Generic placeholder image

Current Diabetes Reviews


ISSN (Print): 1573-3998
ISSN (Online): 1875-6417

Review Article

The Role of Biofactors in Diabetic Microvascular Complications

Author(s): Dan Ziegler*, Massimo Porta, Nikolaos Papanas, Maria Mota, György Jermendy, Elena Beltramo, Aurora Mazzeo, Andrea Caccioppo, Elio Striglia, Victoria Serhiyenko, Alexandr Serhiyenko, László Rosta, Ovidiu Alin Stirban, Zsuzsanna Putz, Ildikó Istenes, Viktor Horváth and Peter Kempler

Volume 18, Issue 4, 2022

Published on: 21 December, 2021

Article ID: e250821195830 Pages: 26

DOI: 10.2174/1871527320666210825112240

open access plus


Microvascular complications are responsible for a major proportion of the burden associated with diabetes contributing to substantial morbidity, mortality, and healthcare burden in people with diabetes. Retinopathy, nephropathy, and neuropathy constitute the leading causes of blindness, end-stage renal disease, and lower-extremity amputations, respectively. Since the efficacy of causal therapies of diabetic microvascular complications is limited, especially in type 2 diabetes, there is an unmet need for adjunct treatments which should be effective despite ongoing hyperglycemia. Experimental studies have indicated that diabetic microvascular complications can be prevented or ameliorated by various biofactors in animal models by interfering with the pathophysiology of the underlying condition. Some of the findings related to biofactors, like α-lipoic acid and benfotiamine, could be translated into the clinical arena and confirmed in clinical trials, especially in those focusing on diabetic polyneuropathy. Given the micronutrient nature of these compounds, their safety profile is excellent. Thus, they have the potential to favorably modify the natural history of the underlying complication, but long-term clinical trials are required to confirm this notion. Ultimately, biofactors should expand our therapeutic armamentarium against these common, debilitating, and even life-threatening sequelae of diabetes.

Keywords: Biofactors, diabetic microvascular complications, diabetic sensorimotor polyneuropathy, cardiovascular autonomic neuropathy, diabetic retinopathy, diabetic nephropathy.

Atlas IDF. IDF diabetes atlas. 9th ed. Available from 2019. Available from: [Cited 2021 January 13]
Harding JL, Pavkov ME, Magliano DJ, Shaw JE, Gregg EW. Global trends in diabetes complications: a review of current evidence. Diabetologia 2019; 62(1): 3-16.
[] [PMID: 30171279]
Eid S, Sas KM, Abcouwer SF, et al. New insights into the mechanisms of diabetic complications: role of lipids and lipid metabolism. Diabetologia 2019; 62(9): 1539-49.
[] [PMID: 31346658]
Ziegler D, Keller J, Maier C, Pannek J. Diabetic neuropathy. Exp Clin Endocrinol Diabetes 2014; 122(7): 406-15.
[] [PMID: 25014092]
Spallone V, Ziegler D, Freeman R, et al. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 2011; 27(7): 639-53.
[] [PMID: 21695768]
Kouidrat Y, Pizzol D, Cosco T, et al. High prevalence of erectile dysfunction in diabetes: a systematic review and meta-analysis of 145 studies. Diabet Med 2017; 34(9): 1185-92.
[] [PMID: 28722225]
Barrett EJ, Liu Z, Khamaisi M, et al. Diabetic microvascular disease: An endocrine society scientific statement. J Clin Endocrinol Metab 2017; 102(12): 4343-410.
[] [PMID: 29126250]
Bönhof GJ, Herder C, Strom A, Papanas N, Roden M, Ziegler D. Emerging biomarkers, tools, and treatments for diabetic polyneuropathy. Endocr Rev 2019; 40(1): 153-92.
[] [PMID: 30256929]
Schellenberg ES, Dryden DM, Vandermeer B, Ha C, Korownyk C. Lifestyle interventions for patients with and at risk for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 2013; 159(8): 543-51.
[] [PMID: 24126648]
Gerstein HC, Miller ME, Genuth S, et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011; 364(9): 818-28.
[] [PMID: 21366473]
Calles-Escandón J, Lovato LC, Simons-Morton DG, et al. Effect of intensive compared with standard glycemia treatment strategies on mortality by baseline subgroup characteristics: the action to control cardiovascular risk in diabetes (ACCORD) trial. Diabetes Care 2010; 33(4): 721-7.
[] [PMID: 20103550]
Bonnefont-Rousselot D. The role of antioxidant micronutrients in the prevention of diabetic complications. Treat Endocrinol 2004; 3(1): 41-52.
[] [PMID: 15743112]
Boulton AJM, Kempler P, Ametov A, Ziegler D. Whither pathogenetic treatments for diabetic polyneuropathy? Diabetes Metab Res Rev 2013; 29(5): 327-33.
[] [PMID: 23381942]
Frank J, Kisters K, Stirban OA, et al. The role of biofactors in the prevention and treatment of age-related diseases. Biofactors 2021; 47(4): 522-50.
[] [PMID: 33772908]
Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature 2001; 414(6865): 813-20.
[] [PMID: 11742414]
Hammes H-P, Du X, Edelstein D, et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med 2003; 9(3): 294-9.
[] [PMID: 12592403]
Beltramo E, Nizheradze K, Berrone E, Tarallo S, Porta M. Thiamine and benfotiamine prevent apoptosis induced by high glucose-conditioned extracellular matrix in human retinal pericytes. Diabetes Metab Res Rev 2009; 25(7): 647-56.
[] [PMID: 19768736]
Jeffrey S, Samraj PI, Raj BS. The role of alpha-lipoic acid supplementation in the prevention of diabetes complications: A comprehensive review of clinical trials. Curr Diabetes Rev 2021; 17(9): e011821190404..
[] [PMID: 33461470]
Dieckmann A, Kriebel M, Andriambeloson E, Ziegler D, Elmlinger M. Treatment with Actovegin® improves sensory nerve function and pathology in streptozotocin-diabetic rats via mechanisms involving inhibition of PARP activation. Exp Clin Endocrinol Diabetes 2012; 120(3): 132-8.
[] [PMID: 22020669]
Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: A position statement by the American diabetes association. Dia Care 2017; 40(1): 136-54.
[] [PMID: 27999003]
Abbott CA, Vileikyte L, Williamson S, Carrington AL, Boulton AJ. Multicenter study of the incidence of and predictive risk factors for diabetic neuropathic foot ulceration. Diabetes Care 1998; 21(7): 1071-5.
[] [PMID: 9653597]
Forsblom CM, Sane T, Groop PH, et al. Risk factors for mortality in Type II (non-insulin-dependent) diabetes: evidence of a role for neuropathy and a protective effect of HLA-DR4. Diabetologia 1998; 41(11): 1253-62.
[] [PMID: 9833930]
Coppini DV, Bowtell PA, Weng C, Young PJ, Sönksen PH. Showing neuropathy is related to increased mortality in diabetic patients - a survival analysis using an accelerated failure time model. J Clin Epidemiol 2000; 53(5): 519-23.
[] [PMID: 10812325]
Young LH, Wackers FJT, Chyun DA, et al. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. JAMA 2009; 301(15): 1547-55.
[] [PMID: 19366774]
Brownrigg JRW, de Lusignan S, McGovern A, et al. Peripheral neuropathy and the risk of cardiovascular events in type 2 diabetes mellitus. Heart 2014; 100(23): 1837-43.
[] [PMID: 25095826]
Ziegler D, Landgraf R, Lobmann R, et al. Painful and painless neuropathies are distinct and largely undiagnosed entities in subjects participating in an educational initiative (PROTECT study). Diabetes Res Clin Pract 2018; 139: 147-54.
[] [PMID: 29518491]
Tesfaye S, Boulton AJM, Dyck PJ, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care 2010; 33(10): 2285-93.
[] [PMID: 20876709]
Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A. Prevalence of polyneuropathy in pre-diabetes and diabetes is associated with abdominal obesity and macroangiopathy: the MONICA/KORA Augsburg Surveys S2 and S3. Diabetes Care 2008; 31(3): 464-9.
[] [PMID: 18039804]
Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA. A practical two-step quantitative clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 1994; 17(11): 1281-9.
[] [PMID: 7821168]
Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen PH. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia 1993; 36(2): 150-4.
[] [PMID: 8458529]
Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia 1995; 38(12): 1425-33.
[] [PMID: 8786016]
Bennett MI, Attal N, Backonja MM, et al. Using screening tools to identify neuropathic pain. Pain 2007; 127(3): 199-203.
[] [PMID: 17182186]
Herder C, Roden M, Ziegler D. Novel insights into sensorimotor and cardiovascular autonomic neuropathy from recent-onset diabetes and population-based cohorts. Trends Endocrinol Metab 2019; 30(5): 286-98.
[] [PMID: 30935671]
Martin CL, Albers JW, Pop-Busui R. Neuropathy and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. Diabetes Care 2014; 37(1): 31-8.
[] [PMID: 24356595]
Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, et al. Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. BMJ 2011; 343: d4169.
[] [PMID: 21791495]
Serhiyenko VA, Serhiyenko AA. Cardiac autonomic neuropathy: Risk factors, diagnosis and treatment. World J Diabetes 2018; 9(1): 1-24.
[] [PMID: 29359025]
Hamilton SJ, Chew GT, Watts GF. Therapeutic regulation of endothelial dysfunction in type 2 diabetes mellitus. Diab Vasc Dis Res 2007; 4(2): 89-102.
[] [PMID: 17654442]
Golbidi S, Badran M, Laher I. Diabetes and alpha lipoic Acid. Front Pharmacol 2011; 2: 69.
[] [PMID: 22125537]
Pitocco D, Tesauro M, Alessandro R, Ghirlanda G, Cardillo C. Oxidative stress in diabetes: implications for vascular and other complications. Int J Mol Sci 2013; 14(11): 21525-50.
[] [PMID: 24177571]
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.
[] [PMID: 26406389]
Serhiyenko V, Serhiyenko L, Serhiyenko A. Alpha-lipoic acid and diabetic cardiac autonomic neuropathy. MOJ Public Health 2019; (8): 1-10.
Vincent AM, Perrone L, Sullivan KA, et al. Receptor for advanced glycation end products activation injures primary sensory neurons via oxidative stress. Endocrinology 2007; 148(2): 548-58.
[] [PMID: 17095586]
Serhiyenko V, Serhiyenko L, Krasnyi M, Serhiyenko A. Alpha-lipoic acid: Therapeutic potential in diabetic neuropathies. Curr Res Diabetes Obes J 2018; 7(3): 555713.
Papanas N, Ziegler D. Efficacy of α-lipoic acid in diabetic neuropathy. Expert Opin Pharmacother 2014; 15(18): 2721-31.
[] [PMID: 25381809]
Ziegler D, Low PA, Litchy WJ, et al. Efficacy and safety of antioxidant treatment with α-lipoic acid over 4 years in diabetic polyneuropathy: the NATHAN 1 trial. Diabetes Care 2011; 34(9): 2054-60.
[] [PMID: 21775755]
Ziegler D, Low PA, Freeman R, Tritschler H, Vinik AI. Predictors of improvement and progression of diabetic polyneuropathy following treatment with α-lipoic acid for 4 years in the NATHAN 1 trial. J Diabetes Complications 2016; 30(2): 350-6.
[] [PMID: 26651260]
Fogacci F, Rizzo M, Krogager C, et al. Safety evaluation of α-lipoic acid supplementation: A systematic review and meta-analysis of randomized placebo-controlled clinical studies. Antioxidants 2020; 9(10): E1011.
[] [PMID: 33086555]
Rahimlou M, Asadi M, Banaei Jahromi N, Mansoori A. Alpha-lipoic acid (ALA) supplementation effect on glycemic and inflammatory biomarkers: A Systematic Review and meta- analysis. Clin Nutr ESPEN 2019; 32: 16-28.
[] [PMID: 31221283]
Mahmoudi-Nezhad M, Vajdi M, Farhangi MA. An updated systematic review and dose-response meta-analysis of the effects of α-lipoic acid supplementation on glycemic markers in adults. Nutrition 2021; 82: 111041.
[] [PMID: 33199187]
Mousavi SM, Shab-Bidar S, Kord-Varkaneh H, Khorshidi M, Djafarian K. Effect of alpha-lipoic acid supplementation on lipid profile: A systematic review and meta-analysis of controlled clinical trials. Nutrition 2019; 59: 121-30.
[] [PMID: 30471524]
Jalilpiran Y, Hajishafiee M, Khorshidi M, et al. The effect of alpha-lipoic acid supplementation on endothelial function: A systematic review and meta-analysis. Phytother Res 2020. [Online ahead of print]
[] [PMID: 33205568]
Vajdi M, Abbasalizad Farhangi M. Alpha-lipoic acid supplementation significantly reduces the risk of obesity in an updated systematic review and dose response meta-analysis of randomised placebo-controlled clinical trials. Int J Clin Pract 2020; 74(6): e13493.
[] [PMID: 32091656]
Reljanovic M, Reichel G, Rett K, et al. Treatment of diabetic polyneuropathy with the antioxidant thioctic acid (alpha-lipoic acid): a two year multicenter randomized double-blind placebo-controlled trial (ALADIN II). Alpha Lipoic Acid in Diabetic Neuropathy. Free Radic Res 1999; 31(3): 171-9.
[] [PMID: 10499773]
Ziegler D, Hanefeld M, Ruhnau KJ, et al. 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.
[] [PMID: 10480774]
Ruhnau KJ, Meissner HP, Finn JR, et al. Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. Diabet Med 1999; 16(12): 1040-3.
[] [PMID: 10656234]
Ametov AS, Barinov A, Dyck PJ, et al. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care 2003; 26(3): 770-6.
[] [PMID: 12610036]
Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care 2006; 29(11): 2365-70.
[] [PMID: 17065669]
El-Nahas MR, Elkannishy G, Abdelhafez H, Elkhamisy ET, El-Sehrawy AA. Oral alpha lipoic acid treatment for symptomatic diabetic peripheral neuropathy: A randomized double-blinded placebo-controlled study. Endocr Metab Immune Disord Drug Targets 2020; 20(9): 1531-4.
[] [PMID: 32370731]
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.
[] [PMID: 14984445]
McIlduff CE, Rutkove SB. Critical appraisal of the use of alpha lipoic acid (thioctic acid) in the treatment of symptomatic diabetic polyneuropathy. Ther Clin Risk Manag 2011; 7: 377-85.
[PMID: 21941444]
Mijnhout GS, Kollen BJ, Alkhalaf A, Kleefstra N, Bilo HJG. Alpha lipoic Acid for symptomatic peripheral neuropathy in patients with diabetes: a meta-analysis of randomized controlled trials. Int J Endocrinol 2012; 2012: 456279.
[] [PMID: 22331979]
Çakici N, Fakkel TM, van Neck JW, Verhagen AP, Coert JH. Systematic review of treatments for diabetic peripheral neuropathy. Diabet Med 2016; 33(11): 1466-76.
[] [PMID: 26822889]
Dy SM, Bennett WL, Sharma R, et al. Preventing complications and treating symptoms of diabetic peripheral neuropathy. Rockville, MD 2017 : Agency for Healthcare Research and Quality (US); Report No.: 17-EHC005-EF.
Amato Nesbit S, Sharma R, Waldfogel JM, et al. Non-pharmacologic treatments for symptoms of diabetic peripheral neuropathy: a systematic review. Curr Med Res Opin 2019; 35(1): 15-25.
[] [PMID: 30114983]
Nguyen N, Takemoto JK. A case for alpha-lipoic acid as an alternative treatment for diabetic polyneuropathy. J Pharm Pharm Sci 2018; 21(1): 177s-91s.
[] [PMID: 30139425]
Xie F, Cheng Z, Li S, et al. Pharmacokinetic study of benfotiamine and the bioavailability assessment compared to thiamine hydrochloride. J Clin Pharmacol 2014; 54(6): 688-95.
[] [PMID: 24399744]
Thornalley PJ, Babaei-Jadidi R, Al Ali H, et al. High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. Diabetologia 2007; 50(10): 2164-70.
[] [PMID: 17676306]
Anwar A, Ahmed Azmi M, Siddiqui JA, Panhwar G, Shaikh F, Ariff M. Thiamine level in type I and type II diabetes mellitus patients: A comparative study focusing on hematological and biochemical evaluations. Cureus 2020; 12(5): e8027.
[PMID: 32528766]
Stracke H, Gaus W, Achenbach U, Federlin K, Bretzel RG. Benfotiamine in diabetic polyneuropathy (BENDIP): results of a randomised, double blind, placebo-controlled clinical study. Exp Clin Endocrinol Diabetes 2008; 116(10): 600-5.
[] [PMID: 18473286]
Haupt E, Ledermann H, Köpcke W. Benfotiamine in the treatment of diabetic polyneuropathy-a three-week randomized, controlled pilot study (BEDIP study). Int J Clin Pharmacol Ther 2005; 43(2): 71-7.
[] [PMID: 15726875]
Ledermann H, Wiedey KD, Ledermann H, Wiedey KD. Behandlung der manifesten diabetischen Polyneuropathie. Therapeutische Wirkung des neurotropen Vitamin-B-Komplexes B1-B6- B12 Treatment of manifest diabetic polyneuropathy. Therapeutic Effect of the Neurotropic Vitamin B Complex B1-B6-B12. Therapiewoche 1989; (39): 1445-9.
Stracke H, Lindemann A, Federlin K. A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes 1996; 104(4): 311-6.
[] [PMID: 8886748]
Fraser DA, Diep LM, Hovden IA, et al. The effects of long-term oral benfotiamine supplementation on peripheral nerve function and inflammatory markers in patients with type 1 diabetes: a 24- month, double-blind, randomized, placebo-controlled trial. Dia Care 2012; 35(5): 1095-7.
[] [PMID: 22446172]
Ziegler D, Tesfaye S, Kempler P. Comment on: Fraser et al. The effects of long-term oral benfotiamine supplementation on peripheral nerve function and inflammatory markers in patients with type 1 diabetes: a 24-month, double-blind, randomized, placebo- controlled trial. Diabetes care 2012; 35: 1095-7.
Du X, Edelstein D, Brownlee M. Oral benfotiamine plus alpha-lipoic acid normalises complication-causing pathways in type 1 diabetes. Diabetologia 2008; 51(10): 1930-2.
[] [PMID: 18663426]
Popa AR, Bungau S, Vesa CM, et al. Evaluating the efficacy of the treatment with benfotiamine and alpha-lipoic acid in distal symmetric painful diabetic polyneuropathy. Rev Chim 2019; 70(9): 3108-14.
Ziegler D, Schleicher E, Strom A, et al. Association of transketolase polymorphisms with measures of polyneuropathy in patients with recently diagnosed diabetes. Diabetes Metab Res Rev 2017; 33(4): e2811.
[] [PMID: 27103086]
Spallone V. Might genetics play a role in understanding and treating diabetic polyneuropathy? Diabetes Metab Res Rev 2017; 33(4): e2882.
[] [PMID: 28032668]
Yang W, Cai X, Wu H, Ji L. Associations between metformin use and vitamin B12 levels, anemia, and neuropathy in patients with diabetes: a meta-analysis. J Diabetes 2019; 11(9): 729-43.
[] [PMID: 30615306]
American Diabetes Association. 11. Microvascular complications and foot care: Standards of medical care in diabetes-2020. Diabetes Care 2020; 43(Suppl. 1): S135-51.
[] [PMID: 31862754]
Didangelos T, Karlafti E, Kotzakioulafi E, et al. Vitamin B12 supplementation in diabetic neuropathy: A 1-year, randomized, double-blind, placebo-controlled trial. Nutrients 2021; 13(2): 395.
[] [PMID: 33513879]
Nix WA, Zirwes R, Bangert V, et al. Vitamin B status in patients with type 2 diabetes mellitus with and without incipient nephropathy. Diabetes Res Clin Pract 2015; 107(1): 157-65.
[] [PMID: 25458341]
Wang D, Zhai J-X, Liu D-W. Serum folate, vitamin B12 levels and diabetic peripheral neuropathy in type 2 diabetes: A meta-analysis. Mol Cell Endocrinol 2017; 443: 72-9.
[] [PMID: 28081987]
Gorson KC, Ropper AH. Additional causes for distal sensory polyneuropathy in diabetic patients. J Neurol Neurosurg Psychiatry 2006; 77(3): 354-8.
[] [PMID: 16484643]
Shevalye H, Watcho P, Stavniichuk R, Dyukova E, Lupachyk S, Obrosova IG. Metanx alleviates multiple manifestations of peripheral neuropathy and increases intraepidermal nerve fiber density in Zucker diabetic fatty rats. Diabetes 2012; 61(8): 2126-33.
[] [PMID: 22751692]
Fonseca VA, Lavery LA, Thethi TK, et al. Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial. Am J Med 2013; 126(2): 141-9.
[] [PMID: 23218892]
Sun Y, Lai M-S, Lu C-J. Effectiveness of vitamin B12 on diabetic neuropathy: systematic review of clinical controlled trials. Acta Neurol Taiwan 2005; 14(2): 48-54.
[PMID: 16008162]
Deng H, Yin J, Zhang J, et al. Meta-analysis of methylcobalamin alone and in combination with prostaglandin E1 in the treatment of diabetic peripheral neuropathy. Endocrine 2014; 46(3): 445-54.
[] [PMID: 24522613]
Xu Q, Pan J, Yu J, 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.
[] [PMID: 23664235]
Sawangjit R, Thongphui S, Chaichompu W, Phumart P. Efficacy and safety of mecobalamin on peripheral neuropathy: A systematic review and meta-analysis of randomized controlled trials. J Altern Complement Med 2020; 26(12): 1117-29.
[] [PMID: 32716261]
Ang CD, Alviar MJM, Dans AL, et al. Vitamin B for treating peripheral neuropathy. Cochrane Database Syst Rev 2008; (3): CD004573.
[PMID: 18646107]
Karaganis S, Song X-J. B vitamins as a treatment for diabetic pain and neuropathy. J Clin Pharm Ther 2021; 46(5): 1199-212.
[] [PMID: 33565138]
Ziegler D, Movsesyan L, Mankovsky B, Gurieva I, Abylaiuly Z, Strokov I. Treatment of symptomatic polyneuropathy with actovegin in type 2 diabetic patients. Diabetes Care 2009; 32(8): 1479-84.
[] [PMID: 19470838]
Ziegler D, Edmundson S, Gurieva I, Mankovsky B, Papanas N, Strokov I. Predictors of response to treatment with actovegin for 6 months in patients with type 2 diabetes and symptomatic polyneuropathy. J Diabetes Complications 2017; 31(7): 1181-7.
[] [PMID: 28438471]
Guekht A, Skoog I, Edmundson S, Zakharov V, Korczyn AD. ARTEMIDA trial (a randomized trial of efficacy, 12 months international double-blind actovegin): A randomized controlled trial to assess the efficacy of actovegin in poststroke cognitive impairment. Stroke 2017; 48(5): 1262-70.
[] [PMID: 28432265]
Radbakhsh S, Barreto GE, Bland AR, Sahebkar A. Curcumin: A small molecule with big functionality against amyloid aggregation in neurodegenerative diseases and type 2 diabetes. Biofactors 2021; 47(4): 570-86.
[] [PMID: 33893674]
Caillaud M, Aung Myo YP, McKiver BD, et al. Key developments in the potential of curcumin for the treatment of peripheral neuropathies. Antioxidants 2020; 9(10): E950.
[] [PMID: 33023197]
Asadi S, Gholami MS, Siassi F, Qorbani M, Khamoshian K, Sotoudeh G. Nano curcumin supplementation reduced the severity of diabetic sensorimotor polyneuropathy in patients with type 2 diabetes mellitus: A randomized double-blind placebo- controlled clinical trial. Complement Ther Med 2019; 43: 253-60.
[] [PMID: 30935539]
Basu P, Maier C, Basu A. Effects of curcumin and its different formulations in preclinical and clinical studies of peripheral neuropathic and postoperative pain: A comprehensive review. Int J Mol Sci 2021; 22(9): 4666.
[] [PMID: 33925121]
Rolim LC, da Silva EM, Flumignan RL, Abreu MM, Dib SA. Acetyl-L-carnitine for the treatment of diabetic peripheral neuropathy. Cochrane Database Syst Rev 2019; 6: CD011265.
[] [PMID: 31201734]
Didangelos T, Karlafti E, Kotzakioulafi E, et al. Efficacy and safety of the combination of superoxide dismutase, alpha lipoic acid, vitamin B12, and carnitine for 12 months in patients with diabetic neuropathy. Nutrients 2020; 12(11): 3254.
[] [PMID: 33114210]
Yorek MA. The potential role of fatty acids in treating diabetic neuropathy. Curr Diab Rep 2018; 18(10): 86.
[] [PMID: 30145729]
Coppey L, Davidson E, Shevalye H, Obrosov A, Torres M, Yorek MA. Progressive loss of corneal nerve fibers and sensitivity in rats modeling obesity and type 2 diabetes is reversible with omega-3 fatty acid intervention: Supporting cornea analyses as a marker for peripheral neuropathy and treatment. Diabetes Metab Syndr Obes 2020; 13: 1367-84.
[] [PMID: 32425569]
Lewis EJH, Perkins BA, Lovblom LE, Bazinet RP, Wolever TMS, Bril V. Effect of omega-3 supplementation on neuropathy in type 1 diabetes: A 12-month pilot trial. Neurology 2017; 88(24): 2294-301.
[] [PMID: 28515269]
Won JC, Kwon HS, Moon SS, et al. γ-linolenic acid versus α-lipoic acid for treating painful diabetic neuropathy in adults: A 12-week, double-placebo, randomized, noninferiority trial. Diabetes Metab J 2020; 44(4): 542-54.
[] [PMID: 31701699]
de Baaij JHF, Hoenderop JGJ, Bindels RJM. Magnesium in man: implications for health and disease. Physiol Rev 2015; 95(1): 1-46.
[] [PMID: 25540137]
Eisinger J, Bagneres D, Arroyo P, Plantamura A, Ayavou T. Effects of magnesium, high energy phosphates, piracetam and thiamin on erythrocyte transketolase. Magnes Res 1994; 7(1): 59-61.
[PMID: 8054263]
Mooren FC. Magnesium and disturbances in carbohydrate metabolism. Diabetes Obes Metab 2015; 17(9): 813-23.
[] [PMID: 25974209]
Gommers LMM, Hoenderop JGJ, Bindels RJM, de Baaij JHF. Hypomagnesemia in type 2 diabetes: A vicious circle? Diabetes 2016; 65(1): 3-13.
[] [PMID: 26696633]
Zhang Q, Ji L, Zheng H, et al. Low serum phosphate and magnesium levels are associated with peripheral neuropathy in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2018; 146: 1-7.
[] [PMID: 30273706]
Hasanein P, Parviz M, Keshavarz M, Javanmardi K, Mansoori M, Soltani N. Oral magnesium administration prevents thermal hyperalgesia induced by diabetes in rats. Diabetes Res Clin Pract 2006; 73(1): 17-22.
[] [PMID: 16417942]
De Leeuw I, Engelen W, De Block C, Van Gaal L. Long term magnesium supplementation influences favourably the natural evolution of neuropathy in Mg-depleted type 1 diabetic patients (T1dm). Magnes Res 2004; 17(2): 109-14.
[PMID: 15319143]
Karonova T, Stepanova A, Bystrova A, Jude EB. High-dose vitamin D supplementation improves microcirculation and reduces inflammation in diabetic neuropathy patients. Nutrients 2020; 12(9): E2518.
[] [PMID: 32825324]
Lv WS, Zhao WJ, Gong SL, et al. Serum 25-hydroxyvitamin D levels and peripheral neuropathy in patients with type 2 diabetes: a systematic review and meta-analysis. J Endocrinol Invest 2015; 38(5): 513-8.
[] [PMID: 25527161]
Shillo P, Selvarajah D, Greig M, et al. Reduced vitamin D levels in painful diabetic peripheral neuropathy. Diabet Med 2019; 36(1): 44-51.
[] [PMID: 30102801]
Alam U, Petropoulos IN, Ponirakis G, et al. Vitamin D deficiency is associated with painful diabetic neuropathy. Diabetes Metab Res Rev 2021; 37(1): e3361.
[] [PMID: 32506740]
Dai J, Jiang C, Chen H, Chai Y. Vitamin D and diabetic foot ulcer: a systematic review and meta-analysis. Nutr Diabetes 2019; 9(1): 8.
[] [PMID: 30858355]
Yammine K, Hayek F, Assi C. Is there an association between vitamin D and diabetic foot disease? A meta-analysis. Wound Repair Regen 2020; 28(1): 90-6.
[] [PMID: 31633861]
Yammine K, Wehbe R, Assi C. A systematic review on the efficacy of vitamin D supplementation on diabetic peripheral neuropathy. Clin Nutr 2020; 39(10): 2970-4.
[] [PMID: 32089370]
Putz Z, Martos T, Németh N, et al. Is there an association between diabetic neuropathy and low vitamin D levels? Curr Diab Rep 2014; 14(10): 537.
[] [PMID: 25142719]
Hor CP, Fung WY, Ang HA, et al. Efficacy of oral mixed tocotrienols in diabetic peripheral neuropathy: A randomized clinical trial. JAMA Neurol 2018; 75(4): 444-52.
[] [PMID: 29379943]
Ng YT, Phang SCW, Tan GCJ, et al. The effects of tocotrienol-rich vitamin E (tocovid) on diabetic neuropathy: A phase II randomized controlled trial. Nutrients 2020; 12(5): E1522.
[] [PMID: 32456230]
Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015; 14(2): 162-73.
[] [PMID: 25575710]
Ziegler D, Fonseca V. From guideline to patient: a review of recent recommendations for pharmacotherapy of painful diabetic neuropathy. J Diabetes Complications 2015; 29(1): 146-56.
[] [PMID: 25239450]
Dosenovic S, Jelicic Kadic A, Miljanovic M, et al. Interventions for neuropathic pain: An overview of systematic reviews. Anesth Analg 2017; 125(2): 643-52.
[] [PMID: 28731977]
Putz Z, Tabák AG, Tóth N, et al. Noninvasive evaluation of neural impairment in subjects with impaired glucose tolerance. Diabetes Care 2009; 32(1): 181-3.
[] [PMID: 18835942]
Maser RE, Mitchell BD, Vinik AI, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis. Diabetes Care 2003; 26(6): 1895-901.
[] [PMID: 12766130]
Ziegler D. Diabetic cardiovascular autonomic neuropathy: prognosis, diagnosis and treatment. Diabetes Metab Rev 1994; 10(4): 339-83.
[] [PMID: 7796704]
Papanas N, Vinik AI, Ziegler D. Neuropathy in prediabetes: does the clock start ticking early? Nat Rev Endocrinol 2011; 7(11): 682-90.
[] [PMID: 21750507]
Spallone V. Update on the impact, diagnosis and management of cardiovascular autonomic neuropathy in diabetes: What is defined, what is new, and what is unmet. Diabetes Metab J 2019; 43(1): 3-30.
[] [PMID: 30793549]
Jermendy G. Clinical consequences of cardiovascular autonomic neuropathy in diabetic patients. Acta Diabetol 2003; 40(Suppl. 2): S370-4.
[] [PMID: 14704871]
Ewing DJ, Martyn CN, Young RJ, Clarke BF. The value of cardiovascular autonomic function tests: 10 years experience in diabetes. Diabetes Care 1985; 8(5): 491-8.
[] [PMID: 4053936]
Spallone V, Bellavere F, Scionti L, et al. Recommendations for the use of cardiovascular tests in diagnosing diabetic autonomic neuropathy. Nutr Metab Cardiovasc Dis 2011; 21(1): 69-78.
[] [PMID: 21247746]
Körei AE, Kempler M, Istenes I, et al. Why not to use the handgrip test in the assessment of cardiovascular autonomic neuropathy among patients with diabetes mellitus? Curr Vasc Pharmacol 2017; 15(1): 66-73.
[] [PMID: 27550055]
Jermendy G, Koltai MZ, Pogátsa G. QT interval prolongation in type 2 (non-insulin-dependent) diabetic patients with cardiac autonomic neuropathy. Acta Diabetol Lat 1990; 27(4): 295-301.
[] [PMID: 2087930]
Pop-Busui R, Herman WH, Feldman EL, et al. DCCT and EDIC studies in type 1 diabetes: lessons for diabetic neuropathy regarding metabolic memory and natural history. Curr Diab Rep 2010; 10(4): 276-82.
[] [PMID: 20464532]
Gaede P, Vedel P, Larsen N, Jensen GVH, Parving H-H, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003; 348(5): 383-93.
[] [PMID: 12556541]
Gibbons CH, Schmidt P, Biaggioni I, et al. The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol 2017; 264(8): 1567-82.
[] [PMID: 28050656]
Ziegler D, Schatz H, Conrad F, Gries FA, Ulrich H, Reichel G. Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial (DEKAN Study). Deutsche Kardiale Autonome Neuropathie. Diabetes Care 1997; 20(3): 369-73.
[] [PMID: 9051389]
Tankova T, Koev D, Dakovska L. Alpha-lipoic acid in the treatment of autonomic diabetic neuropathy (controlled, randomized, open-label study). Rom J Intern Med 2004; 42(2): 457-64.
[PMID: 15529636]
Lee SJ, Jeong SJ, Lee YC, et al. 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(4): 275-83.
[] [PMID: 28868825]
Bender DA. Optimum nutrition: thiamin, biotin and pantothenate. Proc Nutr Soc 1999; 58(2): 427-33.
[] [PMID: 10466187]
Rasic-Milutinovic Z, Gluvic Z, Perunicic-Pekovic G, Milicevic D, Lackovic M, Pencic B. Improvement of heart rate variability with benfothiamine and alpha-lipoic acid in type 2 diabetic patients- Pilot study. J Cardiol Ther 2014; 2(1): 49-55.
Stabler SP. Vitamin B12 deficiency. N Engl J Med 2013; 368(21): 2041-2.
[PMID: 23697526]
Chapman LE, Darling AL, Brown JE. Association between metformin and vitamin B12 deficiency in patients with type 2 diabetes: A systematic review and meta-analysis. Diabetes Metab 2016; 42(5): 316-27.
[] [PMID: 27130885]
Sözen AB, Demirel S, Akkaya V, et al. Autonomic dysfunction in vitamin B12 deficiency: a heart rate variability study. J Auton Nerv Syst 1998; 71(1): 25-7.
[] [PMID: 9722191]
Hansen CS, Jensen JS, Ridderstråle M, Vistisen D, Jørgensen ME, Fleischer J. Vitamin B12 deficiency is associated with cardiovascular autonomic neuropathy in patients with type 2 diabetes. J Diabetes Complications 2017; 31(1): 202-8.
[] [PMID: 27638143]
Holick MF. Vitamin D deficiency. N Engl J Med 2007; 357(3): 266-81.
[] [PMID: 17634462]
Dobnig H, Pilz S, Scharnagl H, et al. Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Arch Intern Med 2008; 168(12): 1340-9.
[] [PMID: 18574092]
Cigolini M, Iagulli MP, Miconi V, Galiotto M, Lombardi S, Targher G. Serum 25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular disease among type 2 diabetic patients. Diabetes Care 2006; 29(3): 722-4.
[] [PMID: 16505539]
Mann MC, Exner DV, Hemmelgarn BR, et al. Vitamin D supplementation is associated with improved modulation of cardiac autonomic tone in healthy humans. Int J Cardiol 2014; 172(2): 506-8.
[] [PMID: 24502876]
Jung C-H, Jung S-H, Kim K-J, et al. The relationship between vitamin D status and cardiac autonomic neuropathy in patients with type 2 diabetes mellitus. Diab Vasc Dis Res 2015; 12(5): 342-51.
[] [PMID: 26150192]
Silva LSD, de Queiroz NNM, de Melo FTC, et al. Improvement in cardiovascular autonomic neuropathy after high-dose vitamin D supplementation in patients with type 1 diabetes. Front Endocrinol (Lausanne) 2020; 11: 605681.
[] [PMID: 33329405]
Christensen JH. Omega-3 polyunsaturated fatty acids and heart rate variability. Front Physiol 2011; 2: 84.
[] [PMID: 22110443]
Serhiyenko VA, Mankovsky BN, Serhiyenko LM, Serhiyenko AA. The effect of OMEGA-3 polyunsaturated fatty acids on ambulatory blood pressure monitoring parameters in patients with type 2 diabetes mellitus and cardiovascular autonomic neuropathy. Diabetes mellitus 2019; 22(1): 62-9.
Serhiyenko VA, Segin VB, Serhiyenko AA. Effects of omega-3 polyunsaturated fatty acids on the circadian rhythm of heart rate variability parameters in patients with type 2 Diabetes mellitus and cardiovascular autonomic neuropathy. Russ J Cardiol 2018; (5): 56-60.
Serhiyenko V, Serhiyenko L, Serhiyenko A. Omega-3 polyunsaturated fatty acids improved arterial stiffness parameters in type 2 diabetic patients with cardiac autonomic neuropathy. Rom J Diabetes Nutr Metab Dis 2018; 25(4): 363-8.
Flaxman SR, Bourne RRA, Resnikoff S, et al. Global causes of blindness and distance vision impairment 1990-2020: a systematic review and meta-analysis. Lancet Glob Health 2017; 5(12): e1221-34.
[] [PMID: 29032195]
Scanlon PH. The english national screening programme for diabetic retinopathy 2003-2016. Acta Diabetol 2017; 54(6): 515-25.
[] [PMID: 28224275]
Yau JWY, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012; 35(3): 556-64.
[] [PMID: 22301125]
Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet 2010; 376(9735): 124-36.
[] [PMID: 20580421]
Porta M, Bandello F. Diabetic retinopathyA clinical update. Diabetologia 2002; 45(12): 1617-34.
[] [PMID: 12488951]
Lee PP, Feldman ZW, Ostermann J, Brown DS, Sloan FA. Longitudinal rates of annual eye examinations of persons with diabetes and chronic eye diseases. Ophthalmology 2003; 110(10): 1952-9.
[] [PMID: 14522771]
Olson J, Sharp P, Goatman K, et al. Improving the economic value of photographic screening for optical coherence tomography-detectable macular oedema: a prospective, multicentre, UK study. Health Technol Assess 2013; 17(51): 1-142.
[] [PMID: 24225334]
Ishibazawa A, Nagaoka T, Takahashi A, et al. Optical coherence tomography angiography in diabetic retinopathy: A prospective pilot study. Am J Ophthalmol 2015; 160(1): 35-44.e1.
[] [PMID: 25896459]
UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352(9131): 837-53.
[] [PMID: 9742976]
UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317(7160): 703-13.
[] [PMID: 9732337]
Nathan DM, Genuth S, Lachin J, et al. The effect of intensive diabetes therapy on measures of autonomic nervous system function in the Diabetes Control and Complications Trial (DCCT). Diabetologia 1998; 41(4): 416-23.
[] [PMID: 9562345]
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359(15): 1577-89.
[] [PMID: 18784090]
American Diabetes Association. 10. Cardiovascular disease and risk management: Standards of medical care in diabetes-2020. Dia Care 2020; 43(Suppl. 1): S111-34.
[] [PMID: 31862753]
American Diabetes Association. 6. Glycemic targets: Standards of medical care in diabetes-2020. Dia Care 2020; 43(Suppl. 1): S66-76.
[] [PMID: 31862749]
Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med 2012; 366(13): 1227-39.
[] [PMID: 22455417]
Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008; 358(24): 2545-59.
[] [PMID: 18539917]
Beulens JWJ, Patel A, Vingerling JR, et al. Effects of blood pressure lowering and intensive glucose control on the incidence and progression of retinopathy in patients with type 2 diabetes mellitus: a randomised controlled trial. Diabetologia 2009; 52(10): 2027-36.
[] [PMID: 19633827]
Chaturvedi N, Sjolie A-K, Stephenson JM, et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID study group. EURODIAB controlled trial of lisinopril in insulin-dependent diabetes mellitus. Lancet 1998; 351(9095): 28-31.
[] [PMID: 9433426]
Chaturvedi N, Porta M, Klein R, et al. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet 2008; 372(9647): 1394-402.
[] [PMID: 18823656]
Sjølie AK, Klein R, Porta M, et al. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial. Lancet 2008; 372(9647): 1385-93.
[] [PMID: 18823658]
Chew EY, Ambrosius WT, Davis MD, et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med 2010; 363(3): 233-44.
[] [PMID: 20587587]
Keech AC, Mitchell P, Summanen PA, et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 2007; 370(9600): 1687-97.
[] [PMID: 17988728]
The DAMAD Study Group. Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy. A multicenter randomized controlled clinical trial. Diabetes 1989; 38(4): 491-8.
[] [PMID: 2647556]
The TIMAD Study Group. Ticlopidine treatment reduces the progression of nonproliferative diabetic retinopathy. Arch Ophthalmol 1990; 108(11): 1577-83.
[] [PMID: 2244843]
Early Treatment Diabetic Retinopathy Study Research Group. Effects of aspirin treatment on diabetic retinopathy. ETDRS report number 8. Ophthalmology 1991; 98(5): 757-65.
[] [PMID: 2062511]
Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res 2005; 97(6): 512-23.
[] [PMID: 16166562]
Raza A, Franklin MJ, Dudek AZ. Pericytes and vessel maturation during tumor angiogenesis and metastasis. Am J Hematol 2010; 85(8): 593-8.
[] [PMID: 20540157]
Nishikawa T, Edelstein D, Brownlee M. The missing link: a single unifying mechanism for diabetic complications. Kidney Int Suppl 2000; 77: S26-30.
[] [PMID: 10997687]
La Selva M, Beltramo E, Pagnozzi F, et al. Thiamine corrects delayed replication and decreases production of lactate and advanced glycation end-products in bovine retinal and human umbilical vein endothelial cells cultured under high glucose conditions. Diabetologia 1996; 39(11): 1263-8.
[] [PMID: 8932990]
Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, Thornalley PJ. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes 2003; 52(8): 2110-20.
[] [PMID: 12882930]
Lin J, Bierhaus A, Bugert P, et al. Effect of R-(+)-alpha-lipoic acid on experimental diabetic retinopathy. Diabetologia 2006; 49(5): 1089-96.
[] [PMID: 16520919]
Packer L, Witt EH, Tritschler HJ. alpha-Lipoic acid as a biological antioxidant. Free Radic Biol Med 1995; 19(2): 227-50.
[] [PMID: 7649494]
Hammes HP, Bartmann A, Engel L, Wülfroth P. Antioxidant treatment of experimental diabetic retinopathy in rats with nicanartine. Diabetologia 1997; 40(6): 629-34.
[] [PMID: 9222640]
Mayer-Davis EJ, Bell RA, Reboussin BA, Rushing J, Marshall JA, Hamman RF. Antioxidant nutrient intake and diabetic retinopathy: the San Luis Valley Diabetes Study. Ophthalmology 1998; 105(12): 2264-70.
[] [PMID: 9855158]
Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355(9200): 253-9.
[] [PMID: 10675071]
Santos JM, Kowluru RA. Role of mitochondria biogenesis in the metabolic memory associated with the continued progression of diabetic retinopathy and its regulation by lipoic acid. Invest Ophthalmol Vis Sci 2011; 52(12): 8791-8.
[] [PMID: 22003111]
Kan E, Alici Ö, Kan EK, Ayar A. Effects of alpha-lipoic acid on retinal ganglion cells, retinal thicknesses, and VEGF production in an experimental model of diabetes. Int Ophthalmol 2017; 37(6): 1269-78.
[] [PMID: 27848046]
Kim YS, Kim M, Choi MY, et al. Alpha-lipoic acid reduces retinal cell death in diabetic mice. Biochem Biophys Res Commun 2018; 503(3): 1307-14.
[] [PMID: 30017190]
Haritoglou C, Gerss J, Hammes HP, Kampik A, Ulbig MW. Alpha-lipoic acid for the prevention of diabetic macular edema. Ophthalmologica 2011; 226(3): 127-37.
[] [PMID: 21811051]
Nebbioso M, Federici M, Rusciano D, Evangelista M, Pescosolido N. Oxidative stress in preretinopathic diabetes subjects and antioxidants. Diabetes Technol Ther 2012; 14(3): 257-63.
[] [PMID: 22044044]
Gębka A, Serkies-Minuth E, Raczyńska D. Effect of the administration of alpha-lipoic acid on contrast sensitivity in patients with type 1 and type 2 diabetes. Mediators Inflamm 2014; 2014: 131538.
[] [PMID: 24665163]
Beltramo E, Berrone E, Tarallo S, Porta M. Effects of thiamine and benfotiamine on intracellular glucose metabolism and relevance in the prevention of diabetic complications. Acta Diabetol 2008; 45(3): 131-41.
[] [PMID: 18581039]
Beltramo E, Berrone E, Tarallo S, Porta M. Different apoptotic responses of human and bovine pericytes to fluctuating glucose levels and protective role of thiamine. Diabetes Metab Res Rev 2009; 25(6): 566.
[] [PMID: 19593734]
Berrone E, Beltramo E, Solimine C, Ape AU, Porta M. Regulation of intracellular glucose and polyol pathway by thiamine and benfotiamine in vascular cells cultured in high glucose. J Biol Chem 2006; 281(14): 9307-13.
[] [PMID: 16452468]
Beltramo E, Mazzeo A, Lopatina T, Trento M, Porta M. Thiamine transporter 2 is involved in high glucose-induced damage and altered thiamine availability in cell models of diabetic retinopathy. Diab Vasc Dis Res 2020; 17(1): 1479164119878427.
[] [PMID: 31726874]
Beltramo E, Pomero F, Allione A, D’Alù F, Ponte E, Porta M. Pericyte adhesion is impaired on extracellular matrix produced by endothelial cells in high hexose concentrations. Diabetologia 2002; 45(3): 416-9.
[] [PMID: 11914747]
Porta M, Toppila I, Sandholm N, et al. Variation in SLC19A3 and protection from microvascular damage in type 1 diabetes. Diabetes 2016; 65(4): 1022-30.
[] [PMID: 26718501]
Cinici E, Dilekmen N, Senol O, Arpalı E, Cinici O, Tanas S. Blood thiamine pyrophosphate concentration and its correlation with the stage of diabetic retinopathy. Int Ophthalmol 2020; 40(12): 3279-84.
[] [PMID: 32715366]
Pearce SH, Cheetham TD. Diagnosis and management of vitamin D deficiency. BMJ 2010; 340: b5664-4.
Vanoirbeek E, Krishnan A, Eelen G, et al. The anti-cancer and anti-inflammatory actions of 1,25(OH)2D3. Best Pract Res Clin Endocrinol Metab 2011; 25(4): 593-604.
[] [PMID: 21872801]
Holick MF. The vitamin D deficiency pandemic: Approaches for diagnosis, treatment and prevention. Rev Endocr Metab Disord 2017; 18(2): 153-65.
[] [PMID: 28516265]
Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin D: modulator of the immune system. Curr Opin Pharmacol 2010; 10(4): 482-96.
[] [PMID: 20427238]
Lee V, Rekhi E, Hoh Kam J, Jeffery G. Vitamin D rejuvenates aging eyes by reducing inflammation, clearing amyloid beta and improving visual function. Neurobiol Aging 2012; 33(10): 2382-9.
[] [PMID: 22217419]
Jamali N, Sorenson CM, Sheibani N. Vitamin D and regulation of vascular cell function. Am J Physiol Heart Circ Physiol 2018; 314(4): H753-65.
[] [PMID: 29351464]
Zittermann A. Vitamin D in preventive medicine: are we ignoring the evidence? Br J Nutr 2003; 89(5): 552-72.
[] [PMID: 12720576]
Chagas CEA, Borges MC, Martini LA, Rogero MM. Focus on vitamin D, inflammation and type 2 diabetes. Nutrients 2012; 4(1): 52-67.
[] [PMID: 22347618]
Albert DM, Scheef EA, Wang S, et al. Calcitriol is a potent inhibitor of retinal neovascularization. Invest Ophthalmol Vis Sci 2007; 48(5): 2327-34.
[] [PMID: 17460298]
Ren Z, Li W, Zhao Q, Ma L, Zhu J. The impact of 1,25-dihydroxy vitamin D3 on the expressions of vascular endothelial growth factor and transforming growth factor-β1 in the retinas of rats with diabetes. Diabetes Res Clin Pract 2012; 98(3): 474-80.
[] [PMID: 23089551]
Lu L, Lu Q, Chen W, Li J, Li C, Zheng Z. Vitamin D 3 protects against diabetic retinopathy by inhibiting high-glucose-induced activation of the ROS/TXNIP/NLRP3 inflammasome pathway. J Diabetes Res 2018; 2018: 1-11.
Aksoy H, Akçay F, Kurtul N, Baykal O, Avci B. Serum 1,25 dihydroxy vitamin D (1,25(OH)2D3), 25 hydroxy vitamin D (25(OH)D) and parathormone levels in diabetic retinopathy. Clin Biochem 2000; 33(1): 47-51.
[] [PMID: 10693986]
Payne JF, Ray R, Watson DG, et al. Vitamin D insufficiency in diabetic retinopathy. Endocr Pract 2012; 18(2): 185-93.
[] [PMID: 21940279]
Kaur H, Donaghue KC, Chan AK, et al. Vitamin D deficiency is associated with retinopathy in children and adolescents with type 1 diabetes. Diabetes Care 2011; 34(6): 1400-2.
[] [PMID: 21515836]
National Kidney Foundation. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013; (3): 1-150.
Meena BL, Sharma KR, Agrawal R P, Sirohi P. High dose thiamine therapy for type 2 diabetes with microalbuminuria patients: A randomized double blind placebo controlled study. IJSR - international journal of scientific research 2018; 7(1)
Bonora E, DeFronzo RA, Eds. Diabetes complications, comorbidities and related disorders: Diabetes and the kidney. Cham: Springer international publishing 2018. Imprint, Springer
Fox CS, Matsushita K, Woodward M, et al. Associations of kidney disease measures with mortality and end-stage renal disease in individuals with and without diabetes: a meta-analysis. Lancet 2012; 380(9854): 1662-73.
[] [PMID: 23013602]
Koopman RJ, Mainous AG III, Liszka HA, et al. Evidence of nephropathy and peripheral neuropathy in US adults with undiagnosed diabetes. Ann Fam Med 2006; 4(5): 427-32.
[] [PMID: 17003143]
Middleton RJ, Foley RN, Hegarty J, et al. The unrecognized prevalence of chronic kidney disease in diabetes. Nephrol Dial Transplant 2006; 21(1): 88-92.
Afkarian M, Zelnick LR, Hall YN, et al. Clinical manifestations of kidney disease among us adults with diabetes, 1988-2014. JAMA 2016; 316(6): 602-10.
[] [PMID: 27532915]
Whitham D. Nutrition for the prevention and treatment of chronic kidney disease in diabetes. Can J Diabetes 2014; 38(5): 344-8.
[] [PMID: 25201774]
Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. N Engl J Med 1994; 330(13): 877-84.
[] [PMID: 8114857]
FDA. FDA drug safety communication: FDA revises warnings regarding use of the diabetes medicine metformin in certain patients with reduced kidney function. 2016. Available from: [Cited 2021 January 14]
He F, Xia X, Wu XF, Yu XQ, Huang FX. Diabetic retinopathy in predicting diabetic nephropathy in patients with type 2 diabetes and renal disease: a meta-analysis. Diabetologia 2013; 56(3): 457-66.
[] [PMID: 23232641]
Rabbani N, Thornalley PJ. Emerging role of thiamine therapy for prevention and treatment of early-stage diabetic nephropathy. Diabetes Obes Metab 2011; 13(7): 577-83.
[] [PMID: 21342411]
Alicic RZ, Rooney MT, Tuttle KR. Diabetic kidney disease: Challenges, progress, and possibilities. Clin J Am Soc Nephrol 2017; 12(12): 2032-45.
[] [PMID: 28522654]
Kanter M, Sen S, Donmez S, Aktas C, Ustundag S, Erboga M. Protective effects of irbesartan and alpha lipoic acid in STZ-induced diabetic nephropathy in rats. Ren Fail 2010; 32(4): 498-505.
[] [PMID: 20446791]
Obrosova IG, Fathallah L, Liu E, Nourooz-Zadeh J. Early oxidative stress in the diabetic kidney: effect of DL-alpha-lipoic acid. Free Radic Biol Med 2003; 34(2): 186-95.
[] [PMID: 12521600]
Siu B, Saha J, Smoyer WE, Sullivan KA, Brosius FC III. Reduction in podocyte density as a pathologic feature in early diabetic nephropathy in rodents: prevention by lipoic acid treatment. BMC Nephrol 2006; 7: 6.
[] [PMID: 16539708]
Yi X, Nickeleit V, James LR, Maeda N. α-Lipoic acid protects diabetic apolipoprotein E-deficient mice from nephropathy. J Diabetes Complications 2011; 25(3): 193-201.
[] [PMID: 20801062]
Feng B, Yan X-F, Xue J-L, Xu L, Wang H. The protective effects of α-lipoic acid on kidneys in type 2 diabetic Goto-Kakisaki rats via reducing oxidative stress. Int J Mol Sci 2013; 14(4): 6746-56.
[] [PMID: 23531536]
Lin H, Ye S, Xu J, Wang W. The alpha-lipoic acid decreases urinary podocalyxin excretion in type 2 diabetics by inhibiting oxidative stress in vivo. J Diabetes Complications 2015; 29(1): 64-7.
[] [PMID: 25312599]
Morcos M, Borcea V, Isermann B, et al. Effect of alpha-lipoic acid on the progression of endothelial cell damage and albuminuria in patients with diabetes mellitus: an exploratory study. Diabetes Res Clin Pract 2001; 52(3): 175-83.
[] [PMID: 11323087]
Noori N, Tabibi H, Hosseinpanah F, Hedayati M, Nafar M. Effects of combined lipoic acid and pyridoxine on albuminuria, advanced glycation end-products, and blood pressure in diabetic nephropathy. Int J Vitam Nutr Res 2013; 83(2): 77-85.
[] [PMID: 24491880]
Sun H, Yao W, Tang Y, et al. Urinary exosomes as a novel biomarker for evaluation of α-lipoic acid’s protective effect in early diabetic nephropathy. J Clin Lab Anal 2017; 31(6): e22129.
[] [PMID: 28116765]
Chang JW, Lee EK, Kim TH, et al. Effects of alpha-lipoic acid on the plasma levels of asymmetric dimethylarginine in diabetic end-stage renal disease patients on hemodialysis: a pilot study. Am J Nephrol 2007; 27(1): 70-4.
[] [PMID: 17259696]
Mittermayer F, Pleiner J, Francesconi M, Wolzt M. Treatment with alpha-lipoic acid reduces asymmetric dimethylarginine in patients with type 2 diabetes mellitus. Transl Res 2010; 155(1): 6-9.
[] [PMID: 20004356]
Schreeb KH, Freudenthaler S, Vormfelde SV, Gundert-Remy U, Gleiter CH. Comparative bioavailability of two vitamin B1 preparations: benfotiamine and thiamine mononitrate. Eur J Clin Pharmacol 1997; 52(4): 319-20.
[PMID: 9248773]
Bakker SJ, Heine RJ, Gans RO. Thiamine may indirectly act as an antioxidant. Diabetologia 1997; 40(6): 741-2.
[PMID: 9222658]
Thornalley PJ. The potential role of thiamine (vitamin B1) in diabetic complications. Curr Diabetes Rev 2005; 1(3): 287-98.
[] [PMID: 18220605]
Rabbani N, Alam SS, Riaz S, et al. High-dose thiamine therapy for patients with type 2 diabetes and microalbuminuria: a randomised, double-blind placebo-controlled pilot study. Diabetologia 2009; 52(2): 208-12.
[] [PMID: 19057893]
Alkhalaf A, Klooster A, van Oeveren W, et al. A double-blind, randomized, placebo-controlled clinical trial on benfotiamine treatment in patients with diabetic nephropathy. Dia Care 2010; 33(7): 1598-601.
[] [PMID: 20413516]
Nakamura S, Li H, Adijiang A, Pischetsrieder M, Niwa T. Pyridoxal phosphate prevents progression of diabetic nephropathy. Nephrol Dial Transplant 2007; 22(8): 2165-74.
[] [PMID: 17449494]
House AA, Eliasziw M, Cattran DC, et al. Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial. JAMA 2010; 303(16): 1603-9.
[] [PMID: 20424250]
Onuigbo MAC. Nephrotoxic effects of water-soluble B-vitamin therapy in diabetic nephropathy?-How true can this be? QJM 2011; 104(2): 171-2.
[] [PMID: 20630906]
Thornalley PJ, Rabbani N. Therapy: Vitamin B6, B9 and B12 in diabetic nephropathy-beware. Nat Rev Endocrinol 2010; 6(9): 477-8.
[] [PMID: 20720587]
Polizzi FC, Andican G, Çetin E, Civelek S, Yumuk V, Burçak G. Increased DNA-glycation in type 2 diabetic patients: the effect of thiamine and pyridoxine therapy. Exp Clin Endocrinol Diabetes 2012; 120(6): 329-34.
[] [PMID: 22231921]
Cetin E, Civelek S, Andican G, Candan Polizzi F, Yumuk V, Burçak G. Plasma AGE-peptides and C-peptide in early-stage diabetic nephropathy patients on thiamine and pyridoxine therapy. Minerva Med 2013; 104(1): 93-101.
[PMID: 23392542]
Dwyer JP, Greco BA, Umanath K, et al. Pyridoxamine dihydrochloride in diabetic nephropathy (PIONEER-CSG-17): lessons learned from a pilot study. Nephron 2015; 129(1): 22-8.
[] [PMID: 25532068]
Bherwani S, Saumya AS, Ahirwar AK, et al. The association of folic acid deficiency and diabetic nephropathy in patients with type 2 diabetes mellitus. Endocr Metab Immune Disord Drug Targets 2016; 16(2): 120-3.
[] [PMID: 27087197]
Bherwani S, Ahirwar AK, Saumya AS, et al. The study of association of Vitamin B12 deficiency in type 2 diabetes mellitus with and without diabetic nephropathy in North Indian Population. Diabetes Metab Syndr 2017; 11(Suppl. 1): S365-8.
[] [PMID: 28283394]
Wang H, Wang J, Qu H, et al. In vitro and in vivo inhibition of mTOR by 1,25-dihydroxyvitamin D3 to improve early diabetic nephropathy via the DDIT4/TSC2/mTOR pathway. Endocrine 2016; 54(2): 348-59.
[] [PMID: 27395420]
Hu X, Liu W, Yan Y, et al. Vitamin D protects against diabetic nephropathy: Evidence-based effectiveness and mechanism. Eur J Pharmacol 2019; 845: 91-8.
[] [PMID: 30287151]
Mager DR, Jackson ST, Hoffmann MR, Jindal K, Senior PA. Vitamin D3 supplementation, bone health and quality of life in adults with diabetes and chronic kidney disease: Results of an open label randomized clinical trial. Clin Nutr 2017; 36(3): 686-96.
[] [PMID: 27302208]
Huang Y, Yu H, Lu J, et al. Oral supplementation with cholecalciferol 800 IU ameliorates albuminuria in Chinese type 2 diabetic patients with nephropathy. PLoS One 2012; 7(11): e50510.
[] [PMID: 23209764]
Liyanage GC, Lekamwasam S, Weerarathna TP, Liyanage CE. Effects of high-dose parenteral vitamin D therapy on lipid profile and blood pressure in patients with diabetic nephropathy: A randomized double-blind clinical trial. Diabetes Metab Syndr 2017; 11(Suppl. 2): S767-70.
[] [PMID: 28606441]
Esfandiari A, Pourghassem Gargari B, Noshad H, et al. The effects of vitamin D3 supplementation on some metabolic and inflammatory markers in diabetic nephropathy patients with marginal status of vitamin D: A randomized double blind placebo controlled clinical trial. Diabetes Metab Syndr 2019; 13(1): 278-83.
[] [PMID: 30641712]
Zhao J, Dong J, Wang H, Shang H, Zhang D, Liao L. Efficacy and safety of vitamin D3 in patients with diabetic nephropathy: a meta-analysis of randomized controlled trials. Chin Med J (Engl) 2014; 127(15): 2837-43.
[PMID: 25146624]
Nascimento Gomes G, Barbosa FT, Radaeli RF, Cavanal MF, Mello Aires M, Zaladek Gil F. Effect of D-alpha-tocopherol on tubular nephron acidification by rats with induced diabetes mellitus. Braz J Med Biol Res 2005; 38(7): 1043-51.
[] [PMID: 16007275]
Dávila-Esqueda ME, Vertiz-Hernández AA, Martínez-Morales F. Comparative analysis of the renoprotective effects of pentoxifylline and vitamin E on streptozotocin-induced diabetes mellitus. Ren Fail 2005; 27(1): 115-22.
[] [PMID: 15717644]
Yokoyama M, Torita M, Yoshizawa M, Usuda R. Indication of vitamin E on microalbuminuria in patients with incipient diabetic nephropathy. Diabetes Metab 2001; 27(5 Pt 1): 611-2.
[PMID: 11694862]
Zitouni K, Harry DD, Nourooz-Zadeh J, Betteridge DJ, Earle KA. Circulating vitamin E, transforming growth factor beta1, and the association with renal disease susceptibility in two racial groups with type 2 diabetes. Kidney Int 2005; 67(5): 1993-8.
[] [PMID: 15840049]
Hirnerová E, Krahulec B, Strbová L, Stecová A, Dekrét J, Hájovská A. Vplyv liecby vitamínom E na progresiu diabetickej nefropatie. Vnitr Lek 2003; 49(7): 529-34.
[PMID: 12931434]
Khatami PG, Soleimani A, Sharifi N, Aghadavod E, Asemi Z. The effects of high-dose vitamin E supplementation on biomarkers of kidney injury, inflammation, and oxidative stress in patients with diabetic nephropathy: A randomized, double-blind, placebo-controlled trial. J Clin Lipidol 2016; 10(4): 922-9.
[] [PMID: 27578124]
Tan GCJ, Tan SMQ, Phang SCW, et al. Tocotrienol-rich vitamin E improves diabetic nephropathy and persists 6-9 months after washout: a phase IIa randomized controlled trial. Ther Adv Endocrinol Metab 2019; 10: 2042018819895462.
[] [PMID: 31903178]
Bherwani S, Jibhkate SB, Saumya AS, Patel SK, Singh R, Ghotekar LH. Hypomagnesaemia: a modifiable risk factor of diabetic nephropathy. Horm Mol Biol Clin Investig 2017; 29(3): 79-84.
[] [PMID: 27416617]
Sakaguchi Y, Shoji T, Hayashi T, et al. Hypomagnesemia in type 2 diabetic nephropathy: a novel predictor of end-stage renal disease. Diabetes Care 2012; 35(7): 1591-7.
[] [PMID: 22498805]
Lu J, Gu Y, Guo M, Chen P, Wang H, Yu X. Serum magnesium concentration is inversely associated with albuminuria and retinopathy among patients with diabetes. J Diabetes Res 2016; 2016: 1260141.
[] [PMID: 27547762]
Silva AP, Mendes F, Fragoso A, et al. Altered serum levels of FGF-23 and magnesium are independent risk factors for an increased albumin-to-creatinine ratio in type 2 diabetics with chronic kidney disease. J Diabetes Complications 2016; 30(2): 275-80.
[] [PMID: 26750742]
Sadeghian M, Azadbakht L, Khalili N, Mortazavi M, Esmaillzadeh A. Oral magnesium supplementation improved lipid profile but increased insulin resistance in patients with diabetic nephropathy: a double-blind randomized controlled clinical trial. Biol Trace Elem Res 2020; 193(1): 23-35.
[] [PMID: 30835085]
Kumar GS, Kulkarni A, Khurana A, Kaur J, Tikoo K. Selenium nanoparticles involve HSP-70 and SIRT1 in preventing the progression of type 1 diabetic nephropathy. Chem Biol Interact 2014; 223: 125-33.
[] [PMID: 25301743]
Bahmani F, Kia M, Soleimani A, Asemi Z, Esmaillzadeh A. Effect of selenium supplementation on glycemic control and lipid profiles in patients with diabetic nephropathy. Biol Trace Elem Res 2016; 172(2): 282-9.
[] [PMID: 26686847]
Sourris KC, Harcourt BE, Tang PH, et al. Ubiquinone (coenzyme Q10) prevents renal mitochondrial dysfunction in an experimental model of type 2 diabetes. Free Radic Biol Med 2012; 52(3): 716-23.
[] [PMID: 22172526]
Gholnari T, Aghadavod E, Soleimani A, Hamidi GA, Sharifi N, Asemi Z. The effects of coenzyme Q10 supplementation on glucose metabolism, lipid profiles, inflammation, and oxidative stress in patients with diabetic nephropathy: A randomized, double-blind, placebo-controlled trial. J Am Coll Nutr 2018; 37(3): 188-93.
[] [PMID: 29111905]
Zhang X, Shi Z, Liu Q, Quan H, Cheng X. Effects of coenzyme Q10 intervention on diabetic kidney disease: A systematic review and meta-analysis. Medicine (Baltimore) 2019; 98(24): e15850.
[] [PMID: 31192915]
Heidari A, Hamidi G, Soleimani A, Aghadavod E, Asemi Z. Effects of coenzyme Q10 supplementation on gene expressions related to insulin, lipid, and inflammation pathways in patients with diabetic nephropathy. Iran J Kidney Dis 2018; 12(1): 14-21.
[PMID: 29421772]

© 2023 Bentham Science Publishers | Privacy Policy