Diabetes & Metabolism Journal

Original Articles

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

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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

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245 Download
12 Web of Science
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Abstract PDF Supplementary Material PubReader 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

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68 Download
18 Web of Science
16 Crossref

Abstract PDF PubReader

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
An updated systematic review and dose-response meta-analysis of the effects of α-lipoic acid supplementation on glycemic markers in adults
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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