformin and DM+ALA groups showed similar trends to diverse sensory tests at 24 weeks compared to DM group although the degree of change were different according to the stimulated senses. There was no significant difference in the comparison of the intraepidermal nerve fiber density (IENFD) of peripheral nerves between the DM+metformin and DM+ALA groups (11.83±0.07 fibers/mm vs. 12.37±1.82 fibers/mm, respectively). Both groups showed preserved IENFD significantly compared with DM group (8.46±1.98 fibers/mm, P<0.05). Sciatic nerve morphology of the experimental animals showed a similar trend to the IENFD, with respect to axonal diameter, myelin sheath thickness, and myelinated fiber diameter.

Conclusion

Metformin has beneficial pharmacological effects on the preservation of peripheral nerves in diabetic rats and its effects are comparable to those of ALA.

Citations

Citations to this article as recorded by  
  • Metformin improves diabetic neuropathy by reducing inflammation through up-regulating the expression of miR-146a and suppressing oxidative stress
    Fengmin Liu, Fangqin You, Lihang Yang, Siyun Wang, Diya Xie
    Journal of Diabetes and its Complications.2024; 38(6): 108737.     CrossRef
  • Effect of Metformin on the Functional and Electrophysiological Recovery of Crush Injury-Induced Facial Nerve Paralysis in Diabetic Rats
    Kyung Hoon Sun, Cheol Hee Choi, Gwang-Won Cho, Chul Ho Jang
    Journal of Personalized Medicine.2023; 13(9): 1317.     CrossRef
  • Is metformin neuroprotective against diabetes mellitus-induced neurodegeneration? An updated graphical review of molecular basis
    Fatemeh Karami, Hamidreza Jamaati, Natalie Coleman-Fuller, Maryam Shokrian Zeini, A. Wallace Hayes, Mina Gholami, Mahsa Salehirad, Mohammad Darabi, Majid Motaghinejad
    Pharmacological Reports.2023; 75(3): 511.     CrossRef
  • Early Diagnosis through Estimation of Inflammatory Biomarkers and the Neuroprotective Role of Metformin in Diabetic Peripheral Neuropathy
    Laxmi Sri, Prabhakar Orsu
    International Journal of Pharmaceutical Sciences and Nanotechnology(IJPSN).2023; 16(2): 6427.     CrossRef
  • Bidirectional association between diabetic peripheral neuropathy and vitamin B12 deficiency: Two longitudinal 9-year follow-up studies using a national sample cohort
    Heung Yong Jin, Kyung Ae Lee, Yu Ji Kim, In Sun Gwak, Tae Sun Park, Sang Woo Yeom, Jong Seung Kim
    Primary Care Diabetes.2023; 17(5): 436.     CrossRef
  • An overview of painful diabetic peripheral neuropathy: Diagnosis and treatment advancements
    Jonathan M. Hagedorn, Alyson M. Engle, Tony K. George, Jay Karri, Newaj Abdullah, Erik Ovrom, Jhon E. Bocanegra-Becerra, Ryan S. D'Souza
    Diabetes Research and Clinical Practice.2022; 188: 109928.     CrossRef
  • The role of MicroRNA networks in tissue-specific direct and indirect effects of metformin and its application
    Qinzhi Yang, Gang Wang, Dan Fang, Xiaojun Gao, Yu Liang, Liqun Wang, Jianbo Wu, Min Zeng, Mao Luo
    Biomedicine & Pharmacotherapy.2022; 151: 113130.     CrossRef
  • Is metformin a possible treatment for diabetic neuropathy?
    Juechun Wei, Yanling Wei, Meiyan Huang, Peng Wang, Shushan Jia
    Journal of Diabetes.2022; 14(10): 658.     CrossRef
  • Metformin as a potential therapeutic for neurological disease: mobilizing AMPK to repair the nervous system
    Sarah Demaré, Asha Kothari, Nigel A. Calcutt, Paul Fernyhough
    Expert Review of Neurotherapeutics.2021; 21(1): 45.     CrossRef
  • Metformin Preserves Peripheral Nerve Damage with Comparable Effects to Alpha Lipoic Acid in Streptozotocin/High-Fat Diet Induced Diabetic Rats (Diabetes Metab J 2020;44:842-53)
    Bo Kyung Koo
    Diabetes & Metabolism Journal.2021; 45(1): 125.     CrossRef
  • Metformin Preserves Peripheral Nerve Damage with Comparable Effects to Alpha Lipoic Acid in Streptozotocin/High-Fat Diet Induced Diabetic Rats (Diabetes Metab J 2020;44:842-53)
    Sun Hee Kim, Tae Sun Park, Heung Yong Jin
    Diabetes & Metabolism Journal.2021; 45(1): 127.     CrossRef
  • Impacts of statin and metformin on neuropathy in patients with type 2 diabetes mellitus: Korean Health Insurance data
    Hong Ki Min, Se Hee Kim, Jong Han Choi, Kyomin Choi, Hae-Rim Kim, Sang-Heon Lee
    World Journal of Clinical Cases.2021; 9(33): 10198.     CrossRef
Drug/Regimen
γ-Linolenic Acid versus α-Lipoic Acid for Treating Painful Diabetic Neuropathy in Adults: A 12-Week, Double-Placebo, Randomized, Noninferiority Trial
Jong Chul Won, Hyuk-Sang Kwon, Seong-Su Moon, Sung Wan Chun, Chong Hwa Kim, Ie Byung Park, In Joo Kim, Jihyun Lee, Bong Yun Cha, Tae Sun Park
Diabetes Metab J. 2020;44(4):542-554.   Published online November 4, 2019
DOI: https://doi.org/10.4093/dmj.2019.0099
  • 8,141 View
  • 248 Download
  • 13 Web of Science
  • 16 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background

This study was a multicenter, parallel-group, double-blind, double-dummy, randomized, noninferiority trial to evaluate the efficacy and safety of γ-linolenic acid (GLA) relative to α-lipoic acid (ALA) over a 12-week treatment period in type 2 diabetes mellitus (T2DM) patients with painful diabetic peripheral neuropathy (DPN).

Methods

This study included 100 T2DM patients between 20 and 75 years of age who had painful DPN and received either GLA (320 mg/day) and placebo or ALA (600 mg/day) and placebo for 12 weeks. The primary outcome measures were mean changes in pain intensities as measured by the visual analogue scale (VAS) and the total symptom scores (TSS).

Results

Of the 100 subjects who initially participated in the study, 73 completed the 12-week treatment period. Per-protocol analyses revealed significant decreases in the mean VAS and TSS scores compared to baseline in both groups, but there were no significant differences between the groups. The treatment difference for the VAS (95% confidence interval [CI]) between the two groups was −0.65 (−1.526 to 0.213) and the upper bound of the 95% CI did not exceed the predefined noninferiority margin (δ1=0.51). For the TSS, the treatment difference was −0.05 (−1.211 to 1.101) but the upper bound of the 95% CI crossed the noninferiority margin (δ2=0.054). There were no serious adverse events associated with the treatments.

Conclusion

GLA treatment in patients with painful DPN was noninferior to ALA in terms of reducing pain intensity measured by the VAS over 12 weeks.

Citations

Citations to this article as recorded by  
  • Cell metabolism pathways involved in the pathophysiological changes of diabetic peripheral neuropathy
    Yaowei Lv, Xiangyun Yao, Xiao Li, Yuanming Ouyang, Cunyi Fan, Yun Qian
    Neural Regeneration Research.2024; 19(3): 598.     CrossRef
  • Diyabet Tedavisinde Antioksidan Etki: Alfa Lipoik Asit
    Umut DALMIŞ, Emine Merve EKİCİ
    Avrasya Sağlık Bilimleri Dergisi.2024; 7(1): 68.     CrossRef
  • Ranking Alpha Lipoic Acid and Gamma Linolenic Acid in Terms of Efficacy and Safety in the Management of Adults With Diabetic Peripheral Neuropathy: A Systematic Review and Network Meta-analysis
    Mario B. Prado, Karen Joy B. Adiao
    Canadian Journal of Diabetes.2024;[Epub]     CrossRef
  • Comprehensive comparison of a new technology with traditional methods for extracting Ougan (Citrus reticulata cv. Suavissima) seed oils: Physicochemical properties, fatty acids, functional components, and antioxidant activities
    Huaxia Yang, Yudan Lin, Xiaoxu Zhu, Haishuo Mu, Yi Li, Shuangyang Chen, Jia Li, Xuedan Cao
    LWT.2024; 197: 115857.     CrossRef
  • Genetic and Transcriptomic Background of Oxidative Stress and Antioxidative Therapies in Late Complications of Type 2 Diabetes Mellitus: A Systematic Review
    Gašper Tonin, Vita Dolžan, Jasna Klen
    Antioxidants.2024; 13(3): 277.     CrossRef
  • Antinociceptive effects of gamma-linolenic acid in the formalin test in the rats
    Kaveh Rahimi, Arman Nourishirazi, Hamidreza Delaviz, Zohreh Ghotbeddin
    Annals of Medicine & Surgery.2024; 86(5): 2677.     CrossRef
  • Alpha-lipoic acid activates AMPK to protect against oxidative stress and apoptosis in rats with diabetic peripheral neuropathy
    Tianya Zhang, Dong Zhang, Zhihong Zhang, Jiaxin Tian, Jingwen An, Wang Zhang, Ying Ben
    Hormones.2023; 22(1): 95.     CrossRef
  • Pathogenetic treatments for diabetic peripheral neuropathy
    Dan Ziegler
    Diabetes Research and Clinical Practice.2023; 206: 110764.     CrossRef
  • Omega-3 Nutrition Therapy for the Treatment of Diabetic Sensorimotor Polyneuropathy
    Deepak Menon, Evan J. H. Lewis, Bruce A. Perkins, Vera Bril
    Current Diabetes Reviews.2022;[Epub]     CrossRef
  • Effect of Alpha-Lipoic Acid in the Treatment of Diabetic Neuropathy: A Systematic Review
    Saleh A Abubaker, Abdulaziz M Alonazy, Albasseet Abdulrahman
    Cureus.2022;[Epub]     CrossRef
  • Insight into the possible mechanism(s) involved in the antinociceptive and antineuropathic activity of Descurainia sophia L. Webb ex Prantl essential oil
    Donya Ziafatdoost Abed, Sajjad Jabbari, Zainul Amiruddin Zakaria, Saeed Mohammadi
    Journal of Ethnopharmacology.2022; 298: 115638.     CrossRef
  • A novel approach to alpha-lipoic acid therapy in the treatment of diabetic peripheral neuropathy
    Alicja Sementina, Mateusz Cierzniakowski, Julia Rogalska, Izabela Piechowiak, Marek Spichalski, Aleksandra Araszkiewicz
    Journal of Medical Science.2022; : e714.     CrossRef
  • Pathogenesis and Treatment of Diabetic Peripheral Neuropathy
    Seon Mee Kang
    The Journal of Korean Diabetes.2022; 23(4): 222.     CrossRef
  • Diabetic Neuropathy: a Critical, Narrative Review of Published Data from 2019
    Ameet S. Nagpal, Jennifer Leet, Kaitlyn Egan, Rudy Garza
    Current Pain and Headache Reports.2021;[Epub]     CrossRef
  • Therapeutic Potential of Ursolic Acid in Cancer and Diabetic Neuropathy Diseases
    Manzar Alam, Sabeeha Ali, Sarfraz Ahmed, Abdelbaset Mohamed Elasbali, Mohd Adnan, Asimul Islam, Md. Imtaiyaz Hassan, Dharmendra Kumar Yadav
    International Journal of Molecular Sciences.2021; 22(22): 12162.     CrossRef
  • Diagnosis and treatment of the early stages of diabetic polyneuropathy
    V. N. Khramilin, A. N. Zavyalov, I. Yu. Demidova
    Meditsinskiy sovet = Medical Council.2020; (7): 56.     CrossRef
Clinical Diabetes & Therapeutics
Effects of High-Dose α-Lipoic Acid on Heart Rate Variability of Type 2 Diabetes Mellitus Patients with Cardiac Autonomic Neuropathy in Korea
Sol Jae Lee, Su Jin Jeong, Yu Chang Lee, Yong Hoon Lee, Jung Eun Lee, Chong Hwa Kim, Kyung Wan Min, Bong Yun Cha
Diabetes Metab J. 2017;41(4):275-283.   Published online July 6, 2017
DOI: https://doi.org/10.4093/dmj.2017.41.4.275
  • 4,990 View
  • 69 Download
  • 18 Web of Science
  • 16 Crossref
AbstractAbstract PDFPubReader   
Background

Diabetic cardiac autonomic neuropathy (CAN) is one of the important complications of diabetes. It is characterized by reduced heart rate variability (HRV).

Methods

In this randomized, double-blind, placebo-controlled, multicenter trial, 75 patients were randomly assigned to one of two groups. One group (n=41) received α-lipoic acid (ALA) at an oral dose of 600 mg/day for the first 12 weeks and then 1,200 mg/day for the next 12 weeks. The other group (n=34) received placebo treatment for 24 weeks. CAN was assessed by measuring HRVs in people with diabetes.

Results

Most of the baseline measures for HRVs were similar between the ALA and placebo groups. Although there were no statistically significant HRV changes in the ALA group compared to the placebo group after 24 weeks of trial, we found a positive tendency in some of the HRV parameters of the ALA group. The standard deviations of normal-to-normal RR intervals in the standing position increased by 1.87 ms in the ALA group but decreased by −3.97 ms in the placebo group (P=0.06). The power spectrum of the low frequency (LF) band in the standing position increased by 15.77 ms2 in the ALA group, whereas it declined by −15.04 ms2 in the placebo group (P=0.08). The high frequency/LF ratio in the upright position increased by 0.35 in the ALA group, whereas it declined by −0.42 in the placebo group (P=0.06). There were no differences between the two groups regarding rates of adverse events.

Conclusion

Although a slight improvement tendency was seen in HRV in the ALA group, there were no statistically significant HRV changes in the ALA group compared to the placebo group after 24 weeks of trial. However, the high oral dose of ALA was well-tolerated.

Citations

Citations to this article as recorded by  
  • Effect of Ramipril on Cardiac Autonomic Neuropathy in Patients With Type II Diabetes Mellitus
    Chaitali A Chindhalore, Ganesh N Dakhale, Prathamesh H Kamble, Bharatsing D Rathod, Sunita Kumbhalkar, Mrunal S Phatak
    Cureus.2023;[Epub]     CrossRef
  • Evaluating treatment options for cardiovascular autonomic neuropathy in patients with diabetes mellitus: a systematic review
    Jasmine KaiLi Goh, Leroy Koh
    Diabetology International.2023; 14(3): 224.     CrossRef
  • The effects of alpha lipoic acid (ALA) supplementation on blood pressure in adults: a GRADE-assessed systematic review and dose-response meta-analysis of randomized controlled trials
    Mahdi Vajdi, Nooshin Noshadi, Shirin Hassanizadeh, Atefeh Bonyadian, Hooria Seyedhosseini-Ghaheh, Gholamreza Askari
    Frontiers in Cardiovascular Medicine.2023;[Epub]     CrossRef
  • Combination Therapy of Alpha-Lipoic Acid, Gliclazide and Ramipril Protects Against Development of Diabetic Cardiomyopathy via Inhibition of TGF-β/Smad Pathway
    George J. Dugbartey, Quinsker L. Wonje, Karl K. Alornyo, Louis Robertson, Ismaila Adams, Vincent Boima, Samuel D. Mensah
    Frontiers in Pharmacology.2022;[Epub]     CrossRef
  • Diabetic Gastroenteropathy: Soothe the Symptoms or Unravel a Cure?
    Sondre Meling, Davide Bertoli, Dag A. Sangnes, Christina Brock, Asbjørn Drewes, Niels Ejskjaer, Georg Dimcevski, Eirik Søfteland
    Current Diabetes Reviews.2022;[Epub]     CrossRef
  • 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
    Aliyu Tijani Jibril, Ahmad Jayedi, Sakineh Shab-Bidar
    Endocrine Connections.2022;[Epub]     CrossRef
  • Cardiac Autonomic Neuropathy in Type 1 and 2 Diabetes: Epidemiology, Pathophysiology, and Management
    Scott Williams, Siddig Abdel Raheim, Muhammad Ilyas Khan, Umme Rubab, Prathap Kanagala, Sizheng Steven Zhao, Anne Marshall, Emily Brown, Uazman Alam
    Clinical Therapeutics.2022; 44(10): 1394.     CrossRef
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    Mahsa Mahmoudi-Nezhad, Mahdi Vajdi, Mahdieh Abbasalizad Farhangi
    Nutrition.2021; 82: 111041.     CrossRef
  • Management of diabetic neuropathy
    Simona Cernea, Itamar Raz
    Metabolism.2021; 123: 154867.     CrossRef
  • Effect of alpha-lipoic acid on arterial stiffness parameters in type 2 diabetes mellitus patients with cardiac autonomic neuropathy
    Victoria A. Serhiyenko, Ludmila M. Serhiyenko, Volodymyr B. Sehin, Alexandr A. Serhiyenko
    Endocrine Regulations.2021; 55(4): 224.     CrossRef
  • The Role of Alpha-lipoic Acid Supplementation in the Prevention of Diabetes Complications: A Comprehensive Review of Clinical Trials
    Sarah Jeffrey, Punitha Isaac Samraj, Behin Sundara Raj
    Current Diabetes Reviews.2021;[Epub]     CrossRef
  • Safety Evaluation of α-Lipoic Acid Supplementation: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Clinical Studies
    Federica Fogacci, Manfredi Rizzo, Christoffer Krogager, Cormac Kennedy, Coralie M.G. Georges, Tamara Knežević, Evangelos Liberopoulos, Alexandre Vallée, Pablo Pérez-Martínez, Eliane F.E. Wenstedt, Agnė Šatrauskienė, Michal Vrablík, Arrigo F.G. Cicero
    Antioxidants.2020; 9(10): 1011.     CrossRef
  • Update on the Impact, Diagnosis and Management of Cardiovascular Autonomic Neuropathy in Diabetes: What Is Defined, What Is New, and What Is Unmet
    Vincenza Spallone
    Diabetes & Metabolism Journal.2019; 43(1): 3.     CrossRef
  • Alpha-lipoic acid (ALA) supplementation effect on glycemic and inflammatory biomarkers: A Systematic Review and meta- analysis
    Mehran Rahimlou, Maryam Asadi, Nasrin Banaei Jahromi, Anahita Mansoori
    Clinical Nutrition ESPEN.2019; 32: 16.     CrossRef
  • Response: Effects of High-Dose α-Lipoic Acid on Heart Rate Variability of Type 2 Diabetes Mellitus Patients with Cardiac Autonomic Neuropathy in Korea (Diabetes Metab J 2017;41:275-83)
    Chong Hwa Kim, Sol Jae Lee, Bong Yun Cha
    Diabetes & Metabolism Journal.2017; 41(5): 420.     CrossRef
  • Letter: Effects of High-Dose α-Lipoic Acid on Heart Rate Variability of Type 2 Diabetes Mellitus Patients with Cardiac Autonomic Neuropathy in Korea (Diabetes Metab J2017;41:275-83)
    Jeongmin Lee, Jae Hyoung Cho
    Diabetes & Metabolism Journal.2017; 41(5): 417.     CrossRef

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