|
1
|
Bhrigu B, Sharma S, Kumar N, Banik BK. Assessment for Diabetic Neuropathy: Treatment and Neurobiological Perspective. Curr Diabetes Rev 2025; 21:12-31. [PMID: 38798207 DOI: 10.2174/0115733998290606240521113832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 04/01/2024] [Accepted: 04/19/2024] [Indexed: 05/29/2024]
Abstract
Diabetic neuropathy, also known as diabetic peripheral sensorimotor neuropathy (DPN), is a consequential complexity of diabetes, alongside diabetic nephropathy, diabetic cardiomyopathy, and diabetic retinopathy. It is characterized by signs and symptoms of peripheral nerve damage in diabetes patients after ruling out other causes. Approximately 20% of people with diabetes are affected by this painful and severe condition. The development of diabetic neuropathy is influenced by factors such as impaired blood flow to the peripheral nerves and metabolic issues, including increased polyol pathway activation, myo-inositol loss, and nonenzymatic glycation. The present review article provides a brief overview of the pathological changes in diabetic neuropathy and the mechanisms and types of DPN. Various diagnostic tests and biomarkers are available to assess nerve damage and its severity. Pharmacotherapy for neuropathic pain in diabetic neuropathy is complex. This review will explore current treatment options and potential future developments to improve the quality of life for patients suffering from diabetic neuropathy.
Collapse
Affiliation(s)
- Bhanupriya Bhrigu
- Department of Pharmaceutical Science, Lords University, Alwar, 301028, Rajasthan, India
| | - Shikha Sharma
- Department of Pharmaceutical Science, Lords University, Alwar, 301028, Rajasthan, India
| | - Nitin Kumar
- Department of Pharmaceutical Science, Lords University, Alwar, 301028, Rajasthan, India
| | - Bimal Krishna Banik
- Department of Mathematics and Natural Sciences, College of Sciences and Human Studies, Prince Mohammad Bin Fahd University, Al Khobar, Kingdom of Saudi Arabia
| |
Collapse
|
|
2
|
Ferraz L, Barros M, Almeida K, Silva M, Bueno N. Effects of dietary supplementation in treatment and control of progression and complications of insulin-dependent diabetes mellitus: a systematic review with meta-analyses of randomized clinical trials. Braz J Med Biol Res 2024; 57:e13649. [PMID: 39194033 PMCID: PMC11349153 DOI: 10.1590/1414-431x2024e13649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Accepted: 06/19/2024] [Indexed: 08/29/2024] Open
Abstract
There is no safe and effective prevention for insulin-dependent diabetes (IDDM) mellitus, which makes it highly dependent on its treatment. This systematic review with meta-analyses of randomized clinical trials investigated the overall effects of dietary supplements of vitamins, minerals, trace elements, and non-essential compounds with antioxidant properties, fatty acids, and amino acids in IDDM. Searches of MEDLINE, Embase, CENTRAL, LILACS, The Grey Literature Report, and ClinicaTrials.gov, and citations from previous reviews were used to identify reports published through July 2023. The Risk of Bias 2 (RoB2) tool was used to analyze the risk of bias and GRADE was used to assess the quality of the results. Fifty-eight studies (n=3,044) were included in qualitative analyses and seventeen (n=723) in meta-analyses. Qualitative analyses showed few positive effects on some metabolic function markers, such as endothelial and renal function and lipid profile. Meta-analyses showed a positive effect of omega-3 on glycated hemoglobin (HbA1c) (RMD=-0.33; 95%CI: -0.53, -0.12, P=0.002; I2=0%; GRADE: low quality; 4 studies) and of vitamin D on fasting C-peptide (FCP) (RMD=0.05; 95%CI: 0.01, 0.9, P=0.023; I2=0%; GRADE: very low quality; 4 studies). Most studies showed bias concern or high risk of bias. A recommendation for dietary supplementation in IDDM cannot be made because of the few positive results within different interventions and markers, the serious risk of bias in the included studies, and the low quality of evidence from meta-analyses. The positive result of vitamin D on FCP is preliminary, requiring further investigation.
Collapse
Affiliation(s)
- L.C. Ferraz
- Laboratório de Nutrição e Metabolismo, Faculdade de Nutrição, Universidade Federal de Alagoas, Maceió, AL, Brasil
| | - M.D.R. Barros
- Laboratório de Nutrição e Metabolismo, Faculdade de Nutrição, Universidade Federal de Alagoas, Maceió, AL, Brasil
| | - K.M.M. Almeida
- Laboratório de Nutrição e Metabolismo, Faculdade de Nutrição, Universidade Federal de Alagoas, Maceió, AL, Brasil
| | - M.B.G. Silva
- Laboratório de Nutrição e Metabolismo, Faculdade de Nutrição, Universidade Federal de Alagoas, Maceió, AL, Brasil
| | - N.B. Bueno
- Laboratório de Nutrição e Metabolismo, Faculdade de Nutrição, Universidade Federal de Alagoas, Maceió, AL, Brasil
| |
Collapse
|
|
3
|
Uceda AB, Mariño L, Casasnovas R, Adrover M. An overview on glycation: molecular mechanisms, impact on proteins, pathogenesis, and inhibition. Biophys Rev 2024; 16:189-218. [PMID: 38737201 PMCID: PMC11078917 DOI: 10.1007/s12551-024-01188-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/21/2024] [Indexed: 05/14/2024] Open
Abstract
The formation of a heterogeneous set of advanced glycation end products (AGEs) is the final outcome of a non-enzymatic process that occurs in vivo on long-life biomolecules. This process, known as glycation, starts with the reaction between reducing sugars, or their autoxidation products, with the amino groups of proteins, DNA, or lipids, thus gaining relevance under hyperglycemic conditions. Once AGEs are formed, they might affect the biological function of the biomacromolecule and, therefore, induce the development of pathophysiological events. In fact, the accumulation of AGEs has been pointed as a triggering factor of obesity, diabetes-related diseases, coronary artery disease, neurological disorders, or chronic renal failure, among others. Given the deleterious consequences of glycation, evolution has designed endogenous mechanisms to undo glycation or to prevent it. In addition, many exogenous molecules have also emerged as powerful glycation inhibitors. This review aims to provide an overview on what glycation is. It starts by explaining the similarities and differences between glycation and glycosylation. Then, it describes in detail the molecular mechanism underlying glycation reactions, and the bio-molecular targets with higher propensity to be glycated. Next, it discusses the precise effects of glycation on protein structure, function, and aggregation, and how computational chemistry has provided insights on these aspects. Finally, it reports the most prevalent diseases induced by glycation, and the endogenous mechanisms and the current therapeutic interventions against it.
Collapse
Affiliation(s)
- Ana Belén Uceda
- Departament de Química, Universitat de Les Illes Balears, Health Research Institute of the Balearic Islands (IdISBa), Ctra. Valldemossa Km 7.5, 07122 Palma, Spain
| | - Laura Mariño
- Departament de Química, Universitat de Les Illes Balears, Health Research Institute of the Balearic Islands (IdISBa), Ctra. Valldemossa Km 7.5, 07122 Palma, Spain
| | - Rodrigo Casasnovas
- Departament de Química, Universitat de Les Illes Balears, Health Research Institute of the Balearic Islands (IdISBa), Ctra. Valldemossa Km 7.5, 07122 Palma, Spain
| | - Miquel Adrover
- Departament de Química, Universitat de Les Illes Balears, Health Research Institute of the Balearic Islands (IdISBa), Ctra. Valldemossa Km 7.5, 07122 Palma, Spain
| |
Collapse
|
|
4
|
Thakur V, Gonzalez MA, Parada M, Martinez RD, Chattopadhyay M. Role of Histone Deacetylase Inhibitor in Diabetic Painful Neuropathy. Mol Neurobiol 2024; 61:2283-2296. [PMID: 37875708 DOI: 10.1007/s12035-023-03701-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 10/06/2023] [Indexed: 10/26/2023]
Abstract
Diabetic painful neuropathy (DPN) is one of the most detrimental complications of diabetes. Alterations in neuroinflammatory mediators play significant roles in the development of DPN. Infiltration of the neutrophils and monocyte/macrophages contributes substantial role in the degenerative process of the distal sciatic nerve by forming neutrophil extracellular traps (NETs) under diabetic condition. Citrullination of histones due to increase in protein arginine deiminase (PAD) enzyme activity under hyperglycemia may promote NET formation, which can further increase the cytokine production by activating macrophages and proliferation of neutrophils. This study reveals that the increase in histone deacetylases (HDAC) is crucial in DPN and inhibition of HDAC using HDAC inhibitor (HDACi) FK228 would suppress NETosis and alleviate diabetic nerve degeneration and pain. FK228, also known as romidepsin, is FDA approved for the treatment of cutaneous T-cell lymphoma yet the molecular mechanisms of this drug are not completely understood in DPN. In this study, type 2 diabetic (T2D) mice with pain were treated with HDACi, FK228 1 mg/kg; I.P. 2 × /week for 3 weeks. The results demonstrate that FK228 treatment can alleviate thermal hyperalgesia and mechanical allodynia significantly along with changes in the expression of HDACs in the dorsal root ganglia (DRG) and spinal cord dorsal horn neurons of diabetic animals. The results also indicate that FK228 treatment can alter the expression of neutrophil elastase (NE), extracellular or cell free DNA (cfDNA), citrullinated histone-3 (CitH3), PADI4, growth-associated protein (GAP)-43, and glucose transporter (GLUT)-4. Overall, this study suggests that FK228 could amend the expression of nerve regeneration markers and inflammatory mediators in diabetic animals and may offer an alternative treatment approach for DPN.
Collapse
Affiliation(s)
- Vikram Thakur
- Department of Molecular and Translational Medicine, Center of Emphasis in Diabetes and Metabolism, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Mayra A Gonzalez
- Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Maria Parada
- Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Robert D Martinez
- Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA
| | - Munmun Chattopadhyay
- Department of Molecular and Translational Medicine, Center of Emphasis in Diabetes and Metabolism, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA.
- Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA.
- Francis Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA.
| |
Collapse
|
|
5
|
Lv Y, Yao X, Li X, Ouyang Y, Fan C, Qian Y. Cell metabolism pathways involved in the pathophysiological changes of diabetic peripheral neuropathy. Neural Regen Res 2024; 19:598-605. [PMID: 37721290 PMCID: PMC10581560 DOI: 10.4103/1673-5374.380872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/31/2023] [Accepted: 06/08/2023] [Indexed: 09/19/2023] Open
Abstract
Diabetic peripheral neuropathy is a common complication of diabetes mellitus. Elucidating the pathophysiological metabolic mechanism impels the generation of ideal therapies. However, existing limited treatments for diabetic peripheral neuropathy expose the urgent need for cell metabolism research. Given the lack of comprehensive understanding of energy metabolism changes and related signaling pathways in diabetic peripheral neuropathy, it is essential to explore energy changes and metabolic changes in diabetic peripheral neuropathy to develop suitable treatment methods. This review summarizes the pathophysiological mechanism of diabetic peripheral neuropathy from the perspective of cellular metabolism and the specific interventions for different metabolic pathways to develop effective treatment methods. Various metabolic mechanisms (e.g., polyol, hexosamine, protein kinase C pathway) are associated with diabetic peripheral neuropathy, and researchers are looking for more effective treatments through these pathways.
Collapse
Affiliation(s)
- Yaowei Lv
- Department of Orthopedics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, China
| | - Xiangyun Yao
- Department of Orthopedics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, China
- Youth Science and Technology Innovation Studio of Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao Li
- Department of Orthopedics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, China
- College of Fisheries and Life Science, Shanghai Ocean University, Shanghai, China
| | - Yuanming Ouyang
- Department of Orthopedics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, China
- Youth Science and Technology Innovation Studio of Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Cunyi Fan
- Department of Orthopedics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, China
- Youth Science and Technology Innovation Studio of Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yun Qian
- Department of Orthopedics, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Engineering Research Center for Orthopaedic Material Innovation and Tissue Regeneration, Shanghai, China
- Youth Science and Technology Innovation Studio of Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
6
|
Spallone V. Diabetic neuropathy: Current issues in diagnosis and prevention. CHRONIC COMPLICATIONS OF DIABETES MELLITUS 2024:117-163. [DOI: 10.1016/b978-0-323-88426-6.00016-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
|
|
7
|
Bozic I, Lavrnja I. Thiamine and benfotiamine: Focus on their therapeutic potential. Heliyon 2023; 9:e21839. [PMID: 38034619 PMCID: PMC10682628 DOI: 10.1016/j.heliyon.2023.e21839] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 10/27/2023] [Accepted: 10/30/2023] [Indexed: 12/02/2023] Open
Abstract
Thiamine, also known as vitamin B1, is an essential nutrient that plays a crucial role in energy metabolism and overall health. It is a water-soluble vitamin that plays an important role in the conversion of carbohydrates into energy in the body. Thiamine is essential for the proper functioning of the nervous system, heart and muscles. Thiamine deficiency is a life-threatening disease that leads to various disorders and lesions in the nerves and brain, at least in vertebrates. Several thiamine precursors with higher bioavailability have been developed to compensate for thiamine deficiency, including benfotiamine. Benfotiamine is more bioavailable and has higher tissue penetration than thiamine. Studies have shown its antioxidant and anti-inflammatory potential in activated immune and glial cells. It also improves complications observed in type 2 diabetes and has beneficial effects in mouse models of neurodegenerative disease. Benfotiamine represents an off-the-shelf agent used to support nerve health, promote healthy aging and support glucose metabolism. Accordingly, the present review aimed to provide an overview of the neuroprotective effects of thiamine/benfotiamine in the context of inflammation and oxidative stress.
Collapse
Affiliation(s)
- Iva Bozic
- Institute for Biological Research "Sinisa Stankovic"- National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| | - Irena Lavrnja
- Institute for Biological Research "Sinisa Stankovic"- National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia
| |
Collapse
|
|
8
|
Muley A, Fernandez R, Green H, Muley P. Effect of thiamine supplementation on glycaemic outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. BMJ Open 2022; 12:e059834. [PMID: 36008064 PMCID: PMC9422810 DOI: 10.1136/bmjopen-2021-059834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Patients with type 2 diabetes mellitus (T2DM) have been shown to have thiamine deficiency. Dietary supplementation is an economic strategy to control blood glucose. Objective: To evaluate effectiveness of thiamine supplementation on glycaemic outcomes in patients with T2DM. METHODS Eligibility criteria: Studies that assessed effect of thiamine supplementation in adults with T2DM which measured glycaemic outcomes-HbA1c, fasting blood glucose (FBG) and/or postprandial blood glucose (PPG) were included. Information sources: PUBMED, Tripdatabase, the Cochrane Central Register, National Institute of Health Clinical Database and Google Scholar were searched until December 2021 for RCTs. Risk of bias: It was assessed using standardised critical appraisal instruments from the Joanna Briggs Institute for RCTs. Synthesis of results: Where possible, studies were pooled in a meta-analysis. Results were presented in a narrative format if statistical pooling was not possible. RESULTS Included studies: Six trials involving 364 participants. Synthesis of results: No significant beneficial effects were observed on glycaemic outcomes with 100-900 mg/day of thiamine or benfotiamine for up to 3 months (HbA1c: MD, -0.02%, 95% CI: -0.35 to 0.31; FBG: MD,-0.20 mmol/L; 95% CI: -0.69 to 0.29; PPG: MD, - 0.20 mmol/L, 95% CI: -2.05 to 1.65 (mean difference, MD)). There was a significant increase in high-density lipoprotein (HDL) (MD, 0.10; 95% CI: 0.10 to 0.20) at 3-month follow-up. Benfotiamine reduced triglyceride level (MD, -1.10; 95% CI: -1.90 to -0.30) in 120 mg/day dose as compared with placebo 150 mg/day, however this was not demonstrated in higher doses. DISCUSSION Limitations of evidence: Inclusion of single-centre trials published only in English, small sample sizes of included studies, lack of trials investigating outcomes for same comparisons and varying follow-up periods. Interpretation: Thiamine supplementation does not affect glycaemic outcomes, however reduces triglycerides while increasing HDL. Multicentre well-designed RCT with higher doses of thiamine and a follow-up period of 1-2 years will provide better evidence. PROSPERO REGISTRATION NUMBER CRD42020170520.
Collapse
Affiliation(s)
- Arti Muley
- Medicine, PIMSR, Parul University, Vadodara, Gujarat, India
| | - Ritin Fernandez
- Nursing, University of Wollongong Faculty of Science Medicine and Health, Wollongong, New South Wales, Australia
| | - Heidi Green
- Nursing, Centre for Research in Nursing and Health, St George Hospital, Sydney, New South Wales, Australia
| | - Prasad Muley
- Pediatrics, PIMSR, Parul University, Vadodara, Gujarat, India
| |
Collapse
|
|
9
|
Therapeutic potential of vitamin B 1 derivative benfotiamine from diabetes to COVID-19. Future Med Chem 2022; 14:809-826. [PMID: 35535731 DOI: 10.4155/fmc-2022-0040] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Benfotiamine (S-benzoylthiamine-O-monophosphate), a unique, lipid-soluble derivative of thiamine, is the most potent allithiamine found in roasted garlic, as well as in other herbs of the genus Allium. In addition to potent antioxidative properties, benfotiamine has also been shown to be a strong anti-inflammatory agent with therapeutic significance to several pathological complications. Specifically, over the past decade or so, benfotiamine has been shown to prevent not only various secondary diabetic complications but also several inflammatory complications such as uveitis and endotoxemia. Recent studies also demonstrate that this compound could be used to prevent the symptoms associated with various infectious diseases such as HIV and COVID-19. In this review article, the authors discuss the significance of benfotiamine in the prevention of various pathological complications.
Collapse
|
|
10
|
Franceschi R, Mozzillo E, Di Candia F, Rosanio FM, Leonardi L, Liguori A, Micheli F, Cauvin V, Franzese A, Piona CA, Marcovecchio ML. A systematic review of the prevalence, risk factors and screening tools for autonomic and diabetic peripheral neuropathy in children, adolescents and young adults with type 1 diabetes. Acta Diabetol 2022; 59:293-308. [PMID: 35089443 DOI: 10.1007/s00592-022-01850-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 01/09/2022] [Indexed: 01/09/2023]
Abstract
AIMS We aimed to estimate the prevalence of Diabetic peripheral neuropathy (DPN) and Cardiac autonomic neuropathy (CAN) in youth with type 1 diabetes; identify key risk factors; identify the most useful tests for the diagnostic evaluation of DPN and CAN; identify key treatment options for DPN and CAN. METHODS A systematic search was performed including studies published in the last 15 years. PICO framework was used in the selection process and evidence was assessed using the GRADE system. RESULTS A total of 758 studies were identified and a final number of 49 studies were included in this systematic review. According to moderate-high level quality studies, the prevalence of probable DPN, ranged between 13.5 and 62%; subclinical DPN between 22 and 88%; confirmed DPN between 2.6 and 11%. The Michigan Neuropathy Screening Instrument was the tool with higher sensitivity and specificity for detecting DPN, which needs to be confirmed by nerve conduction velocity. The prevalence of CAN was 4-39%. Specific treatment options for DPN or CAN in patients younger than 25 years are not available. Key risk factors for DPN and CAN are hyperglycemia/HbA1c, age, diabetes duration, the presence of other microvascular complications, waist/height ratio, lipid profile and blood pressure. For CAN, additional risk factors were cigarette smoking, BMI and total daily insulin. CONCLUSIONS Prevalence of neuropathy in youth with type 1 diabetes varies depending on different screening methods and characteristics of the study populations. However, the assessed studies confirmed a relatively high prevalence of subclinical neuropathy, reiterating the importance of early identification of risk factors to prevent this complication.
Collapse
Affiliation(s)
- Roberto Franceschi
- Pediatric Diabetology Unit, Pediatric Department, S. Chiara General Hospital, Largo Medaglie d'Oro, 9, 38122, Trento, Italy.
| | - Enza Mozzillo
- Department of Translational Medical Science, Section of Pediatrics, Regional Center of Pediatric Diabetes, Federico II University of Naples, Naples, Italy
| | - Francesca Di Candia
- Department of Translational Medical Science, Section of Pediatrics, Regional Center of Pediatric Diabetes, Federico II University of Naples, Naples, Italy
| | - Francesco Maria Rosanio
- Department of Translational Medical Science, Section of Pediatrics, Regional Center of Pediatric Diabetes, Federico II University of Naples, Naples, Italy
| | - Letizia Leonardi
- Pediatric Diabetology Unit, Pediatric Department, S. Chiara General Hospital, Largo Medaglie d'Oro, 9, 38122, Trento, Italy
| | - Alice Liguori
- Pediatric Diabetology Unit, Pediatric Department, S. Chiara General Hospital, Largo Medaglie d'Oro, 9, 38122, Trento, Italy
| | - Francesca Micheli
- Pediatric Diabetology Unit, Pediatric Department, S. Chiara General Hospital, Largo Medaglie d'Oro, 9, 38122, Trento, Italy
| | - Vittoria Cauvin
- Pediatric Diabetology Unit, Pediatric Department, S. Chiara General Hospital, Largo Medaglie d'Oro, 9, 38122, Trento, Italy
| | - Adriana Franzese
- Department of Translational Medical Science, Section of Pediatrics, Regional Center of Pediatric Diabetes, Federico II University of Naples, Naples, Italy
| | - Claudia Anita Piona
- Section of Pediatric Diabetes and Metabolism, Department of Surgery, Dentistry, Gynecology and Pediatrics, University and Azienda Ospedaliera, Universitaria Integrata of Verona, Verona, Italy
| | - M Loredana Marcovecchio
- Department of Paediatrics, University of Cambridge and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| |
Collapse
|
|
11
|
Bönhof GJ, Sipola G, Strom A, Herder C, Strassburger K, Knebel B, Reule C, Wollmann JC, Icks A, Al-Hasani H, Roden M, Kuss O, Ziegler D. BOND study: a randomised double-blind, placebo-controlled trial over 12 months to assess the effects of benfotiamine on morphometric, neurophysiological and clinical measures in patients with type 2 diabetes with symptomatic polyneuropathy. BMJ Open 2022; 12:e057142. [PMID: 35115359 PMCID: PMC8814806 DOI: 10.1136/bmjopen-2021-057142] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION Diabetic sensorimotor polyneuropathy (DSPN) affects approximately 30% of people with diabetes, while around half of cases are symptomatic. Currently, there are only few pathogenetically oriented pharmacotherapies for DSPN, one of which is benfotiamine, a prodrug of thiamine with a high bioavailability and favourable safety profile. While benfotiamine has shown positive effects in preclinical and short-term clinical studies, no long-term clinical trials are available to demonstrate disease-modifying effects on DSPN using a comprehensive set of disease-related endpoints. METHODS AND ANALYSIS The benfotiamine on morphometric, neurophysiological and clinical measures in patients with type 2 diabetes trial is a randomised double-blind, placebo-controlled parallel group monocentric phase II clinical trial to assess the effects of treatment with benfotiamine compared with placebo in participants with type 2 diabetes and mild to moderate symptomatic DSPN. Sixty participants will be 1:1 randomised to treatment with benfotiamine 300 mg or placebo two times a day over 12 months. The primary endpoint will be the change in corneal nerve fibre length assessed by corneal confocal microscopy (CCM) after 12 months of benfotiamine treatment compared with placebo. Secondary endpoints will include other CCM measures, skin biopsy and function indices, variables from somatic and autonomic nerve function tests, clinical examination and questionnaires, general health, health-related quality of life, cost, safety and blood tests. ETHICS AND DISSEMINATION The trial was approved by the competent authority and the local independent ethics committee. Trial results will be published in peer-reviewed journals, conference abstracts, and via online and print media. TRIAL REGISTRATION NUMBER DRKS00014832.
Collapse
Affiliation(s)
- Gidon J Bönhof
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Gundega Sipola
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | - Alexander Strom
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research, Partner Düsseldorf, Munich-Neuherberg, Germany
| | - Christian Herder
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Klaus Strassburger
- German Center for Diabetes Research, Partner Düsseldorf, Munich-Neuherberg, Germany
- Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | - Birgit Knebel
- German Center for Diabetes Research, Partner Düsseldorf, Munich-Neuherberg, Germany
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | | | | | - Andrea Icks
- Institute for Health Services Research and Health Economics, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- Institute for Health Services Research and Health Economics, Centre for Health and Society, Medical Faculty and University Hospital Düsseldorf at Heinrich-Heine-University, Düsseldorf, Germany
| | - Hadi Al-Hasani
- German Center for Diabetes Research, Partner Düsseldorf, Munich-Neuherberg, Germany
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| | - Oliver Kuss
- Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- Centre for Health and Society, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany
| | - Dan Ziegler
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany
| |
Collapse
|
|
12
|
Farah S, Yammine K. A systematic review on the efficacy of vitamin B supplementation on diabetic peripheral neuropathy. Nutr Rev 2022; 80:1340-1355. [PMID: 34990506 DOI: 10.1093/nutrit/nuab116] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
CONTEXT Diabetic peripheral neuropathy (DPN) is a common complication. OBJECTIVE To re-evaluate the role of vitamin B supplementation on reducing the signs and symptoms of DPN. DATA SOURCES Electronic databases such as PubMed, Cochrane Library, and Medline. DATA EXTRACTION An Excel spreadsheet was used to report the extracted relevant data. DATA ANALYSIS Fourteen randomized controlled trials were selected, comprising a pooled sample of 997 study subjects. The pooled odds ratio values were 3.1 (95%CI, 1.197-8.089) and 3.04 (95%CI, 1.556-5.937) for pain and dysesthesia outcomes, respectively. For the amplitude change in electromyography of the sensory sural nerve, the weighted difference from 2 studies was 0.37 (95%CI, 0.034-0.709) in favor of intervention. Peak latency changes were in favor of the intervention group. Two studies yielded a weighted difference of 0.571 (95%CI, 0.310-0.831) for the velocity outcome in favor of intervention. Unlike the fibular nerve, the electromyographic motor outcomes of the tibial nerve were in favor of vitamin B supplementation. CONCLUSION Vitamin B supplementation could improve many symptoms and signs of DPN.
Collapse
Affiliation(s)
- Stephanie Farah
- Postdoctoral Research Fellow, Lebanese American University Medical Center, Beirut, Lebanon
| | - Kaissar Yammine
- Department of Orthopedic Surgery, Lebanese American University Medical Center-Rizk Hospital; Diabetic Foot Clinic; and the Center for Evidence-Based Anatomy, Sport & Orthopedic Research, Lebanese American University, School of Medicine, Beirut, Lebanon
| |
Collapse
|
|
13
|
Khalil H, Ang CD, Khalil V. Vitamin B for treating diabetic peripheral neuropathy - A systematic review. Diabetes Metab Syndr 2021; 15:102213. [PMID: 34298270 DOI: 10.1016/j.dsx.2021.102213] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 07/12/2021] [Accepted: 07/13/2021] [Indexed: 11/21/2022]
Abstract
UNLABELLED This systematic review assesses the effectiveness and safety of vitamin B supplements for the management of neuropathy in people with diabetes. METHODS Several databases including, the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL Plus were searched from their inception until May 2020. RESULTS Five studies were eligible to be included in this review with a total of 348 participants. Overall, the evidence is too uncertain to draw conclusions on the effects of B vitamins in people with DPN. CONCLUSION It is uncertain whether vitamin B supplements change pain intensity or impairment in the short or long term in people with DPN.
Collapse
Affiliation(s)
- Hanan Khalil
- School of Psychology and Public Health La Trobe University, 360 Collins Street Melbourne Victoria, Vic, 3000, Australia.
| | - Cynthia D Ang
- Department of Rehabilitation Medicine, University of the Philippines, College of Medicine and Philippine General Hospital, Manila, Philippines
| | - Viviane Khalil
- Pharmacy Department, Monash Health, Monash University, Clayton, Vic, Australia
| |
Collapse
|
|
14
|
Cho E, Kim W. Effect of Acupuncture on Diabetic Neuropathy: A Narrative Review. Int J Mol Sci 2021; 22:ijms22168575. [PMID: 34445280 PMCID: PMC8395323 DOI: 10.3390/ijms22168575] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/02/2021] [Accepted: 08/05/2021] [Indexed: 12/17/2022] Open
Abstract
Diabetic neuropathy, a major complication of diabetes mellitus, refers to a collection of clinically diverse disorders affecting the nervous system that may present with pain. Although the number of patients suffering from severe neuropathy is increasing, no optimal treatment method has been developed yet. Acupuncture is well known for its ability to reduce various kinds of pain, and a number of studies have also reported its effect on diabetes mellitus; however, its effect and underlying mechanism against diabetic neuropathy are not yet clearly understood. In this review, ten and five studies performed in humans and animals, respectively, were analyzed. All studies reported that acupuncture significantly relieved diabetic neuropathy. ST36, BL13, BL20, SP6, and SP9 were the most widely used acupoints. Five studies used electro-acupuncture, whereas other studies used manual acupuncture. Furthermore, the effect of acupuncture was shown to be mediated through the various molecules present in the peripheral nerves and spinal cord, such as P65, GPR78, and TRPV1. Five studies reported side effects, such as swelling, numbness, and nausea, but none were reported to be serious. Based on these results, we suggest that acupuncture should be considered as a treatment option for diabetic neuropathy.
Collapse
|
|
15
|
Sloan G, Selvarajah D, Tesfaye S. Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy. Nat Rev Endocrinol 2021; 17:400-420. [PMID: 34050323 DOI: 10.1038/s41574-021-00496-z] [Citation(s) in RCA: 222] [Impact Index Per Article: 55.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/15/2021] [Indexed: 02/08/2023]
Abstract
Diabetic sensorimotor peripheral neuropathy (DSPN) is a serious complication of diabetes mellitus and is associated with increased mortality, lower-limb amputations and distressing painful neuropathic symptoms (painful DSPN). Our understanding of the pathophysiology of the disease has largely been derived from animal models, which have identified key potential mechanisms. However, effective therapies in preclinical models have not translated into clinical trials and we have no universally accepted disease-modifying treatments. Moreover, the condition is generally diagnosed late when irreversible nerve damage has already taken place. Innovative point-of-care devices have great potential to enable the early diagnosis of DSPN when the condition might be more amenable to treatment. The management of painful DSPN remains less than optimal; however, studies suggest that a mechanism-based approach might offer an enhanced benefit in certain pain phenotypes. The management of patients with DSPN involves the control of individualized cardiometabolic targets, a multidisciplinary approach aimed at the prevention and management of foot complications, and the timely diagnosis and management of neuropathic pain. Here, we discuss the latest advances in the mechanisms of DSPN and painful DSPN, originating both from the periphery and the central nervous system, as well as the emerging diagnostics and treatments.
Collapse
Affiliation(s)
- Gordon Sloan
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Dinesh Selvarajah
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
- Department of Oncology and Human Metabolism, University of Sheffield, Sheffield, UK
| | - Solomon Tesfaye
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
| |
Collapse
|
|
16
|
Karaganis S, Song XJ. B vitamins as a treatment for diabetic pain and neuropathy. J Clin Pharm Ther 2021; 46:1199-1212. [PMID: 33565138 DOI: 10.1111/jcpt.13375] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 01/06/2021] [Accepted: 01/20/2021] [Indexed: 12/16/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE B vitamin therapy is a common treatment for diabetic pain and neuropathy, yet its use remains controversial in patients lacking B vitamin deficiencies. The aim of this review was to summarize the current evidence for the efficacy of B vitamin therapy in diabetic patients with neuropathy. COMMENT We screened the English literature for clinical studies evaluating B vitamins as a therapy for pain and neuropathy in diabetic patients. We selected 43 relevant studies for qualitative analysis based on our selection criteria. Our survey of the literature revealed substantive heterogeneity with respect to efficacies of reported outcomes, as well as study design. Most beneficial outcomes were reported against baseline measures, with few positive comparisons against placebo. This highlights the need for larger, placebo-controlled studies. WHAT IS NEW AND CONCLUSION B vitamins should be considered a plausible therapy for diabetic neuropathy, but its overall efficacy remains uncertain and requires further study.
Collapse
Affiliation(s)
- Stephen Karaganis
- Department of Life, Earth, and Environmental Science, West Texas A&M University, Canyon, TX, USA.,SUSTech Center for Pain Medicine and the Medical School, Southern University of Science and Technology, Shenzhen, China
| | - Xue-Jun Song
- SUSTech Center for Pain Medicine and the Medical School, Southern University of Science and Technology, Shenzhen, China
| |
Collapse
|
|
17
|
Røikjer J, Mørch CD, Ejskjaer N. Diabetic Peripheral Neuropathy: Diagnosis and Treatment. Curr Drug Saf 2020; 16:2-16. [PMID: 32735526 DOI: 10.2174/1574886315666200731173113] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/04/2020] [Accepted: 06/16/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND Diabetic peripheral neuropathy (DPN) is traditionally divided into large and small fibre neuropathy (SFN). Damage to the large fibres can be detected using nerve conduction studies (NCS) and often results in a significant reduction in sensitivity and loss of protective sensation, while damage to the small fibres is hard to reliably detect and can be either asymptomatic, associated with insensitivity to noxious stimuli, or often manifests itself as intractable neuropathic pain. OBJECTIVE To describe the recent advances in both detection, grading, and treatment of DPN as well as the accompanying neuropathic pain. METHODS A review of relevant, peer-reviewed, English literature from MEDLINE, EMBASE and Cochrane Library between January 1st 1967 and January 1st 2020 was used. RESULTS We identified more than three hundred studies on methods for detecting and grading DPN, and more than eighty randomised-controlled trials for treating painful diabetic neuropathy. CONCLUSION NCS remains the method of choice for detecting LFN in people with diabetes, while a gold standard for the detection of SFN is yet to be internationally accepted. In the recent years, several methods with huge potential for detecting and grading this condition have become available including skin biopsies and corneal confocal microscopy, which in the future could represent reliable endpoints for clinical studies. While several newer methods for detecting SFN have been developed, no new drugs have been accepted for treating neuropathic pain in people with diabetes. Tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors and anticonvulsants remain first line treatment, while newer agents targeting the proposed pathophysiology of DPN are being developed.
Collapse
Affiliation(s)
- Johan Røikjer
- Department of Health Science and Technology, Aalborg University Hospital, Aalborg University, Aalborg, Denmark
| | - Carsten Dahl Mørch
- Department of Health Science and Technology, Aalborg University Hospital, Aalborg University, Aalborg, Denmark
| | - Niels Ejskjaer
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| |
Collapse
|
|
18
|
Jain R, Özgümüş T, Jensen TM, du Plessis E, Keindl M, Møller CL, Falhammar H, Nyström T, Catrina SB, Jörneskog G, Jessen LE, Forsblom C, Haukka JK, Groop PH, Rossing P, Groop L, Eliasson M, Eliasson B, Brismar K, Al-Majdoub M, Nilsson PM, Taskinen MR, Ferrannini E, Spégel P, Berg TJ, Lyssenko V. Liver nucleotide biosynthesis is linked to protection from vascular complications in individuals with long-term type 1 diabetes. Sci Rep 2020; 10:11561. [PMID: 32665614 PMCID: PMC7360755 DOI: 10.1038/s41598-020-68130-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 05/29/2020] [Indexed: 12/11/2022] Open
Abstract
Identification of biomarkers associated with protection from developing diabetic complications is a prerequisite for an effective prevention and treatment. The aim of the present study was to identify clinical and plasma metabolite markers associated with freedom from vascular complications in people with very long duration of type 1 diabetes (T1D). Individuals with T1D, who despite having longer than 30 years of diabetes duration never developed major macro- or microvascular complications (non-progressors; NP) were compared with those who developed vascular complications within 25 years from diabetes onset (rapid progressors; RP) in the Scandinavian PROLONG (n = 385) and DIALONG (n = 71) cohorts. The DIALONG study also included 75 healthy controls. Plasma metabolites were measured using gas and/or liquid chromatography coupled to mass spectrometry. Lower hepatic fatty liver indices were significant common feature characterized NPs in both studies. Higher insulin sensitivity and residual ß-cell function (C-peptide) were also associated with NPs in PROLONG. Protection from diabetic complications was associated with lower levels of the glycolytic metabolite pyruvate and APOCIII in PROLONG, and with lower levels of thiamine monophosphate and erythritol, a cofactor and intermediate product in the pentose phosphate pathway as well as higher phenylalanine, glycine and serine in DIALONG. Furthermore, T1D individuals showed elevated levels of picolinic acid as compared to the healthy individuals. The present findings suggest a potential beneficial shunting of glycolytic substrates towards the pentose phosphate and one carbon metabolism pathways to promote nucleotide biosynthesis in the liver. These processes might be linked to higher insulin sensitivity and lower liver fat content, and might represent a mechanism for protection from vascular complications in individuals with long-term T1D.
Collapse
Affiliation(s)
- Ruchi Jain
- Department of Clinical Science/Diabetes and Endocrinology, Lund University Diabetes Centre, 205 02, Malmö, Sweden
| | - Türküler Özgümüş
- Department of Clinical Science, Center for Diabetes Research, University of Bergen, 5032, Bergen, Norway
| | - Troels Mygind Jensen
- Research Unit for General Practice, Danish Aging Research Center, University of Southern Denmark, Odense, Denmark.,Steno Diabetes Center Copenhagen, Gentofte, Denmark
| | - Elsa du Plessis
- Department of Clinical Science, Center for Diabetes Research, University of Bergen, 5032, Bergen, Norway
| | - Magdalena Keindl
- Department of Clinical Science, Center for Diabetes Research, University of Bergen, 5032, Bergen, Norway
| | | | - Henrik Falhammar
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.,Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden
| | - Thomas Nyström
- Department of Clinical Science and Education, Division of Internal Medicine, Unit for Diabetes Research, Karolinska Institute, South Hospital, Stockholm, Sweden
| | - Sergiu-Bogdan Catrina
- Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.,Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.,Center for Diabetes, Academica Specialist Centrum, Stockholm, Sweden
| | - Gun Jörneskog
- Department of Clinical Sciences, Division of Internal Medicine, Karolinska Institute, Danderyd University Hospital, Stockholm, Sweden
| | - Leon Eyrich Jessen
- Department of Health Technology, Section for Bioinformatics, Technical University of Denmark, Lyngby, Denmark
| | - Carol Forsblom
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.,Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Biomedicum Helsinki, Helsinki, Finland.,Research Programs for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Jani K Haukka
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.,Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Biomedicum Helsinki, Helsinki, Finland.,Research Programs for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Per-Henrik Groop
- Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.,Abdominal Center, Nephrology, University of Helsinki and Helsinki University Hospital, Biomedicum Helsinki, Helsinki, Finland.,Research Programs for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.,Department of Diabetes, Central Clinical School, Monash University, Melbourne, VIC, Australia
| | - Peter Rossing
- Steno Diabetes Center Copenhagen, Gentofte, Denmark.,Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Leif Groop
- Department of Clinical Science/Diabetes and Endocrinology, Lund University Diabetes Centre, 205 02, Malmö, Sweden.,Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland
| | - Mats Eliasson
- Department of Public Health and Clinical Medicine, Sunderby Research Unit, Umeå University, Umeå, Sweden
| | - Björn Eliasson
- Department of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Kerstin Brismar
- Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden.,Department of Molecular Medicine and Surgery, Rolf Luft Center for Diabetes Research, Karolinska Institutet, Stockholm, Sweden.,Karolinska University Hospital, Solna, Stockholm, Sweden
| | - Mahmoud Al-Majdoub
- Department of Clinical Science/Diabetes and Endocrinology, Lund University Diabetes Centre, 205 02, Malmö, Sweden
| | - Peter M Nilsson
- Department of Clinical Science/Diabetes and Endocrinology, Lund University Diabetes Centre, 205 02, Malmö, Sweden
| | - Marja-Riitta Taskinen
- Research Program Unit, Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
| | | | - Peter Spégel
- Centre for Analysis and Synthesis, Department of Chemistry, Lund University, 223 62, Lund, Sweden
| | - Tore Julsrud Berg
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Department of Endocrinology, Oslo University Hospital, Oslo, Norway
| | - Valeriya Lyssenko
- Department of Clinical Science/Diabetes and Endocrinology, Lund University Diabetes Centre, 205 02, Malmö, Sweden. .,Department of Clinical Science, Center for Diabetes Research, University of Bergen, 5032, Bergen, Norway.
| |
Collapse
|
|
19
|
Stino AM, Rumora AE, Kim B, Feldman EL. Evolving concepts on the role of dyslipidemia, bioenergetics, and inflammation in the pathogenesis and treatment of diabetic peripheral neuropathy. J Peripher Nerv Syst 2020; 25:76-84. [PMID: 32412144 PMCID: PMC7375363 DOI: 10.1111/jns.12387] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/11/2020] [Accepted: 05/11/2020] [Indexed: 12/14/2022]
Abstract
Diabetic peripheral neuropathy (DPN) is one of the most widespread and disabling neurological conditions, accounting for half of all neuropathy cases worldwide. Despite its high prevalence, no approved disease modifying therapies exist. There is now a growing body of evidence that DPN secondary to type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) represents different disease processes, with T2DM DPN best understood within the context of metabolic syndrome rather than hyperglycemia. In this review, we highlight currently understood mechanisms of DPN, along with their corresponding potential therapeutic targets. We frame this discussion within a practical overview of how the field evolved from initial human observations to murine pathomechanistic and therapeutic models into ongoing and human clinical trials, with particular emphasis on T2DM DPN and metabolic syndrome.
Collapse
Affiliation(s)
- Amro Maher Stino
- Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, USA 48109
- Division of Neuromuscular Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA 48109
| | - Amy E. Rumora
- Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, USA 48109
| | - Bhumsoo Kim
- Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, USA 48109
| | - Eva L. Feldman
- Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI, USA 48109
- Division of Neuromuscular Medicine, University of Michigan School of Medicine, Ann Arbor, MI, USA 48109
| |
Collapse
|
|
20
|
Le Bagge S, Fotheringham AK, Leung SS, Forbes JM. Targeting the receptor for advanced glycation end products (RAGE) in type 1 diabetes. Med Res Rev 2020; 40:1200-1219. [PMID: 32112452 DOI: 10.1002/med.21654] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 11/09/2019] [Accepted: 11/12/2019] [Indexed: 12/18/2022]
Abstract
Type 1 diabetes (T1D) is one of the most common chronic diseases manifesting in early life, with the prevalence increasing worldwide at a rate of approximately 3% per annum. The prolonged hyperglycaemia characteristic of T1D upregulates the receptor for advanced glycation end products (RAGE) and accelerates the formation of RAGE ligands, including advanced glycation end products, high-mobility group protein B1, S100 calcium-binding proteins, and amyloid-beta. Interestingly, changes in the expression of RAGE and these ligands are evident in patients before the onset of T1D. RAGE signals via various proinflammatory cascades, resulting in the production of reactive oxygen species and cytokines. A large number of proinflammatory ligands that can signal via RAGE have been implicated in several chronic diseases, including T1D. Therefore, it is unsurprising that RAGE has become a potential therapeutic target for the treatment and prevention of disease. In this review, we will explore how RAGE might be targeted to prevent the development of T1D.
Collapse
Affiliation(s)
- Selena Le Bagge
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Amelia K Fotheringham
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Sherman S Leung
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - Josephine M Forbes
- Glycation and Diabetes, Translational Research Institute (TRI), Mater Research Institute-The University of Queensland (MRI-UQ), Brisbane, Queensland, Australia.,Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.,Mater Clinical School, The University of Queensland, Brisbane, Queensland, Australia
| |
Collapse
|
|
21
|
Ge T, Yang J, Zhou S, Wang Y, Li Y, Tong X. The Role of the Pentose Phosphate Pathway in Diabetes and Cancer. Front Endocrinol (Lausanne) 2020; 11:365. [PMID: 32582032 PMCID: PMC7296058 DOI: 10.3389/fendo.2020.00365] [Citation(s) in RCA: 247] [Impact Index Per Article: 49.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Accepted: 05/11/2020] [Indexed: 12/14/2022] Open
Abstract
The pentose phosphate pathway (PPP) branches from glucose 6-phosphate (G6P), produces NADPH and ribose 5-phosphate (R5P), and shunts carbons back to the glycolytic or gluconeogenic pathway. The PPP has been demonstrated to be a major regulator for cellular reduction-oxidation (redox) homeostasis and biosynthesis. Enzymes in the PPP are reported to play important roles in many human diseases. In this review, we will discuss the role of the PPP in type 2 diabetes and cancer.
Collapse
|
|
22
|
Abstract
The global epidemic of prediabetes and diabetes has led to a corresponding epidemic of complications of these disorders. The most prevalent complication is neuropathy, of which distal symmetric polyneuropathy (for the purpose of this Primer, referred to as diabetic neuropathy) is very common. Diabetic neuropathy is a loss of sensory function beginning distally in the lower extremities that is also characterized by pain and substantial morbidity. Over time, at least 50% of individuals with diabetes develop diabetic neuropathy. Glucose control effectively halts the progression of diabetic neuropathy in patients with type 1 diabetes mellitus, but the effects are more modest in those with type 2 diabetes mellitus. These findings have led to new efforts to understand the aetiology of diabetic neuropathy, along with new 2017 recommendations on approaches to prevent and treat this disorder that are specific for each type of diabetes. In parallel, new guidelines for the treatment of painful diabetic neuropathy using distinct classes of drugs, with an emphasis on avoiding opioid use, have been issued. Although our understanding of the complexities of diabetic neuropathy has substantially evolved over the past decade, the distinct mechanisms underlying neuropathy in type 1 and type 2 diabetes remains unknown. Future discoveries on disease pathogenesis will be crucial to successfully address all aspects of diabetic neuropathy, from prevention to treatment.
Collapse
|
|
23
|
Feldman EL, Callaghan BC, Pop-Busui R, Zochodne DW, Wright DE, Bennett DL, Bril V, Russell JW, Viswanathan V. Diabetic neuropathy. Nat Rev Dis Primers 2019; 5:42. [PMID: 31197183 PMCID: PMC7096070 DOI: 10.1038/s41572-019-0097-9] [Citation(s) in RCA: 115] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The global epidemic of prediabetes and diabetes has led to a corresponding epidemic of complications of these disorders. The most prevalent complication is neuropathy, of which distal symmetric polyneuropathy (for the purpose of this Primer, referred to as diabetic neuropathy) is very common. Diabetic neuropathy is a loss of sensory function beginning distally in the lower extremities that is also characterized by pain and substantial morbidity. Over time, at least 50% of individuals with diabetes develop diabetic neuropathy. Glucose control effectively halts the progression of diabetic neuropathy in patients with type 1 diabetes mellitus, but the effects are more modest in those with type 2 diabetes mellitus. These findings have led to new efforts to understand the aetiology of diabetic neuropathy, along with new 2017 recommendations on approaches to prevent and treat this disorder that are specific for each type of diabetes. In parallel, new guidelines for the treatment of painful diabetic neuropathy using distinct classes of drugs, with an emphasis on avoiding opioid use, have been issued. Although our understanding of the complexities of diabetic neuropathy has substantially evolved over the past decade, the distinct mechanisms underlying neuropathy in type 1 and type 2 diabetes remains unknown. Future discoveries on disease pathogenesis will be crucial to successfully address all aspects of diabetic neuropathy, from prevention to treatment.
Collapse
Affiliation(s)
- Eva L. Feldman
- Department of Neurology, University of Michigan, Ann Arbor, MI, USA.,
| | | | - Rodica Pop-Busui
- Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes (MEND), University of Michigan, Ann Arbor, MI, USA
| | - Douglas W. Zochodne
- Division of Neurology, Department of Medicine and the Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Douglas E. Wright
- Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - David L. Bennett
- Nuffield Department of Clinical Neuroscience, University of Oxford, Oxford, UK
| | - Vera Bril
- Division of Neurology, Department of Medicine, University of Toronto and University Health Network, Toronto, Ontario, Canada.,Institute for Research and Medical Consultations, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - James W. Russell
- Department of Neurology, University of Maryland and VA Maryland Health Care System, Baltimore, MD, USA
| | | |
Collapse
|
|
24
|
Fishman SL, Sonmez H, Basman C, Singh V, Poretsky L. The role of advanced glycation end-products in the development of coronary artery disease in patients with and without diabetes mellitus: a review. Mol Med 2018; 24:59. [PMID: 30470170 PMCID: PMC6251169 DOI: 10.1186/s10020-018-0060-3] [Citation(s) in RCA: 197] [Impact Index Per Article: 28.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 11/04/2018] [Indexed: 12/18/2022] Open
Abstract
Background Traditional risk factors are insufficient to explain all cases of coronary artery disease (CAD) in patients with diabetes mellitus (DM). Advanced glycation end-products (AGEs) and their receptors may play important roles in the development and progression of CAD. Body Hyperglycemia is the hallmark feature of DM. An increase in the incidence of both micro-and macrovascular complications of diabetes has been observed with increased duration of hyperglycemia. This association persists even after glycemic control has been achieved, suggesting an innate mechanism of “metabolic memory.” AGEs are glycated proteins that may serve as mediators of metabolic memory due to their increased production in the setting of hyperglycemia and generally slow turnover. Elevated AGE levels can lead to abnormal cross linking of extracellular and intracellular proteins disrupting their normal structure and function. Furthermore, activation of AGE receptors can induce complex signaling pathways leading to increased inflammation, oxidative stress, enhanced calcium deposition, and increased vascular smooth muscle apoptosis, contributing to the development of atherosclerosis. Through these mechanisms, AGEs may be important mediators of the development of CAD. However, clinical studies regarding the role of AGEs and their receptors in advancing CAD are limited, with contradictory results. Conclusion AGEs and their receptors may be useful biomarkers for the presence and severity of CAD. Further studies are needed to evaluate the utility of circulating and tissue AGE levels in identifying asymptomatic patients at risk for CAD or to identify patients who may benefit from invasive intervention.
Collapse
Affiliation(s)
- Sarah Louise Fishman
- Division of Endocrinology, Department of Medicine, Lenox Hill Hospital, Northwell Health, 110 East 59th St #8B, New York, NY, 10022, USA
| | - Halis Sonmez
- Center for Diabetes and Endocrinology, 111 Salem Tpke, Norwich, CT, 06360, USA
| | - Craig Basman
- Department of Cardiology, Lenox Hill Hospital, Northwell Health, 100 East 77th St, New York, NY, 10065, USA
| | - Varinder Singh
- Department of Cardiology, Lenox Hill Hospital, Northwell Health, 100 East 77th St, New York, NY, 10065, USA
| | - Leonid Poretsky
- Division of Endocrinology, Department of Medicine, Lenox Hill Hospital, Northwell Health, 110 East 59th St #8B, New York, NY, 10022, USA.
| |
Collapse
|
|
25
|
Chen JH, Lin X, Bu C, Zhang X. Role of advanced glycation end products in mobility and considerations in possible dietary and nutritional intervention strategies. Nutr Metab (Lond) 2018; 15:72. [PMID: 30337945 PMCID: PMC6180645 DOI: 10.1186/s12986-018-0306-7] [Citation(s) in RCA: 115] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 09/21/2018] [Indexed: 02/08/2023] Open
Abstract
Advanced glycation end products (AGEs), a group of compounds that are formed by non-enzymatic reactions between carbonyl groups of reducing sugars and free amino groups of proteins, lipids or nucleic acids, can be obtained exogenously from diet or formed endogenously within the body. AGEs accumulate intracellularly and extracellularly in all tissues and body fluids and can cross-link with other proteins and thus affect their normal functions. Furthermore, AGEs can interact with specific cell surface receptors and hence alter cell intracellular signaling, gene expression, the production of reactive oxygen species and the activation of several inflammatory pathways. High levels of AGEs in diet as well as in tissues and the circulation are pathogenic to a wide range of diseases. With respect to mobility, AGEs accumulate in bones, joints and skeletal muscles, playing important roles in the development of osteoporosis, osteoarthritis, and sarcopenia with aging. This report covered the related pathological mechanisms and the potential pharmaceutical and dietary intervention strategies in reducing systemic AGEs. More prospective studies are needed to determine whether elevated serum AGEs and/or skin autofluorescence predict a decline in measures of mobility. In addition, human intervention studies are required to investigate the beneficial effects of exogenous AGEs inhibitors on mobility outcomes.
Collapse
Affiliation(s)
- Jie-Hua Chen
- Science and Technology Centre, By-Health Co. Ltd, No. 3 Kehui 3rd Street, No. 99 Kexue Avenue Central, Science City, Luogang District, Guangzhou, 510000 China
| | - Xu Lin
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200031 China
| | - Cuihong Bu
- Science and Technology Centre, By-Health Co. Ltd, No. 3 Kehui 3rd Street, No. 99 Kexue Avenue Central, Science City, Luogang District, Guangzhou, 510000 China
| | - Xuguang Zhang
- Science and Technology Centre, By-Health Co. Ltd, No. 3 Kehui 3rd Street, No. 99 Kexue Avenue Central, Science City, Luogang District, Guangzhou, 510000 China
| |
Collapse
|
|
26
|
Dewanjee S, Das S, Das AK, Bhattacharjee N, Dihingia A, Dua TK, Kalita J, Manna P. Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets. Eur J Pharmacol 2018; 833:472-523. [DOI: 10.1016/j.ejphar.2018.06.034] [Citation(s) in RCA: 117] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Revised: 06/15/2018] [Accepted: 06/26/2018] [Indexed: 02/07/2023]
|
|
27
|
Fadini GP, DiPersio JF. Diabetes mellitus as a poor mobilizer condition. Blood Rev 2017; 32:184-191. [PMID: 29132746 DOI: 10.1016/j.blre.2017.11.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 11/02/2017] [Accepted: 11/07/2017] [Indexed: 01/04/2023]
Abstract
Hematopoietic stem cell (HSC) transplantation in an effective and curative therapy for numerous hematological malignancies. Mobilization of HSCs from bone marrow (BM) to peripheral blood (PB) followed by apheresis is the gold standard for obtaining HSCs for both autologous and allogeneic stem cell transplantation. After administration of granulocyte-colony stimulating factor (G-CSF), up to 30% of patients fail to mobilize "optimal" numbers of HSCs required for engraftment. This review summarizes the current experimental and clinical evidence that diabetes mellitus is a risk factor for poor mobilization. Diabetes causes a profound remodeling of the HSC niche, resulting in impaired release of HSCs. Experimental studies indicate that hyperglycemia hampers regulation of CXCL12 and clinical studies suggest that diabetes impairs HSC mobilization especially in response to G-CSF, but less to plerixafor. Understanding further the biochemical alterations in the diabetic BM will provide insights into future therapeutic strategies to reverse the so-called "diabetic stem cell mobilopathy".
Collapse
Affiliation(s)
- Gian Paolo Fadini
- Department of Medicine, University of Padova, 35128 Padova, Italy; Venetian Institute of Molecular Medicine, 35128 Padova, Italy.
| | - John F DiPersio
- Washington University School of Medicine, St Louis, MO, United States.
| |
Collapse
|
|
28
|
Chen X, Su T, Chen Y, He Y, Liu Y, Xu Y, Wei Y, Li J, He R. d-Ribose as a Contributor to Glycated Haemoglobin. EBioMedicine 2017; 25:143-153. [PMID: 29033370 PMCID: PMC5704047 DOI: 10.1016/j.ebiom.2017.10.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 09/28/2017] [Accepted: 10/02/2017] [Indexed: 12/19/2022] Open
Abstract
Glycated haemoglobin (HbA1c) is the most important marker of hyperglycaemia in diabetes mellitus. We show that d-ribose reacts with haemoglobin, thus yielding HbA1c. Using mass spectrometry, we detected glycation of haemoglobin with d-ribose produces 10 carboxylmethyllysines (CMLs). The first-order rate constant of fructosamine formation for d-ribose was approximately 60 times higher than that for d-glucose at the initial stage. Zucker Diabetic Fatty (ZDF) rat, a common model for type 2 diabetes mellitus (T2DM), had high levels of d-ribose and HbA1c, accompanied by a decrease of transketolase (TK) in the liver. The administration of benfotiamine, an activator of TK, significantly decreased d-ribose followed by a decline in HbA1c. In clinical investigation, T2DM patients with high HbA1c had a high level of urine d-ribose, though the level of their urine d-glucose was low. That is, d-ribose contributes to HbA1c, which prompts future studies to further explore whether d-ribose plays a role in the pathophysiological mechanism of T2DM.
Collapse
Affiliation(s)
- Xixi Chen
- State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, University of Chinese Academy of Sciences, Beijing 100101, China
| | - Tao Su
- State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, University of Chinese Academy of Sciences, Beijing 100101, China
| | - Yao Chen
- Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Yingge He
- State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, University of Chinese Academy of Sciences, Beijing 100101, China
| | - Ying Liu
- State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, University of Chinese Academy of Sciences, Beijing 100101, China
| | - Yong Xu
- Southwest Medical University, Luzhou, Sichuan 646000, China
| | - Yan Wei
- State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, University of Chinese Academy of Sciences, Beijing 100101, China; CAS Key Laboratory of Mental Health, Institute of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China.
| | - Juan Li
- CAS Key Laboratory of Mental Health, Institute of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China
| | - Rongqiao He
- State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, University of Chinese Academy of Sciences, Beijing 100101, China; CAS Key Laboratory of Mental Health, Institute of Psychology, University of Chinese Academy of Sciences, Beijing 100101, China; Alzheimer's Disease Center, Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China.
| |
Collapse
|
|
29
|
Parasoglou P, Rao S, Slade JM. Declining Skeletal Muscle Function in Diabetic Peripheral Neuropathy. Clin Ther 2017; 39:1085-1103. [PMID: 28571613 PMCID: PMC5503477 DOI: 10.1016/j.clinthera.2017.05.001] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 04/27/2017] [Accepted: 05/01/2017] [Indexed: 12/25/2022]
Abstract
PURPOSE The present review highlights current concepts regarding the effects of diabetic peripheral neuropathy (DPN) in skeletal muscle. It discusses the lack of effective pharmacologic treatments and the role of physical exercise intervention in limb protection and symptom reversal. It also highlights the importance of magnetic resonance imaging (MRI) techniques in providing a mechanistic understanding of the disease and helping develop targeted treatments. METHODS This review provides a comprehensive reporting on the effects of DPN in the skeletal muscle of patients with diabetes. It also provides an update on the most recent trials of exercise intervention targeting DPN pathology. Lastly, we report on emerging MRI techniques that have shown promise in providing a mechanistic understanding of DPN and can help improve the design and implementation of clinical trials in the future. FINDINGS Impairments in lower limb muscles reduce functional capacity and contribute to altered gait, increased fall risk, and impaired balance in patients with DPN. This finding is an important concern for patients with DPN because their falls are likely to be injurious and lead to bone fractures, poorly healing wounds, and chronic infections that may require amputation. Preliminary studies have shown that moderate-intensity exercise programs are well tolerated by patients with DPN. They can improve their cardiorespiratory function and partially reverse some of the symptoms of DPN. MRI has the potential to bring new mechanistic insights into the effects of DPN as well as to objectively measure small changes in DPN pathology as a result of intervention. IMPLICATIONS Noninvasive exercise intervention is particularly valuable in DPN because of its safety, low cost, and potential to augment pharmacologic interventions. As we gain a better mechanistic understanding of the disease, more targeted and effective interventions can be designed.
Collapse
Affiliation(s)
- Prodromos Parasoglou
- Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, New York; Center for Advanced Imaging Innovation and Research (CAI(2)R), Department of Radiology, New York University School of Medicine, New York, New York.
| | - Smita Rao
- Department of Physical Therapy, New York University, New York, New York
| | - Jill M Slade
- Department of Radiology, Michigan State University, East Lansing, Michigan; Biomedical Imaging Research Center, Michigan State University, East Lansing, Michigan
| |
Collapse
|
|
30
|
Spallone V. Might genetics play a role in understanding and treating diabetic polyneuropathy? Diabetes Metab Res Rev 2017; 33. [PMID: 28032668 DOI: 10.1002/dmrr.2882] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2016] [Revised: 10/17/2016] [Accepted: 12/07/2016] [Indexed: 12/17/2022]
Abstract
Despite the high prevalence and impact on quality of life, costs, and survival, there are still unresolved issues regarding diabetic polyneuropathy (DPN): the lack of definite knowledge of its pathogenesis; the limited preventive action of glycaemic control in type 2 diabetes; and the unavailability of evidence-based effective disease-modifying treatment. How can genetics provide the tools to address these gaps? Ziegler et al for the GDS Group explore the novel hypothesis that genetic variability in transketolase (TKT) might contribute to susceptibility to DPN in patients with newly diagnosed type 1 and type 2 diabetes (well characterised for DPN). Transketolase diverts excess glycolytic metabolites from the hexosamine, protein kinase C, and advanced glycation endproduct pathways to the pentose phosphate pathway, with a protective effect against hyperglycaemia-induced damage. Moreover, thiamine and its derivative benfotiamine are among the few disease-modifying agents still under consideration as DPN treatment. The authors find significant associations of single-nucleotide polymorphisms of the TKT gene with the Total Symptom Score and thermal thresholds, in particular in male participants with type 2 diabetes. Moreover, they measure plasma methylglyoxal (a glycating agent, whose availability is hindered by TKT) without however finding a relation with TKT single-nucleotide polymorphisms. The link found between TKT genetic variability and nerve function measures is considered here in the context of DPN genetic studies and of experimental and clinical findings regarding thiamine and benfotiamine. The conclusion is that available data supports the decision to maintain focus on both the search for DPN genetic biomarkers and the therapeutic attempts to target thiamine, TKT, and methylglyoxal.
Collapse
Affiliation(s)
- Vincenza Spallone
- Endocrinology, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| |
Collapse
|
|
31
|
Ziegler D, Schleicher E, Strom A, Knebel B, Fleming T, Nawroth P, Häring HU, Papanas N, Szendrödi J, Müssig K, Al-Hasani H, Roden M. Association of transketolase polymorphisms with measures of polyneuropathy in patients with recently diagnosed diabetes. Diabetes Metab Res Rev 2017; 33. [PMID: 27103086 DOI: 10.1002/dmrr.2811] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Revised: 03/18/2016] [Accepted: 04/06/2016] [Indexed: 01/20/2023]
Abstract
BACKGROUND Shunting of glycolytic intermediates into the pentose phosphate pathway has been suggested to protect from hyperglycaemia-induced microvascular damage. We hypothesized that genetic variability in the gene encoding transketolase, a key pentose phosphate pathway enzyme, contributes to early nerve dysfunction in recent-onset diabetes. METHODS In this cross-sectional study, we assessed nine single nucleotide polymorphisms (SNPs) in the transketolase gene, plasma methylglyoxal concentrations, and clinical and quantitative measures of peripheral nerve function in 165 type 1 and 373 type 2 diabetic patients with a diabetes duration up to 1 year. RESULTS The Total Symptom Score was associated with transketolase SNPs rs7648309, rs62255988, and rs7633966, while peroneal motor nerve conduction velocity (MNCV) correlated only with rs7648309 (P < 0.01). Cold thermal detection threshold (TDT) (foot) was associated with transketolase SNPs rs11130362 and rs7648309, while warm TDT (hand) correlated with rs62255988 and rs7648309 (P < 0.01). After Bonferroni correction, the correlations of transketolase SNP rs7648309 with Total Symptom Score and rs62255988 with warm TDT (hand) remained statistically significant. Among subgroups, men with type 2 diabetes showed the strongest associations. No associations were observed between each of the nine tagged transketolase SNPs and plasma methylglyoxal concentrations. CONCLUSIONS The observed associations of genetic variation in transketolase enzyme with neuropathic symptoms and reduced thermal sensation in recent-onset diabetes suggest a role of pathways metabolizing glycolytic intermediates in early diabetic neuropathy. Copyright © 2016 John Wiley & Sons, Ltd.
Collapse
Affiliation(s)
- Dan Ziegler
- Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Erwin Schleicher
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University Hospital Tübingen, Germany
- Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
| | - Alexander Strom
- Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Birgit Knebel
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany
| | - Thomas Fleming
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Department of Endocrinology and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany
| | - Peter Nawroth
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Department of Endocrinology and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany
| | - Hans-Ulrich Häring
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University Hospital Tübingen, Germany
- Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University of Tübingen, Tübingen, Germany
| | - Nikolaos Papanas
- Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Julia Szendrödi
- Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Karsten Müssig
- Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Hadi Al-Hasani
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
- Institute for Clinical Biochemistry and Pathobiochemistry, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany
- Department of Endocrinology and Diabetology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
- German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| |
Collapse
|
|
32
|
Targeting advanced glycation with pharmaceutical agents: where are we now? Glycoconj J 2016; 33:653-70. [PMID: 27392438 DOI: 10.1007/s10719-016-9691-1] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2016] [Revised: 05/11/2016] [Accepted: 05/26/2016] [Indexed: 02/06/2023]
Abstract
Advanced glycation end products (AGEs) are the final products of the Maillard reaction, a complex process that has been studied by food chemists for a century. Over the past 30 years, the biological significance of advanced glycation has also been discovered. There is mounting evidence that advanced glycation plays a homeostatic role within the body and that food-related Maillard products, intermediates such as reactive α-dicarbonyl compounds and AGEs, may influence this process. It remains to be understood, at what point AGEs and their intermediates become pathogenic and contribute to the pathogenesis of chronic diseases that inflict current society. Diabetes and its complications have been a major focus of AGE biology due to the abundance of excess sugar and α-dicarbonyls in this family of diseases. While further temporal information is required, a number of pharmacological agents that inhibit components of the advanced glycation pathway have already showed promising results in preclinical models. These therapies appear to have a wide range of mechanistic actions to reduce AGE load. Some of these agents including Alagebrium, have translated successfully to clinical trials, while others such as aminoguanidine, have had undesirable side-effect profiles. This review will discuss different pharmacological agents that have been used to reduce AGE burden in preclinical models of disease with a focus on diabetes and its complications, compare outcomes of those therapies that have reached clinical trials, and provide further rationale for the use of inhibitors of the glycation pathway in chronic diseases.
Collapse
|
|
33
|
Abstract
Diabetes has become one of the largest global health-care problems of the 21
st century. According to the Centers for Disease Control and Prevention, the population prevalence of diabetes in the US is approaching 10% and is increasing by 5% each year. Diabetic neuropathy is the most common complication associated with diabetes mellitus. Diabetes causes a broad spectrum of neuropathic complications, including acute and chronic forms affecting each level of the peripheral nerve, from the root to the distal axon. This review will focus on the most common form, distal symmetric diabetic polyneuropathy. There has been an evolution in our understanding of the pathophysiology and the management of diabetic polyneuropathy over the past decade. We highlight these new perspectives and provide updates from the past decade of research.
Collapse
Affiliation(s)
- Kelsey Juster-Switlyk
- Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - A Gordon Smith
- Department of Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA
| |
Collapse
|
|
34
|
Zhu Z, Varadi G, Carter SG. Pharmacokinetics of the transdermal delivery of benfotiamine. Acta Diabetol 2016; 53:317-22. [PMID: 26141141 DOI: 10.1007/s00592-015-0776-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2014] [Accepted: 05/26/2015] [Indexed: 02/06/2023]
Abstract
AIMS Accumulation of advanced glycation endpoints is a trigger to the development of diabetic peripheral neuropathy, which is a common complication of diabetes. Oral administration of benfotiamine (BFT) has shown some preclinical and clinical promise as a treatment for diabetic peripheral neuropathy. The purpose of this study was to evaluate the method of transdermal delivery of BFT as a possible, viable route of administration for the treatment of diabetic peripheral neuropathy. METHODS A single application of 10 mg of BFT was given to guinea pigs topically. The levels of thiamine (T), thiamine monophosphate, thiamine diphosphate, S-benzoylthiamine and BFT were measured in the blood, skin and muscle at different time points within 24 h. RESULTS At the 24-h time point, following the single BFT dose, the T level was increased 10× in the blood, more than 7× in the skin and almost 4× in the muscle compared to the untreated animals. The total T content (total) was increased 7× in the blood, 17× in the skin and 3× in the muscle compared to the untreated animals. CONCLUSIONS This strong increase in the tissue levels of T and the associated metabolic derivatives levels found in the blood and local tissues following a single dose indicate that topically applied BFT may be a viable and advantageous delivery method for the treatment of diabetic peripheral neuropathy.
Collapse
Affiliation(s)
- Zhen Zhu
- BioChemics Inc., 99 Rosewood Drive, Suite 270, Danvers, MA, 01923-4537, USA.
| | - Gyula Varadi
- BioChemics Inc., 99 Rosewood Drive, Suite 270, Danvers, MA, 01923-4537, USA
| | | |
Collapse
|
|
35
|
The progress in understanding and treatment of diabetic retinopathy. Prog Retin Eye Res 2015; 51:156-86. [PMID: 26297071 DOI: 10.1016/j.preteyeres.2015.08.001] [Citation(s) in RCA: 697] [Impact Index Per Article: 69.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Revised: 08/12/2015] [Accepted: 08/13/2015] [Indexed: 12/15/2022]
Abstract
Diabetic retinopathy is the most frequently occurring complication of diabetes mellitus and remains a leading cause of vision loss globally. Its aetiology and pathology have been extensively studied for half a century, yet there are disappointingly few therapeutic options. Although some new treatments have been introduced for diabetic macular oedema (DMO) (e.g. intravitreal vascular endothelial growth factor inhibitors ('anti-VEGFs') and new steroids), up to 50% of patients fail to respond. Furthermore, for people with proliferative diabetic retinopathy (PDR), laser photocoagulation remains a mainstay therapy, even though it is an inherently destructive procedure. This review summarises the clinical features of diabetic retinopathy and its risk factors. It describes details of retinal pathology and how advances in our understanding of pathogenesis have led to identification of new therapeutic targets. We emphasise that although there have been significant advances, there is still a pressing need for a better understanding basic mechanisms enable development of reliable and robust means to identify patients at highest risk, and to intervene effectively before vision loss occurs.
Collapse
|
|
36
|
Nenna A, Nappi F, Avtaar Singh SS, Sutherland FW, Di Domenico F, Chello M, Spadaccio C. Pharmacologic Approaches Against Advanced Glycation End Products (AGEs) in Diabetic Cardiovascular Disease. Res Cardiovasc Med 2015; 4:e26949. [PMID: 26393232 PMCID: PMC4571620 DOI: 10.5812/cardiovascmed.4(2)2015.26949] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Revised: 02/06/2015] [Accepted: 02/17/2015] [Indexed: 01/11/2023] Open
Abstract
Context: Advanced Glycation End-Products (AGEs) are signaling proteins associated to several vascular and neurological complications in diabetic and non-diabetic patients. AGEs proved to be a marker of negative outcome in both diabetes management and surgical procedures in these patients. The reported role of AGEs prompted the development of pharmacological inhibitors of their effects, giving rise to a number of both preclinical and clinical studies. Clinical trials with anti-AGEs drugs have been gradually developed and this review aimed to summarize most relevant reports. Evidence Acquisition: Evidence acquisition process was performed using PubMed and ClinicalTrials.gov with manually checked articles. Results: Pharmacological approaches in humans include aminoguanidine, pyridoxamine, benfotiamine, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, statin, ALT-711 (alagebrium) and thiazolidinediones. The most recent promising anti-AGEs agents are statins, alagebrium and thiazolidinediones. The role of AGEs in disease and new compounds interfering with their effects are currently under investigation in preclinical settings and these newer anti-AGEs drugs would undergo clinical evaluation in the next years. Compounds with anti-AGEs activity but still not available for clinical scenarios are ALT-946, OPB-9195, tenilsetam, LR-90, TM2002, sRAGE and PEDF. Conclusions: Despite most studies confirm the efficacy of these pharmacological approaches, other reports produced conflicting evidences; in almost any case, these drugs were well tolerated. At present, AGEs measurement has still not taken a precise role in clinical practice, but its relevance as a marker of disease has been widely shown; therefore, it is important for clinicians to understand the value of new cardiovascular risk factors. Findings from the current and future clinical trials may help in determining the role of AGEs and the benefits of anti-AGEs treatment in cardiovascular disease.
Collapse
Affiliation(s)
- Antonio Nenna
- Department of Cardiovascular Sciences, Rome University of Campus Bio Medico, Rome, Italy
| | - Francesco Nappi
- Cardiac Surgery Centre Cardiologique du Nord de Saint-Denis, Paris, France
| | | | - Fraser W. Sutherland
- Department of Cardiothoracic Surgery, Golden Jubilee National Hospital, Clydebank, Glasgow, UK
| | - Fabio Di Domenico
- Department of Biochemical Sciences, La Sapienza University of Rome, Rome, Italy
| | - Massimo Chello
- Department of Cardiovascular Sciences, Rome University of Campus Bio Medico, Rome, Italy
| | - Cristiano Spadaccio
- Department of Cardiothoracic Surgery, Golden Jubilee National Hospital, Clydebank, Glasgow, UK
- Corresponding author: Cristiano Spadaccio, Department of Cardiothoracic Surgery, Golden Jubilee National Hospital, Clydebank, Glasgow, UK. Tel: +44-1419515000, Fax: +44-1419515006, E-mail:
| |
Collapse
|
|
37
|
Sugimori N, Espinoza JL, Trung LQ, Takami A, Kondo Y, An DT, Sasaki M, Wakayama T, Nakao S. Paraptosis cell death induction by the thiamine analog benfotiamine in leukemia cells. PLoS One 2015; 10:e0120709. [PMID: 25849583 PMCID: PMC4388699 DOI: 10.1371/journal.pone.0120709] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 01/26/2015] [Indexed: 01/28/2023] Open
Abstract
Benfotiamine is a synthetic thiamine analogue that stimulates transketolase, a cellular enzyme essential for glucose metabolism. Currently, benfotiamine is used to treat diabetic neuropathy. We recently reported that oral benfotiamine induced a temporary but remarkable recovery from acute myeloid leukemia in an elderly patient who was ineligible for standard chemotherapy due to dementia and renal failure. In the present study we present evidences that benfotiamine possess antitumor activity against leukemia cells. In a panel of nine myeloid leukemia cell lines benfotiamine impaired the viability of HL-60, NB4, K562 and KG1 cells and also inhibited the growing of primary leukemic blasts. The antitumor activity of benfotiamine is not mediated by apoptosis, necrosis or autophagy, but rather occurs though paraptosis cell death induction. Mechanistic studies revealed that benfotiamine inhibited the activity of constitutively active ERK1/2 and concomitantly increased the phosphorylation of JNK1/2 kinase in leukemic cells. In addition, benfotiamine induced the down regulation of the cell cycle regulator CDK3 which resulted in G1 cell cycle arrest in the sensitive leukemic cells. Moreover, combination index studies showed that benfotiamine enhanced the antiproliferative activities of cytarabine against leukemia cells. These findings suggest that benfotiamine has antitumor therapeutic potential.
Collapse
Affiliation(s)
- Naomi Sugimori
- Department of Hematology Oncology, Kanazawa University Hospital, Kanazawa University, Kanazawa, Japan Takaramachi 13–1, Kanazawa, Japan
| | - J. Luis Espinoza
- Department of Hematology Oncology, Kanazawa University Hospital, Kanazawa University, Kanazawa, Japan Takaramachi 13–1, Kanazawa, Japan
- * E-mail:
| | - Ly Quoc Trung
- Department of Hematology Oncology, Kanazawa University Hospital, Kanazawa University, Kanazawa, Japan Takaramachi 13–1, Kanazawa, Japan
| | - Akiyoshi Takami
- Department of Hematology Oncology, Kanazawa University Hospital, Kanazawa University, Kanazawa, Japan Takaramachi 13–1, Kanazawa, Japan
- Department of Hematology Oncology, Aichi Medical University School of Medicine, Nagakute, Japan
| | - Yukio Kondo
- Department of Hematology Oncology, Kanazawa University Hospital, Kanazawa University, Kanazawa, Japan Takaramachi 13–1, Kanazawa, Japan
| | - Dao Thi An
- Department of Hematology Oncology, Kanazawa University Hospital, Kanazawa University, Kanazawa, Japan Takaramachi 13–1, Kanazawa, Japan
| | - Motoko Sasaki
- Department of Pathology, Kanazawa University, Kanazawa, Japan
| | - Tomohiko Wakayama
- Department of Anatomy and Histology, Kanazawa University, Kanazawa, Japan
| | - Shinji Nakao
- Department of Hematology Oncology, Kanazawa University Hospital, Kanazawa University, Kanazawa, Japan Takaramachi 13–1, Kanazawa, Japan
| |
Collapse
|
|
38
|
Pácal L, Kuricová K, Kaňková K. Evidence for altered thiamine metabolism in diabetes: Is there a potential to oppose gluco- and lipotoxicity by rational supplementation? World J Diabetes 2014; 5:288-295. [PMID: 24936250 PMCID: PMC4058733 DOI: 10.4239/wjd.v5.i3.288] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2013] [Revised: 04/14/2014] [Accepted: 05/16/2014] [Indexed: 02/05/2023] Open
Abstract
Growing prevalence of diabetes (type 2 as well as type 1) and its related morbidity due to vascular complications creates a large burden on medical care worldwide. Understanding the molecular pathogenesis of chronic micro-, macro- and avascular complications mediated by hyperglycemia is of crucial importance since novel therapeutic targets can be identified and tested. Thiamine (vitamin B1) is an essential cofactor of several enzymes involved in carbohydrate metabolism and published data suggest that thiamine metabolism in diabetes is deficient. This review aims to point out the physiological role of thiamine in metabolism of glucose and amino acids, to present overview of thiamine metabolism and to describe the consequences of thiamine deficiency (either clinically manifest or latent). Furthermore, we want to explain why thiamine demands are increased in diabetes and to summarise data indicating thiamine mishandling in diabetics (by review of the studies mapping the prevalence and the degree of thiamine deficiency in diabetics). Finally, we would like to summarise the evidence for the beneficial effect of thiamine supplementation in progression of hyperglycemia-related pathology and, therefore, to justify its importance in determining the harmful impact of hyperglycemia in diabetes. Based on the data presented it could be concluded that although experimental studies mostly resulted in beneficial effects, clinical studies of appropriate size and duration focusing on the effect of thiamine supplementation/therapy on hard endpoints are missing at present. Moreover, it is not currently clear which mechanisms contribute to the deficient action of thiamine in diabetes most. Experimental studies on the molecular mechanisms of thiamine deficiency in diabetes are critically needed before clear answer to diabetes community could be given.
Collapse
|
|
39
|
Al-Attas O, Al-Daghri N, Alokail M, Abd-Alrahman S, Vinodson B, Sabico S. Metabolic Benefits of Six-month Thiamine Supplementation in Patients With and Without Diabetes Mellitus Type 2. CLINICAL MEDICINE INSIGHTS-ENDOCRINOLOGY AND DIABETES 2014; 7:1-6. [PMID: 24550684 PMCID: PMC3921172 DOI: 10.4137/cmed.s13573] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2013] [Revised: 12/09/2013] [Accepted: 12/10/2013] [Indexed: 02/01/2023]
Abstract
Thiamine deficiency has been documented to be prevalent in patients with diabetes mellitus, and correction of thiamine deficiency in this population may provide beneficial effects in several cardiometabolic parameters, including prevention of impending complications secondary to chronic hyperglycemia. In this interventional study, we aim to determine whether thiamine supplementation is associated with cardiometabolic improvements in patients with diabetes mellitus type 2 (DMT2). A total of 86 subjects (60 DMT2 and 26 age- and BMI-matched controls) were included and were given thiamine supplements (100 mg/day) for six months. Anthropometrics and metabolic profiles were measured routinely. Serum thiamine and its derivatives were measured using high performance liquid chromatography. In all groups, there was a significant decrease in total cholesterol after three months (p = 0.03) as well as in HDL cholesterol after six months of thiamine supplementation (p = 0.009). Significant improvements were also observed in the mean serum levels of creatinine (p = 0.001), as well as thiamine and its derivatives in both serum and urinary levels across follow-up visits (p-values 0.002 and <0.001, respectively). In the DMT2 group, improvements were observed in lipid profile (mean serum LDL and total cholesterol with p-values 0.008 and 0.006, respectively), serum thiamine (p < 0.001), TMP (p < 0.001), TDP (p < 0.001), urinary thiamine (p < 0.001) and serum creatinine (p < 0.001). Thiamine supplementation is a promising adjuvant therapy for patients with DMT2. Longer clinical trials are needed to determine its protective effect in DMT2 complications.
Collapse
Affiliation(s)
- Omar Al-Attas
- Center of Excellence in Biotechnology Research, King Saud University, Riyadh, Saudi Arabia. ; Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia. ; Prince Mutaib Chair for Biomarkers of Osteoporosis, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Nasser Al-Daghri
- Center of Excellence in Biotechnology Research, King Saud University, Riyadh, Saudi Arabia. ; Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia. ; Prince Mutaib Chair for Biomarkers of Osteoporosis, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Majed Alokail
- Center of Excellence in Biotechnology Research, King Saud University, Riyadh, Saudi Arabia. ; Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia. ; Prince Mutaib Chair for Biomarkers of Osteoporosis, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Sherif Abd-Alrahman
- Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Benjamin Vinodson
- Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Shaun Sabico
- Biomarkers Research Program, Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia
| |
Collapse
|
|
40
|
Boulton AJM, Kempler P, Ametov A, Ziegler D. Whither pathogenetic treatments for diabetic polyneuropathy? Diabetes Metab Res Rev 2013; 29:327-33. [PMID: 23381942 DOI: 10.1002/dmrr.2397] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Revised: 01/07/2013] [Accepted: 01/27/2013] [Indexed: 01/17/2023]
Abstract
Diabetic distal symmetric polyneuropathy (DSPN) occurs in around one-third of patients with diabetes and is associated with significant morbidity and increased mortality. Diagnosis and clinical assessment of DSPN remain a challenge, not only for the physician in clinical practice but also for clinical trials. Optimal diabetes control is generally considered an essential first step in the prevention and management of DSPN. However, glycaemic control alone may be insufficient to prevent the development or progression of DSPN, especially in type 2 diabetes. Near-normoglycaemia is also difficult to achieve in a significant proportion of patients. Although considerable advances have been made in symptomatic pain management, these have not addressed the problem of sensory deficits and have no impact on the underlying pathogenesis of DSPN. There remains a lack of treatment options that effectively target the natural history of the disease. Several pathogenetic treatment approaches have been investigated, but evidence from clinical trials is limited with a number of treatments having shown disappointing results. However, some pathogenetic therapies have shown clinically relevant improvements in neuropathic endpoints in randomised controlled trials, in particular α-lipoic acid and Actovegin. These advances in DSPN disease modification need to be confirmed with further robust evidence from clinical trials together with a better understanding of the mechanisms of action of promising treatments.
Collapse
Affiliation(s)
- Andrew J M Boulton
- Centre for Endocrinology and Diabetes, University of Manchester, Manchester, UK.
| | | | | | | |
Collapse
|
|
41
|
Aldini G, Vistoli G, Stefek M, Chondrogianni N, Grune T, Sereikaite J, Sadowska-Bartosz I, Bartosz G. Molecular strategies to prevent, inhibit, and degrade advanced glycoxidation and advanced lipoxidation end products. Free Radic Res 2013; 47 Suppl 1:93-137. [PMID: 23560617 DOI: 10.3109/10715762.2013.792926] [Citation(s) in RCA: 111] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The advanced glycoxidation end products (AGEs) and lipoxidation end products (ALEs) contribute to the development of diabetic complications and of other pathologies. The review discusses the possibilities of counteracting the formation and stimulating the degradation of these species by pharmaceuticals and natural compounds. The review discusses inhibitors of ALE and AGE formation, cross-link breakers, ALE/AGE elimination by enzymes and proteolytic systems, receptors for advanced glycation end products (RAGEs) and blockade of the ligand-RAGE axis.
Collapse
Affiliation(s)
- Giancarlo Aldini
- Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
| | | | | | | | | | | | | | | |
Collapse
|
|
42
|
Stitt AW, Lois N, Medina RJ, Adamson P, Curtis TM. Advances in our understanding of diabetic retinopathy. Clin Sci (Lond) 2013; 125:1-17. [PMID: 23485060 DOI: 10.1042/cs20120588] [Citation(s) in RCA: 128] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Diabetic retinopathy remains the most common complication of diabetes mellitus and is a leading cause of visual loss in industrialized nations. The clinicopathology of the diabetic retina has been extensively studied, although the precise pathogenesis and cellular and molecular defects that lead to retinal vascular, neural and glial cell dysfunction remain somewhat elusive. This lack of understanding has seriously limited the therapeutic options available for the ophthalmologist and there is a need to identify the definitive pathways that initiate retinal cell damage and drive progression to overt retinopathy. The present review begins by outlining the natural history of diabetic retinopathy, the clinical features and risk factors. Reviewing the histopathological data from clinical specimens and animal models, the recent paradigm that neuroretinal dysfunction may play an important role in the early development of the disease is discussed. The review then focuses on the molecular pathogenesis of diabetic retinopathy with perspective provided on new advances that have furthered our understanding of the key mechanisms underlying early changes in the diabetic retina. Studies have also emerged in the past year suggesting that defective repair of injured retinal vessels by endothelial progenitor cells may contribute to the pathogenesis of diabetic retinopathy. We assess these findings and discuss how they could eventually lead to new therapeutic options for diabetic retinopathy.
Collapse
Affiliation(s)
- Alan W Stitt
- Centre for Vision and Vascular Science, Queen's University of Belfast, The Royal Victoria Hospital, Belfast BT12 6BA, UK.
| | | | | | | | | |
Collapse
|
|
43
|
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;35:1095-1097. Diabetes Care 2012; 35:e79; author reply e80. [PMID: 23093690 PMCID: PMC3476903 DOI: 10.2337/dc12-0817] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Dan Ziegler
- From the Institute for Clinical Diabetology, German Diabetes Center at Heinrich Heine University, Leibniz Center for Diabetes Research, Düsseldorf, Germany; the
- Department of Metabolic Diseases, University Hospital, Düsseldorf, Germany; the
| | - Solomon Tesfaye
- Diabetes Research Unit, Sheffield Teaching Hospitals, Sheffield, U.K.; and the
| | - Peter Kempler
- 1st Department of Medicine, Semmelweis University, Budapest, Hungary
| |
Collapse
|