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Blathra E, Anastasiou IA, Eleftheriadou I, Papanas N, Tentolouris N. Charcot Osteoarthropathy: A Comprehensive Analysis of Recent Research on Novel Biomarkers for Early Detection. INT J LOW EXTR WOUND 2025:15347346251328436. [PMID: 40129303 DOI: 10.1177/15347346251328436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2025]
Abstract
Charcot osteoarthropathy (CO) is an unusual and frequently misdiagnosed complication of diabetes mellitus. The delayed diagnosis can have severe consequences for patients' limb and life. Its diagnosis is based firstly in its clinical suspicion, is mainly clinical and is confirmed by imaging tests, like magnetic resorance imaging. Specific biomarkers for its early detection and therapy have not been found yet. The understanding of CO pathogenesis and measurement of molecules involved in this can head to this direction. The purpose of this review is to summarize/describe the most current studies measuring biomarkers in people with CO. Confocal corneal microscopy (CCM), inflammatory markers including IL-1, IL-6 and TNF-a, bone metabolism markers like RANK, RANKL, OPG, advanced glycation end products (AGEs) and bone mineral density (BMD) were among the most popular ones included in a large number of studies of the last 20 years and people with CO have significant different levels of the above comparing to non-Charcot groups. Future and larger studies can lead to the discovery of novel biomarkers of the prompt detection of this special entity at an early stage.
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Affiliation(s)
- Effrosyni Blathra
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Ioanna A Anastasiou
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
- Department of Pharmacology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Ioanna Eleftheriadou
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
| | - Nikolaos Papanas
- Diabetes-Center-Diabetic Foot Clinic, Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Nicholas Tentolouris
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece
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Rukadikar C, Rukadikar A, Kishore S. A Review on Autonomic Functional Assessment in Diabetic Patients. Cureus 2023; 15:e34598. [PMID: 36883072 PMCID: PMC9985918 DOI: 10.7759/cureus.34598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/03/2023] [Indexed: 02/05/2023] Open
Abstract
In today's world, science has progressed significantly, yet most people are still unaware of diabetes. Lack of obesity, physical work, and lifestyle changes are the main factors. Diabetes is becoming more common all around the globe. Type 2 diabetes may go unnoticed for years, resulting in serious consequences and high healthcare expenses. The goal of this study is to look at a wide range of studies in which the autonomic function of diabetic people has been studied with the help of various autonomic function tests (AFTs). AFT is a non-invasive approach to assessing patients for testing sympathetic and parasympathetic responses to stimuli. AFT findings give us comprehensive knowledge of the autonomic physiology reactions in normal and in autonomic diseases like diabetes. This review will concentrate on AFTs that are scientifically valid, trustworthy, and clinically beneficial, according to experts.
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Affiliation(s)
| | - Atul Rukadikar
- Microbiology, All India Institute of Medical Sciences, Gorakhpur, Gorakhpur, IND
| | - Surekha Kishore
- Community Medicine and Family Medicine, All India Institute of Medical Sciences, Gorakhpur, Gorakhpur, IND
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Liu L, Wang Q, Zhang Y, Liang J, Liu P, Zhao H. Therapeutics of Charcot neuroarthropathy and pharmacological mechanisms: A bone metabolism perspective. Front Pharmacol 2023; 14:1160278. [PMID: 37124200 PMCID: PMC10130761 DOI: 10.3389/fphar.2023.1160278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 03/28/2023] [Indexed: 05/02/2023] Open
Abstract
Charcot neuroarthropathy (CN) is a chronic, destructive, and painless damage of the skeletal system that affects the life quality of patients. CN, with an unclear mechanism, is characterized with invasive destruction of bones and a serious abnormality of bone metabolism. Unfortunately, development of an effective prevention and treatment strategy for CN is still a great challenge. Of note, recent studies providing an insight into the molecular mechanisms of bone metabolism and homeostasis have propelled development of novel CN therapeutic strategies. Therefore, this review aims to shed light on the pathogenesis, diagnosis, and treatment of CN. In particular, we highlight the eminent role of the osteoprotegerin (OPG)-receptor activator of nuclear factor-κB (RANK)-RANK ligand (RANKL) system in the development of CN. Furthermore, we summarize and discuss the diagnostic biomarkers of CN as well as the potential pharmacological mechanisms of current treatment regimens from the perspective of bone metabolism. We believe that this review will enhance the current state of knowledge on the diagnosis, prevention, and therapeutic efficacy of CN.
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Abstract
The Charcot diabetic foot presents unique challenges to the podiatric surgeon in the quest to salvage the limb. This disorder is an intersection of prototypical metabolic diseases and neurodegenerative disorder. Furthermore, it can be considered a disease of bone and ligaments that is often complicated by peripheral vascular disease and serious deep infection. Presently, simplistic ablative surgical procedures and the brace-makers art, still have a valid place in treating this disorder. Newer methods of surgical reconstruction are rapidly evolving to address distorted and nonfunctional limb. This article seeks to evidence the principles and practice of beaming the Charcot midfoot. As will be presented, the beam is a load-sharing device, which can be surgically introduced in an intramedullary method to restore architecture and strength to the Charcot foot. Problems with beam failure and migration have resulted in unsatisfactory outcomes as will be discussed. New Charcot-specific beams are currently reaching the podiatric surgeon with hopes of improving durability. In this article, we aim to address the surgical art of the beam, the engineering principles of beaming, and the novel introduction of a truss/tie rod configuration of beaming.
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Affiliation(s)
- William Grant
- Tidewater Foot and Ankle, 760 Independence Boulevard, Virginia Beach, VA 23455, USA.
| | - Lisa Grant-McDonald
- Tidewater Foot and Ankle, 760 Independence Boulevard, Virginia Beach, VA 23455, USA
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Abstract
Bone metabolism in the healthy, young adult is identified as a relatively stable process. Normal bone turnover is a dynamic state, which is conferred through intracellular signaling and complex cellular pathways. It has been well described in the literature that Charcot neuro-osteoarthropathy is a disease state, which is marked by intense bone turnover leading to structural collapse and dissolution of skeletal features of the foot and ankle. Within the last two decades, extensive interest has been placed in characterizing the metabolic pathogenesis of Charcot bone metabolism. Despite this work, there remains an incomplete understanding of this devastating disorder. In this article, we review bone histology, physiologic bone metabolism, biomarkers of bone metabolism, pathologic bone metabolism in Charcot diabetics, and potential avenues for intervention.
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Affiliation(s)
- Lisa Grant-McDonald
- Tidewater Foot and Ankle, 760 Independence Boulevard, Virginia Beach, VA 23455, USA.
| | - William Grant
- Tidewater Foot and Ankle, 760 Independence Boulevard, Virginia Beach, VA 23455, USA
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Cates NK, Furmanek J, Dubois KS, Wynes J. Risk Factors and Outcomes After Surgical Reconstruction of Charcot Neuroarthropathy in Fracture Versus Dislocation Patterns. J Foot Ankle Surg 2022; 61:264-271. [PMID: 34366220 DOI: 10.1053/j.jfas.2021.07.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 07/15/2021] [Accepted: 07/20/2021] [Indexed: 02/03/2023]
Abstract
The primary aim of this study is to compare the preoperative risk factors and postoperative outcomes between Charcot neuroarthropathy patients with dislocation versus purely fracture pattern breakdown. The secondary aim is to compare the same factors between Charcot neuroarthropathy patients with dislocation versus fracture-dislocation pattern breakdown. A total of 55 patients with forefoot, midfoot, or hindfoot Charcot Neuroarthopathy were assessed at a mean follow up of 2.99 years. Bivariate analysis compared preoperative risk factors and postoperative outcomes, and segmented multivariable regression analysis was performed. Dislocation pattern Charcot had statistically significant higher rates of broken hardware (p = .05), mean age (p = .01), and revisional exostectomy (p = .01) compared to pure fracture pattern Charcot. Dislocation pattern Charcot was 12 times more likely to have revisions exostectomy (odds ratio [OR] 12.0, 95% confidence interval [CI] 1.84-78.37), and was 8 times more likely to have osteomyelitis (OR 7.8, 95% CI 1.4-42.7, p = .02) compared to the fracture-dislocation pattern Charcot. The patients with pure fracture pattern Charcot were 58.8 times more likely to have Charcot breakdown involvement of the talonavicular joint compared to the dislocation pattern cohort (OR 58.83, 95% CI 1.1-3220.3). Involvement of the talonavicular joint, in the fracture pattern Charcot associate with medial column collapse occurring at the onset of Charcot breakdown. The dislocation pattern in Charcot Neuroarthropathy demonstrated a higher propensity for residual collapse as demonstrated by the higher rates of broken hardware, osteomyelitis, and need for revisional exostectomy.
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Affiliation(s)
- Nicole K Cates
- Foot and Ankle Surgeon, Fellowship Trained Foot and Ankle Surgeon, Hand & Microsurgery Medical Group, San Francisco, CA.
| | - Jonathan Furmanek
- Resident Physician, Department of Plastic Surgery, MedStar Georgetown University Hospital, Washington, DC
| | - Korey S Dubois
- Limb Preservation and Deformity Correction Fellow, Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD
| | - Jacob Wynes
- Assistant Professor, Fellowship Program Director, Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD
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Long-term foot outcomes following differential abatement of inflammation and osteoclastogenesis for active Charcot neuroarthropathy in diabetes mellitus. PLoS One 2021; 16:e0259224. [PMID: 34748565 PMCID: PMC8575293 DOI: 10.1371/journal.pone.0259224] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Accepted: 10/18/2021] [Indexed: 11/19/2022] Open
Abstract
AIMS Inflammatory osteolysis is sine-qua-non of active Charcot neuroarthropathy (CN) causing decreased foot bone mineral density (BMD) and fractures. We aimed to explore the effect of anti-inflammatory or anti-resorptive agents for effect on foot bone mineral content (BMC) and consequent long-term outcomes of foot deformities, fractures and amputation. METHODS Forty-three patients with active CN (temperature difference >2°C from normal foot) were evaluated. Patients were off-loaded with total contact cast and randomized to receive either methylprednisolone (1gm) (group A), zoledronate (5mg) (group B) or placebo (100ml normal saline) (group C) once monthly infusion for three consecutive months. Change in foot BMC was assessed at 6 months or at remission and followed subsequently up to 4 years for the incidence of new-onset fracture, deformities, or CN recurrence. RESULTS Thirty-six participants (24 male, 12 female) were randomized (11 in group A, 12 group B, 13 group C). The mean age was 57.7± 9.9 years, duration of diabetes 12.3± 5.8 years and symptom duration 6.5± 2.8 weeks. BMC increased by 36% with zoledronate (p = 0.02) but reduced by 13% with methylprednisolone (p = 0.03) and 9% (p = 0.09) with placebo at remission. There were no incident foot fractures, however, two patients sustained ulcers, and 3 had new-onset or worsening deformities and none required amputation during 3.36 ± 0.89 years of follow-up. CONCLUSION Bisphosphonate for active CN is associated with an increase in foot bone mineral content as compared to decrease with steroids or total contact cast but long-term outcomes of foot deformities, ulceration and amputation are similar. TRIAL REGISTRATION ClinicalTrials.gov: NCT03289338.
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Kloska A, Korzon-Burakowska A, Malinowska M, Bruhn-Olszewska B, Gabig-Cimińska M, Jakóbkiewicz-Banecka J. The role of genetic factors and monocyte-to-osteoclast differentiation in the pathogenesis of Charcot neuroarthropathy. Diabetes Res Clin Pract 2020; 166:108337. [PMID: 32707214 DOI: 10.1016/j.diabres.2020.108337] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 05/07/2020] [Accepted: 07/16/2020] [Indexed: 12/29/2022]
Abstract
Charcot neuroarthropathy is a chronic, progressive condition of the skeletal system that affects some patients with diabetic neuropathy. It results in progressive destruction of bones of the foot and disorganisation of pedal joints and ligaments. Effective prevention and treatment for Charcot neuroarthropathy remain a challenge. Currently, there are no reliable repeatable markers to identify patients with diabetes who are at higher risk of developing Charcot neuroarthropathy. The pathogenesis underlying the development of Charcot neuroarthropathy also remains unclear. In this review, we provide an overview of the history, prevalence, symptoms, risk factors, diagnostics and treatment of Charcot neuroarthropathy. We also discuss the potential for OPG and RANKL gene variants to act as predictive markers for the development of Charcot neuroarthropathy. Finally, we summarise the latest research on the role of monocyte-to-osteoclast differentiation in the development of acute Charcot neuroarthropathy.
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Affiliation(s)
- Anna Kloska
- University of Gdańsk, Faculty of Biology, Department of Medical Biology and Genetics, Wita Stwosza 59, 80-308 Gdańsk, Poland
| | - Anna Korzon-Burakowska
- Medical University of Gdańsk, Faculty of Medicine, Department of Hypertension and Diabetology, Dębinki 7, 80-211 Gdańsk, Poland
| | - Marcelina Malinowska
- University of Gdańsk, Faculty of Biology, Department of Medical Biology and Genetics, Wita Stwosza 59, 80-308 Gdańsk, Poland
| | - Bożena Bruhn-Olszewska
- University of Gdańsk, Faculty of Biology, Department of Bacterial Molecular Genetics, Wita Stwosza 59, 80-308 Gdańsk, Poland
| | - Magdalena Gabig-Cimińska
- University of Gdańsk, Faculty of Biology, Department of Medical Biology and Genetics, Wita Stwosza 59, 80-308 Gdańsk, Poland; Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Laboratory of Molecular Biology, Kładki 24, 80-822 Gdańsk, Poland
| | - Joanna Jakóbkiewicz-Banecka
- University of Gdańsk, Faculty of Biology, Department of Medical Biology and Genetics, Wita Stwosza 59, 80-308 Gdańsk, Poland.
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Yates TH, Cooperman SR, Shofler D, Agrawal DK. Current concepts underlying the pathophysiology of acute Charcot neuroarthropathy in the diabetic foot and ankle. Expert Rev Clin Immunol 2020; 16:839-845. [PMID: 32735458 DOI: 10.1080/1744666x.2020.1804869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
INTRODUCTION With a complex and often misunderstood etiology, acute Charcot neuroarthropathy (ACN) is a devastating complication of peripheral neuropathy. In patients with diabetes, timely diagnosis of ACN in the foot and ankle is essential to prevent loss of both limb and life. AREAS COVERED Herein, the authors evaluate the growing body of evidence in identifying targeted pathways for future therapeutic interventions. A literature search was conducted through the PubMed research database. Searched terms included 'Charcot,' 'foot and ankle,' 'neuroarthropathy,' 'pathophysiology,' 'arthropathy,' 'diabetic foot,' and 'Charcot foot.' EXPERT OPINION The interplay between the acute inflammatory response, cytokine signaling, and bone metabolism equilibrium can now be better understood with the aid of several novel immunobiologic mechanisms. The more recently elucidated roles of advanced glycation end-products, neuropeptides, monocyte differentiation, and genomics combine with classical Charcot pathophysiology to aid researchers and clinicians alike in combatting this often puzzling consequence of peripheral neuropathy.
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Affiliation(s)
- Thomas H Yates
- Western University of Health Sciences, College of Podiatric Medicine , Pomona, California, USA
| | - Steven R Cooperman
- Western University of Health Sciences, College of Podiatric Medicine , Pomona, California, USA
| | - David Shofler
- Western University of Health Sciences, College of Podiatric Medicine , Pomona, California, USA
| | - Devendra K Agrawal
- Western University of Health Sciences, College of Podiatric Medicine , Pomona, California, USA
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10
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Abstract
Charcot neuropathic arthropathy (CN) is a devastating condition resulting in non-reducible foot deformity that places patients with distal peripheral neuropathy at risk for the development of chronic neuropathic foot ulcers, major lower extremity amputation, and even death. The condition is often misdiagnosed early in its presentation because of a lack of knowledge among members of the medical community. Consequently, initial therapies for the condition are fewer and patients who present in more advanced stages of the condition are more difficult to manage. We now understand that CN is a multifactorial process resulting in unregulated osteoclastogenesis and bony destruction. Classically, the patient will present with an edematous, erythematous foot with increased temperature. These non-specific findings lead to a multitude of differential diagnoses. However, there are no diagnostic biomarkers or pathognomonic clinical signs to distinguish this condition from other common foot ailments seen in the context of peripheral neuropathy. Advancing our understanding of this condition, while educating the medical community about its devastating impact, is needed to advance and improve outcomes for patients affected by CN.
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Affiliation(s)
- Brian M Schmidt
- Michigan Medicine, Department of Internal Medicine, Division of Metabolism, Endocrinology, and Diabetes, Domino's Farms (Lobby C, Suite 1300) 24 Frank Lloyd Wright Drive Ann Arbor, Michigan 48106, USA.
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Charcot Neuroarthropathy Advances: Understanding Pathogenesis and Medical and Surgical Management. Clin Podiatr Med Surg 2019; 36:663-684. [PMID: 31466574 DOI: 10.1016/j.cpm.2019.07.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Understanding new theories of the epidemiology of Charcot neuroarthropathy is practice changing. Treatment of Charcot neuroarthropathy is evolving from a passive approach to one that sees the urgency of proactive, early recognition, thereby avoiding the cascading events that lead to the complex, limb-threatening deformities. Preventive medicine is the most efficient at avoiding severe deformity, with prolonged offloading and immobilization as the current mainstay of treatment. However, with recent advancements in medical and surgical modalities, this may become the treatment of the past as clinicians begin to favor medical management and early surgical intervention.
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Connors JC, Hardy MA, Kishman LL, Botek GG, Verdin CJ, Rao NM, Kingsley JD. Charcot Pathogenesis: A Study of In Vivo Gene Expression. J Foot Ankle Surg 2019; 57:1067-1072. [PMID: 30368423 DOI: 10.1053/j.jfas.2018.03.023] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2016] [Indexed: 02/03/2023]
Abstract
Charcot neuroarthropathy is a rare but often difficult to manage disease in the neuropathic patient. Early signs such as unremarkable edema, marginal trauma, or minor infection can activate a cascade of bony destruction and lead to gross prominence or deformity, with dire consequences. The exact molecular mechanism is poorly understood. Current theory states that an inflammatory reaction leads to the activation of osteoclasts mediated by specific cytokines. Our study sought to test the genetic expression of certain biomarkers in diabetic patients with and without Charcot neuroarthropathy compared with patients with and without diabetes or neuropathy. A total of 30 patients participated in the study, 17 (57%) males and 13 (43%) females. Peripheral blood samples were drawn, and gene expression was measured using real-time polymerase chain reaction. The expression levels of receptor activator of nuclear factor kappa-B ligand and osteoprotegerin showed no significant increase in the Charcot neuroarthropathy group compared with the healthy control group. We determined that the levels of receptor activator of nuclear factor kappa-B ligand and osteoprotegerin were not significantly increased in Charcot neuroarthropathy patients compared with healthy control patients. These results demonstrate a need for further investigation into alternative molecular pathways to determine the exact mechanism of the disease process.
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Affiliation(s)
- James C Connors
- Assistant Professor, Division of Foot/Ankle Surgery and Biomechanics, Kent State University College of Podiatric Medicine, Independence, OH.
| | - Mark A Hardy
- Division Head and Associate Professor, Division of Foot and Ankle Surgery/Biomechanics, Kent State University College of Podiatric Medicine, Independence, OH
| | | | - Georgeanne G Botek
- Head, Section of Podiatry, Functional Limb Salvage Council, Cleveland Clinic, Cleveland, OH
| | - Craig J Verdin
- Third-Year Medical Student, Kent State University College of Podiatric Medicine, Independence, OH
| | - Nilin M Rao
- First-Year Podiatric Surgery Resident, Highlands-Presbyterian/St. Luke's Medical Center, Denver, CO
| | - J Derek Kingsley
- Assistant Professor, Exercise Physiology, Kent State University, Kent, OH
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Durgia H, Sahoo J, Kamalanathan S, Palui R, Sridharan K, Raj H. Role of bisphosphonates in the management of acute Charcot foot. World J Diabetes 2018; 9:115-126. [PMID: 30079147 PMCID: PMC6068741 DOI: 10.4239/wjd.v9.i7.115] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2018] [Revised: 04/26/2018] [Accepted: 06/13/2018] [Indexed: 02/05/2023] Open
Abstract
Diabetes mellitus is the most common cause of Charcot neuropathy affecting foot and ankle. Acute Charcot foot (CF) presents with a red and swollen foot in contrast to the painless deformed one of chronic CF. Enhanced osteoclastogenesis plays a central role in the pathogenesis of acute CF. Many studies have shown elevated levels of bone turnover markers in patients with acute CF confirming it. These findings have led clinicians to use anti-resorptive agents [bisphosphonates (BP), calcitonin, and denosumab] along with immobilization and offloading in acute CF patients. The maximum evidence among all anti-resorptive agents is available for BPs, although its quality is low. Pamidronate has been shown to reduce the markers of activity of CF like raised skin temperature, pain, edema, and bone turnover markers in the majority of studies. Intravenous BPs are known to cause acute phase reactions leading to flu-like illness following their first infusion, which can be ameliorated by oral acetaminophen. Alendronate is the only oral BP used in these patients. It needs to be taken on an empty stomach with a full glass of water to avoid esophagitis. The side-effects and contraindications to BPs should be kept in mind while treating acute CF patients with them.
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Affiliation(s)
- Harsh Durgia
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Sadishkumar Kamalanathan
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Rajan Palui
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Kalyani Sridharan
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Henith Raj
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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15
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Jansen RB, Svendsen OL. A review of bone metabolism and developments in medical treatment of the diabetic Charcot foot. J Diabetes Complications 2018; 32:708-712. [PMID: 29857955 DOI: 10.1016/j.jdiacomp.2018.04.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Revised: 04/20/2018] [Accepted: 04/23/2018] [Indexed: 02/07/2023]
Abstract
Charcot foot is a rare but severe, and possibly limb-threatening, complication to neuropathy and diabetes mellitus. The current treatment consists of long-term off-loading, and has a large negative impact on the patient's life. Much research has gone into understanding the condition and its biochemical mechanisms, however, the underlying pathogenesis of a Charcot foot is not yet fully understood. In the recent decades several key advances in our understanding of the Charcot foot have been made, both in regards to the changes in bone metabolism and structure an acute Charcot foot can cause, and to the molecular pathways involved in this. This review summerizes the available research into the bone metabolism around a Charcot foot, with an emphasis on the biochemical profile. The existing data regarding attempts at medical treatment is also reviewed, including novel trials targetting specific inflammatory pathways upregulated in the acute diabetic Charcot foot.
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Affiliation(s)
- Rasmus Bo Jansen
- Department of Endocrinology, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen, NV, Denmark.
| | - Ole Lander Svendsen
- Department of Endocrinology, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen, NV, Denmark; Copenhagen Diabetes Foot Center (CODIF), Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen, NV, Denmark
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16
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Abstract
Charcot neuroarthropathy is a rare but serious complication of diabetes, causing progressive destruction of the bones and joints of the foot leading to deformity, altered biomechanics and an increased risk of ulceration. Management is complicated by a lack of consensus on diagnostic criteria and an incomplete understanding of the pathogenesis. In this review, we consider recent insights into the development of Charcot neuroarthropathy. It is likely to be dependent on several interrelated factors which may include a genetic pre-disposition in combination with diabetic neuropathy. This leads to decreased neuropeptides (nitric oxide and calcitonin gene-related peptide), which may affect the normal coupling of bone formation and resorption, and increased levels of Receptor activator of nuclear factor kappa-B ligand, potentiating osteoclastogenesis. Repetitive unrecognized trauma due to neuropathy increases levels of pro-inflammatory cytokines (interleukin-1β, interleukin-6, tumour necrosis factor α) which could also contribute to increased bone resorption, in combination with a pre-inflammatory state, with increased autoimmune reactivity and a profile of monocytes primed to transform into osteoclasts - cluster of differentiation 14 (CD14). Increased blood glucose and loss of circulating Receptor for Advanced Glycation End-Products (AGLEPs), leading to increased non-enzymatic glycation of collagen and accumulation of AGLEPs in the tissues of the foot, may also contribute to the pathological process. An understanding of the relative contributions of each of these mechanisms and a final common pathway for the development of Charcot neuroarthropathy are still lacking. Cite this article: S. E. Johnson-Lynn, A. W. McCaskie, A. P. Coll, A. H. N. Robinson. Neuroarthropathy in diabetes: pathogenesis of Charcot arthropathy. Bone Joint Res 2018;7:373–378. DOI: 10.1302/2046-3758.75.BJR-2017-0334.R1.
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Affiliation(s)
- S E Johnson-Lynn
- Department of Trauma and Orthopaedics, Addenbrookes Hospital, Cambridge, UK
| | - A W McCaskie
- Department of Trauma and Orthopaedics, University of Cambridge, Cambridge, UK
| | - A P Coll
- Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK
| | - A H N Robinson
- Department of Trauma and Orthopaedics, Addenbrookes Hospital, Cambridge, UK
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17
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Jansen RB, Christensen TM, Bülow J, Rørdam L, Holstein PE, Jørgensen NR, Svendsen OL. Bone mineral density and markers of bone turnover and inflammation in diabetes patients with or without a Charcot foot: An 8.5-year prospective case-control study. J Diabetes Complications 2018; 32:164-170. [PMID: 29196119 DOI: 10.1016/j.jdiacomp.2017.11.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2017] [Revised: 11/04/2017] [Accepted: 11/06/2017] [Indexed: 11/21/2022]
Abstract
BACKGROUND AND AIMS Charcot foot is a rare but severe complication to diabetes and peripheral neuropathy. It is still unclear if an acute Charcot foot has long-term effects on the bone metabolism. To investigate this, we conducted a follow-up study to examine if a previously acute Charcot foot has any long-term effects on bone mineral density (BMD) or local or systemic bone metabolism. METHODS An 8.5-year follow-up case-control study of 44 individuals with diabetes mellitus, 24 of whom also had acute or chronic Charcot foot at the baseline visit in 2005-2007, who were followed up in 2015 with DXA scans and blood samples. RESULTS 21 of the 44 baseline participants participated in the follow-up. There were no difference in the change in total hip BMD from baseline to follow-up in either the Charcot or the control group (p = 0.402 and 0.517), and no increased risk of osteoporosis in the previous Charcot feet either. From baseline to follow-up, there was a significant difference in the change in levels of fsRANK-L in the Charcot group, but not in the control group (p = 0.002 and 0.232, respectively). At follow-up, there were no differences in fsRANK-L between the groups. The fsRANK-L/OPG ratio also significantly decreased from baseline to follow-up in the Charcot group (3.4 versus 0.5) (p = 0.009), but not in the control group (1.3 versus 1.1) (p = 0.302). CONCLUSION We found that diabetes patients with an acute Charcot foot have an elevated fsRANK-L/OPG ratio, and that the level decreased from baseline to follow-up to be comparable to the level in diabetes patients without previous or current Charcot foot. We found no permanent effect of an acute Charcot foot on hip or foot BMD.
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Affiliation(s)
- Rasmus Bo Jansen
- Copenhagen Diabetes Foot Center (CODIF), Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen, NV, Denmark; Department of Endocrinology, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen, NV, Denmark.
| | - Tomas Møller Christensen
- Department of Endocrinology, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen, NV, Denmark
| | - Jens Bülow
- Department of Clinical Physiology and Nuclear Medicine, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen, NV, Denmark
| | - Lene Rørdam
- Department of Clinical Physiology and Nuclear Medicine, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen, NV, Denmark
| | - Per E Holstein
- Copenhagen Wound Healing Center, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen, NV, Denmark
| | - Niklas Rye Jørgensen
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, DK-2600 Glostrup, Denmark; OPEN, Odense Patient Data Explorative Network, Odense University Hospital/Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Ole Lander Svendsen
- Copenhagen Diabetes Foot Center (CODIF), Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen, NV, Denmark; Department of Endocrinology, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen, NV, Denmark
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Jansen RB, Christensen TM, Bülow J, Rørdam L, Jørgensen NR, Svendsen OL. Markers of Local Inflammation and Bone Resorption in the Acute Diabetic Charcot Foot. J Diabetes Res 2018; 2018:5647981. [PMID: 30155488 PMCID: PMC6098852 DOI: 10.1155/2018/5647981] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Revised: 06/05/2018] [Accepted: 06/25/2018] [Indexed: 12/30/2022] Open
Abstract
OBJECTIVE Due to the localized nature of Charcot foot, systemically altered levels of inflammation markers can be difficult to measure. The aim of this study was to investigate whether it is possible to detect an arteriovenous (A-V) flux in any locally produced inflammatory biomarkers from an acute Charcot foot by comparing local and systemic measurements. METHODS We included patients with acute diabetic Charcot foot. Blood was sampled from the vena saphena magna on the distal part of the crus bilaterally as well as from the arteria radialis. To minimize the A-V shunting effect, the feet were externally cooled with ice water prior to resampling. RESULTS Both before and after cooling, the A-V flux of interleukin-6 (IL-6) between the Charcot feet and the arterial level was significantly higher than the flux between the healthy feet and the arterial level (Δvaluebefore: 7.25 versus 0.41 pg/mL, resp., p = 0.008; Δvalueafter: 10.04 versus 1.68 pg/mL, resp., p = 0.032). There were no differences in the fluxes for other markers of inflammation. CONCLUSION We have found an increased A-V flux of IL-6 in the acute diabetic Charcot foot compared to the healthy foot in the same patients.
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Affiliation(s)
- Rasmus Bo Jansen
- Copenhagen Diabetes Foot Center (CODIF), Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen NV, Denmark
- Department of Endocrinology, Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen NV, Denmark
| | - Tomas Møller Christensen
- Department of Endocrinology, Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen NV, Denmark
| | - Jens Bülow
- Department of Clinical Physiology and Nuclear Medicine, Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen NV, Denmark
| | - Lene Rørdam
- Department of Clinical Physiology and Nuclear Medicine, Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen NV, Denmark
| | - Niklas Rye Jørgensen
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, 2600 Glostrup, Denmark
- Odense Patient data Explorative Network (OPEN), Odense University Hospital/Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Ole Lander Svendsen
- Copenhagen Diabetes Foot Center (CODIF), Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen NV, Denmark
- Department of Endocrinology, Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen NV, Denmark
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DiDomenico L, Flynn Z, Reed M. Treating Charcot Arthropathy Is a Challenge: Explaining Why My Treatment Algorithm Has Changed. Clin Podiatr Med Surg 2018; 35:105-121. [PMID: 29156160 DOI: 10.1016/j.cpm.2017.08.012] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Charcot deformity is a challenge that foot and ankle surgeons struggle to manage successfully. Despite the advances in knowledge, technology, and treatment modalities, limb loss is still greater than 10%. This article discusses the efficacy of conservative measures and traditional surgical approaches. It proposes a multidisciplinary team approach, medical optimization, and lifestyle modification to put the patient in the best position to heal. Also discussed is the authors' staged surgical treatment protocol to enhance outcomes and decrease the rate of limb loss.
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Affiliation(s)
- Lawrence DiDomenico
- St. Elizabeth Medical Center, 8175 Market Street, Youngstown, OH 44512, USA.
| | - Zachary Flynn
- St. Elizabeth Medical Center, 8175 Market Street, Youngstown, OH 44512, USA
| | - Michael Reed
- Northside Medical Center, 500 Gypsy Lane, Youngstown, OH 44512, USA
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Zhao HM, Diao JY, Liang XJ, Zhang F, Hao DJ. Pathogenesis and potential relative risk factors of diabetic neuropathic osteoarthropathy. J Orthop Surg Res 2017; 12:142. [PMID: 28969714 PMCID: PMC5625723 DOI: 10.1186/s13018-017-0634-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 09/11/2017] [Indexed: 12/18/2022] Open
Abstract
Diabetic neuropathic osteoarthropathy (DNOAP) is an uncommon, but with considerable morbidity and mortality rates, complication of diabetes. The real pathogenesis is still unclear. The two popular theories are the neuro-vascular theory and neuro-traumatic theory. Most theories and pathways focused on the uncontrolled inflammations that resulted in the final common pathway, receptor activator of nuclear factor κβ ligand (RANKL)/osteoprotegerin (OPG) axis, for the decreased bone density in DNOAP with an osteoclast and osteoblast imbalance. However, the RANKL/OPG pathway does not explain all the changes, other pathways and factors also play roles. A lot of DNOAP potential relative risk factors were evaluated and reported in the literature, including age, gender, weight, duration and type of diabetes, bone mineral density, peripheral neuropathy and arterial disease, trauma history, and some others. However, most of them are still in debates. Future studies focus on the pathogenesis of DNOAP are still needed, especially for the genetic factors. And, the relationship between DNOAP and those potential relative risk factors are still need to further clarify.
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Affiliation(s)
- Hong-Mou Zhao
- Foot and Ankle Surgery Department, Honghui Hospital of Xi'an Jiaotong University College of Medicine, No. 76 Nanguo Road, Xi'an, 710054, People's Republic of China
| | - Jia-Yu Diao
- Cardiovascular Medicine Department, The Second Affiliated Hospital of Xi'an Jiaotong University College of Medicine, No. 157 West Fifth Road, Xi'an, 710004, People's Republic of China
| | - Xiao-Jun Liang
- Foot and Ankle Surgery Department, Honghui Hospital of Xi'an Jiaotong University College of Medicine, No. 76 Nanguo Road, Xi'an, 710054, People's Republic of China
| | - Feng Zhang
- School of Public Health, Health Science Center Xi'an Jiaotong University, No. 76 Yan Ta West Road, Xi'an, 710061, People's Republic of China.
| | - Ding-Jun Hao
- Spine Surgery Department, Honghui Hospital of Xi'an Jiaotong University College of Medicine, No. 76 Nanguo Road, Xi'an, 710054, People's Republic of China.
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Grant L, Yoho R, Halaharvi C, Grant W. Charcot Collapse: Does Collapse Pattern Dictate Osseous Metabolism? Foot Ankle Spec 2017; 10:428-434. [PMID: 28030964 DOI: 10.1177/1938640016685144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
UNLABELLED Charcot fracture pattern (FP) and Charcot dislocation pattern (DP) are 2 distinct collapse patterns identified in Charcot neuroarthropathy of the foot and ankle. These patterns are believed to demonstrate relative differences in central bone mineral density (BMD), which has been theoretically extrapolated to describe local BMD. To assess variation in local bone composition of FP and DP patients, 10 patients, 5 DP and 5 FP were recruited. The patient's age, body mass index (BMI), radiographs, central BMD, local BMD, sRANKL (soluble receptor activator nuclear factor kappa-beta ligand), sRAGE (soluble receptors of advanced glycated end-products), and osteocalcin were measured to determined bone metabolic status and density. Central BMD was determined using DEXA (dual-energy X-ray absorptiometry) scans of the hip. peripheral BMD was determined using scans at the level of the ankle mortise and Chopart's joint, depending on the location of collapse. These scans were then compared with controls. Central and peripheral DEXA scans were significantly reduced in the FP ( P = .002 and P < .0001) when compared with healthy controls. Additionally, FP patients demonstrated statistically significant elevations in sRANKL ( P = .05) and sRAGE ( P = .002) when compared with DP. No significant difference was seen in osteocalcin ( P = 0.22); however, elevated values compared with normal reference ranges suggest increase bone production. These elevations combined with an osteoporotic profile may indicate difficulty of FP patients in repairing micro fracture. Results from this study emphasize the increased risk of nonunion during FP reconstruction, and highlight the variation in bone composition in these 2 Charcot subtypes. LEVELS OF EVIDENCE Level III.
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Affiliation(s)
- Lisa Grant
- Western Pennsylvania Hospital Department of Foot and Ankle Surgery, Pittsburgh, Pennsylvania (LG).,College of Podiatric Medicine and Surgery, Des Moines University, Des Moines, Iowa (RY).,Grant Medical Center Department of Foot and Ankle Surgery, Columbus, Ohio (CH).,Tidewater Foot and Ankle Clinic, Virginia Beach, Virginia, (WG)
| | - Robert Yoho
- Western Pennsylvania Hospital Department of Foot and Ankle Surgery, Pittsburgh, Pennsylvania (LG).,College of Podiatric Medicine and Surgery, Des Moines University, Des Moines, Iowa (RY).,Grant Medical Center Department of Foot and Ankle Surgery, Columbus, Ohio (CH).,Tidewater Foot and Ankle Clinic, Virginia Beach, Virginia, (WG)
| | - Chandana Halaharvi
- Western Pennsylvania Hospital Department of Foot and Ankle Surgery, Pittsburgh, Pennsylvania (LG).,College of Podiatric Medicine and Surgery, Des Moines University, Des Moines, Iowa (RY).,Grant Medical Center Department of Foot and Ankle Surgery, Columbus, Ohio (CH).,Tidewater Foot and Ankle Clinic, Virginia Beach, Virginia, (WG)
| | - William Grant
- Western Pennsylvania Hospital Department of Foot and Ankle Surgery, Pittsburgh, Pennsylvania (LG).,College of Podiatric Medicine and Surgery, Des Moines University, Des Moines, Iowa (RY).,Grant Medical Center Department of Foot and Ankle Surgery, Columbus, Ohio (CH).,Tidewater Foot and Ankle Clinic, Virginia Beach, Virginia, (WG)
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Schara K, Štukelj R, Krek J, Lakota K, Sodin-Šemrl S, Boulton A, Kralj-Iglič V. A study of extracellular vesicle concentration in active diabetic Charcot neuroarthropathy. Eur J Pharm Sci 2017; 98:58-63. [DOI: 10.1016/j.ejps.2016.09.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 09/06/2016] [Accepted: 09/08/2016] [Indexed: 10/21/2022]
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Guclu M, Ali A, Eroglu DU, Büyükuysal SO, Cander S, Ocak N. Serum Levels of sRAGE Are Associated with Body Measurements, but Not Glycemic Parameters in Patients with Prediabetes. Metab Syndr Relat Disord 2016; 14:33-9. [DOI: 10.1089/met.2015.0078] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Affiliation(s)
- Metin Guclu
- Department of Endocrinology and Metabolism, Sevket Yilmaz Research and Training Hospital-Bursa, Bursa, Turkey
| | - Asuman Ali
- Department of Neurology, Sevket Yilmaz Research and Training Hospital-Bursa, Bursa, Turkey
| | - Derya Ustun Eroglu
- Department of Internal Medicine, Sevket Yilmaz Research and Training Hospital-Bursa, Bursa, Turkey
| | - Sema Oral Büyükuysal
- Department of Biochemistry, Sevket Yilmaz Research and Training Hospital-Bursa, Bursa, Turkey
| | - Soner Cander
- Department of Endocrinology and Metabolism, Sevket Yilmaz Research and Training Hospital-Bursa, Bursa, Turkey
| | - Nihal Ocak
- Department of Biochemistry, Sevket Yilmaz Research and Training Hospital-Bursa, Bursa, Turkey
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Ray R, Juranek JK, Rai V. RAGE axis in neuroinflammation, neurodegeneration and its emerging role in the pathogenesis of amyotrophic lateral sclerosis. Neurosci Biobehav Rev 2015; 62:48-55. [PMID: 26724598 DOI: 10.1016/j.neubiorev.2015.12.006] [Citation(s) in RCA: 104] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Revised: 10/19/2015] [Accepted: 12/10/2015] [Indexed: 12/13/2022]
Abstract
RAGE, the receptor of advanced glycation end-products, is thought to be one of the potential contributors to the neurodegeneration. It has been shown that RAGE activation triggers an increase in proinflammatory molecules, oxidative stressors and cytokines. RAGE involvement has been documented in the pathogenesis of a number of neurodegenerative diseases such amyotrophic lateral sclerosis (ALS), Alzheimer's, Parkinson's, Huntington's, Creutzfeld-Jakob' diseases and various neurodegenerative conditions such as diabetic neuropathy, familial amyloid polyneuropathy, Charcot neuroarthropathy and vasculitic neuropathy. Although the detailed mechanisms of RAGE contribution to the neurodegeneration remains unclear, studies indicate that RAGE detrimental actions are exerted via its binding to the pro-inflammatory ligands such as advanced glycation end-products, S100/calgranulin and amphoterin and subsequent activation of downstream regulatory pathways such as NF-κB, STAT and JKN pathways. Here, in this review we attempt to shed light onto molecular events and pathological pathways involved in neuroinflammation, neurodegeneration and its emerging role in the pathogenesis of amyotrophic lateral sclerosis (ALS)--a progressive and fatal neurodegenerative disorder, summarizing current knowledge and the prospect of RAGE in the pathogenesis of this disastrous disease.
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Affiliation(s)
- Rashmi Ray
- Institute of Life Sciences, Bhubaneswar 751023, India; Manipal University, Karnataka 576104, India
| | - Judyta K Juranek
- Department of Medicine, New York University Medical Center, New York, USA; Department of Pathophysiology, Faculty of Medicine, University of Warmia and Mazury, 10-557 Olsztyn, Poland.
| | - Vivek Rai
- Institute of Life Sciences, Bhubaneswar 751023, India.
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In diabetic Charcot neuroarthropathy impaired microvascular function is related to long lasting metabolic control and low grade inflammatory process. Microvasc Res 2015; 101:143-7. [DOI: 10.1016/j.mvr.2015.07.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2015] [Revised: 07/30/2015] [Accepted: 07/30/2015] [Indexed: 11/19/2022]
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Abstract
Charcot foot syndrome is an uncommon complication of diabetes but is potentially devastating in its consequences. Outcome is made worse by widespread professional ignorance leading to delayed diagnosis, but it is also hampered by lack of understanding of its causes and lack of treatments with proven effectiveness, other than offloading. There remains a desperate need for studies into its causes as well as comparative audit and trials designed to determine the best treatment for this difficult condition. Such work can probably only be effectively carried out through the establishment of multicentre networks. Nevertheless, improved understanding in recent years of the likely role of inflammatory pathways has raised awareness of the multiple ways in which the effects of neuropathy may be manifest in the development of the Charcot foot. This awareness is also leading to the realization that similar processes may conceivably contribute to the refractoriness of other foot diseases in diabetes, including both chronic unhealing ulcers and osteomyelitis.
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Affiliation(s)
- W J Jeffcoate
- Foot Ulcer Trials Unit, Department of Diabetes and Endocrinology, Nottingham University Hospitals Trust, Nottingham, UK
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The role of receptor for advanced glycation end products in airway inflammation in CF and CF related diabetes. Sci Rep 2015; 5:8931. [PMID: 25754382 PMCID: PMC4354142 DOI: 10.1038/srep08931] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 02/11/2015] [Indexed: 11/28/2022] Open
Abstract
Cystic Fibrosis (CF) is often accompanied by diabetes leading to worsening lung function, the reason for which is unclear. The receptor for advanced-glycation-end-products (RAGE) regulates immune responses and inflammation and has been linked to diabetes and possibly CF. We performed a pilot study to determine if CF and CF-related diabetes (CFRD) are associated with enhanced RAGE expression. Full length (fl)RAGE, soluble (s)RAGE, endogenous soluble (es)RAGE, S100A12 (enRAGE) and advanced-glycation-end-products (AGE) expression was assessed in serum, white blood cells and sputum of patients with CF; diabetes; CFRD and healthy subjects. Sputum enRAGE/sRAGE ratios were high in CF but particularly in CFRD which negatively correlated with % predicted FEV1. Serum AGE and AGE/sRAGE ratios were high in diabetics but not in CF. A complex, multifaceted approach was used to assess the role of RAGE and its ligands which is fundamental to determining their impact on airway inflammation. There is a clear association between RAGE activity in the airways of CF and CFRD patients that is not evident in the vascular compartment and correlates with lung function, in contrast to diabetes. This strongly suggests a role for RAGE in contributing to the inflammatory overdrive seen in CF and to a greater extent in CFRD.
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Ndip A, Wilkinson FL, Jude EB, Boulton AJM, Alexander MY. RANKL-OPG and RAGE modulation in vascular calcification and diabetes: novel targets for therapy. Diabetologia 2014; 57:2251-60. [PMID: 25112376 DOI: 10.1007/s00125-014-3348-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 07/17/2014] [Indexed: 12/18/2022]
Abstract
Type 2 diabetes is associated with increased cardiovascular morbidity and mortality and early vascular ageing. This takes the form of atherosclerosis, with progressive vascular calcification being a major complication in the pathogenesis of this disease. Current research and drug targets in diabetes have hitherto focused on atherosclerosis, but vascular calcification is now recognised as an independent predictor of cardiovascular morbidity and mortality. An emerging regulatory pathway for vascular calcification in diabetes involves the receptor activator for nuclear factor κB (RANK), RANK ligand (RANKL) and osteoprotegerin (OPG). Important novel biomarkers of calcification are related to levels of glycation and inflammation in diabetes. Several therapeutic strategies could have advantageous effects on the vasculature in patients with diabetes, including targeting the RANKL and receptor for AGE (RAGE) signalling pathways, since there has been little success-at least in macrovascular outcomes-with conventional glucose-lowering therapy. There is substantial and relevant clinical and basic science evidence to suggest that modulating RANKL-RANK-OPG signalling, RAGE signalling and the associated proinflammatory milieu alters the natural course of cardiovascular complications and outcomes in people with diabetes. However, further research is critically needed to understand the precise mechanisms underpinning these pathways, in order to translate the anti-calcification strategies into patient benefit.
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Affiliation(s)
- Agbor Ndip
- Department of Medicine and Diabetes, Manchester Royal Infirmary, Manchester, UK,
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Aubert CE, Michel PL, Gillery P, Jaisson S, Fonfrede M, Morel F, Hartemann A, Bourron O. Association of peripheral neuropathy with circulating advanced glycation end products, soluble receptor for advanced glycation end products and other risk factors in patients with type 2 diabetes. Diabetes Metab Res Rev 2014; 30:679-85. [PMID: 24449227 DOI: 10.1002/dmrr.2529] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2013] [Revised: 11/17/2013] [Accepted: 12/24/2013] [Indexed: 01/11/2023]
Abstract
BACKGROUND The pathogenesis of diabetic peripheral neuropathy remains uncertain and nonenzymatic glycoxidation is one of the contributing mechanisms. The aim of this study was to assess the respective relationship of diabetic peripheral neuropathy with glycoxidation, compared with other identified risk factors, in patients with type 2 diabetes. METHODS We included 198 patients with type 2 diabetes and high risk for vascular complications. Circulating concentrations of three advanced glycation end products (carboxymethyllysine, methyl-glyoxal-hydroimidazolone-1, pentosidine) and of their soluble receptor (sRAGE) were measured. Peripheral neuropathy was assessed by the neuropathy disability score and by the monofilament test and defined as either an abnormal monofilament test and/or a neuropathy disability score ≥6. Multivariate regression analyses were performed adjusting for potential confounding factors for neuropathy: age, gender, diabetes duration, current smoking, systolic blood pressure, waist circumference, height, peripheral arterial occlusive disease, glycated haemoglobin, estimated glomerular filtration rate and lipid profile. RESULTS Prevalence of peripheral neuropathy was 20.7%. sRAGE and carboxymethyllysine were independently and positively associated with the presence of peripheral neuropathy. No significant association was found between peripheral neuropathy and methyl-glyoxal-hydroimidazolone-1 or pentosidine. Waist circumference, height and peripheral arterial occlusive disease were independently associated with peripheral neuropathy. CONCLUSIONS Carboxymethyllysine and sRAGE were independently associated with peripheral neuropathy in patients with type 2 diabetes. Although the conclusions are limited by the absence of a healthy control population, this study confirms the relationship between advanced glycoxidation and diabetic peripheral neuropathy, independently of other risk factors.
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Affiliation(s)
- C E Aubert
- Diabetes and Metabolic Diseases Department, AP-HP, Pitié-Salpêtrière Hospital, Paris, France; Internal Medicine Department, Fribourg Cantonal Hospital, Fribourg, Switzerland
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Abstract
Diabetic neuropathies (DNs) differ in clinical course, distribution, fiber involvement (type and size), and pathophysiology, the most typical type being a length-dependent distal symmetric polyneuropathy (DSP) with differing degrees of autonomic involvement. The pathogenesis of diabetic DSP is multifactorial, including increased mitochondrial production of free radicals due to hyperglycemia-induced oxidative stress. Mechanisms that impact neuronal activity, mitochondrial function, membrane permeability, and endothelial function include formation of advanced glycosylation end products, activation of polyol aldose reductase signaling, activation of poly(ADP ribose) polymerase, and altered function of the Na(+)/K(+)-ATPase pump. Hyperglycemia-induced endoplasmic reticulum stress triggers several neuronal apoptotic processes. Additional mechanisms include impaired nerve perfusion, dyslipidemia, altered redox status, low-grade inflammation, and perturbation of calcium balance. Successful therapies require an integrated approach targeting these mechanisms. Intensive glycemic control is essential but is insufficient to prevent onset or progression of DSP, and disease-modifying treatments for DSP have been disappointing. Atypical forms of DN include subacute-onset sensory (symmetric) or motor (asymmetric) predominant conditions that are frequently painful but generally self-limited. DNs are a major cause of disability, associated with reduced quality of life and increased mortality.
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Affiliation(s)
- James W. Albers
- Neuromuscular Section, Department of Neurology, University of Michigan Health System, 1C325 University Hospital, 1500 East Medical Center Drive, Ann Arbor, MI 48109-0032, USA
| | - Rodica Pop-Busui
- Division of Metabolism, Endocrinology and Diabetes, University of Michigan, 5329 Brehm Tower, 1000 Wall Street, Ann Arbor, MI 48105, USA
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Barwick AL, de Jonge XAKJ, Tessier JW, Ho A, Chuter VH. The effect of diabetic neuropathy on foot bones: a systematic review and meta-analysis. Diabet Med 2014; 31:136-47. [PMID: 24151985 DOI: 10.1111/dme.12347] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2013] [Revised: 09/11/2013] [Accepted: 10/18/2013] [Indexed: 01/02/2023]
Abstract
AIMS It is proposed that diabetic neuropathy may affect peripheral bone. Direct innervation of bone as well as neural control over its vascular supply and muscular influences may be affected by diabetes-induced peripheral neuropathies. Associated changes to bone may contribute to the occurrence of foot bone pathology in this population. This systematic review aims to examine the literature related to the effect of diabetic neuropathy on foot bones. METHODS Studies examining relationships between neuropathy and indicators of bone health (e.g. bone mineral density) in populations with diabetes were sought. Relevant publications were obtained from searches in MEDLINE, CINAHL and Embase in the period up to March 2013. Meta-analysis was performed using a random effects model in the statistical package Stata version 12.1. RESULTS Ten studies met the inclusion criteria and were included in the narrative synthesis. All studies were cross-sectional or case-control in design. Four of the 10 included studies found results indicating poorer bone health in those with diabetes and neuropathy compared with those with diabetes without neuropathy. Seven of the 10 studies were able to be included in a meta-analysis. The mean pooled effect was -0.36 (95% CI -0.76 to 0.04; P = 0.08), indicating a non-significant trend towards poorer bone health in those with diabetic neuropathy. CONCLUSIONS We did not find a significant relationship between presence of neuropathy in those with diabetes and poorer peripheral bone health. However, methodological limitations of the included studies mean further research is required to investigate this theoretical relationship.
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Affiliation(s)
- A L Barwick
- School of Health Sciences, Faculty of Health
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Al-Nammari SS, Timothy T, Afsie S. A Surgeon's guide to advances in the pharmacological management of acute Charcot neuroarthropathy. Foot Ankle Surg 2013; 19:212-7. [PMID: 24095226 DOI: 10.1016/j.fas.2013.06.011] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Revised: 03/07/2013] [Accepted: 06/25/2013] [Indexed: 02/04/2023]
Abstract
Acute Charcot neuroarthropathy is a devastating condition and, its incidence is increasing. Currently, treatment consists of immobilisation and off-loading of the involved extremity. Outcomes are frequently poor and novel treatments are being sought urgently. This review aims to outline advances in the pharmacological treatment of this, condition. PubMed and the Cochrane Database of systematic reviews were searched. Relevant papers were cross referenced. Eleven original studies were identified. The limited data available suggest pamidronate, alendronate and calcitonin provide some clinical and biochemical improvements while zoledronic acid is deleterious and, increases off-loading times. However, the data is not robust enough to convincingly demonstrate clinically meaningful effects. The studies were predominantly low quality and heterogeneous. They differed markedly in study type, pharmacological agent used, dosing regimen, disease, aetiology/stage/location, concurrent off-loading regimen, outcomes and, follow-up. Few were rigorous in controlling for associated confounding variables and none investigated long term outcomes. The routine use of pharmacological treatment modalities for this condition is not recommended in the United States by the Food and Drug Administration or in the United Kingdom by the National Institute for Health and Clinical Excellence. Given the evidence available this is justified and further higher quality research is required.
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Affiliation(s)
- Shafic Said Al-Nammari
- Green Templeton College, University of Oxford, Woodstock Road, Oxford OX2 6HG, United Kingdom.
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Madan SS, Pai DR. Charcot neuroarthropathy of the foot and ankle. Orthop Surg 2013; 5:86-93. [PMID: 23658042 DOI: 10.1111/os.12032] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Accepted: 12/20/2012] [Indexed: 12/17/2022] Open
Abstract
Charcot neuroarthropathy (CN) is a rare, progressive, deforming disease of bone and joints, especially affecting the foot and ankle and leading to considerable morbidity. It can also affect other joints such as the wrist, knee, spine and shoulder. This disease, described originally in reference to syphilis, is now one of the most common associates of diabetes mellitus. As the number of diabetics increase, the incidence of CN is bound to rise. Faster initial diagnosis and prompt institution of treatment may help to reduce its sequelae. There should be a low threshold for ordering investigations to assist coming to this diagnosis. No single investigation is the gold standard. Recent studies on pathogenesis and development of newer investigation modalities have helped to clarify the mystery of its pathogenesis and of its diagnosis in the acute phase. Various complementary investigations together allow the correct diagnosis to be made. Osteomyelitis continues to be confused with acute CN. Hybrid positron emission tomography has shown some promise in differentiating these conditions. A multispecialty approach involving diabetologists, orthopaedists and podiatrists should be used to tackle this difficult problem. The aim of this article is to describe current knowledge about CN with particular reference to the status of diagnostic indicators and management options.
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Affiliation(s)
- Simerjit Singh Madan
- Department of Orthopaedics, Melaka Manipal Medical College, Jalan Batu Hampar, Bukit Baru, Melaka, Malaysia.
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Casellini CM, Parson HK, Richardson MS, Nevoret ML, Vinik AI. Sudoscan, a noninvasive tool for detecting diabetic small fiber neuropathy and autonomic dysfunction. Diabetes Technol Ther 2013; 15:948-53. [PMID: 23889506 PMCID: PMC3817891 DOI: 10.1089/dia.2013.0129] [Citation(s) in RCA: 204] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Sudomotor dysfunction may be an early detectable abnormality in diabetic small fiber neuropathy. The aim of this study was to evaluate the efficacy of Sudoscan™ (Impeto Medical, Paris, France) in detecting diabetic neuropathy (DN), in comparison with other standardized tests, in patients with diabetes mellitus (DM). SUBJECTS AND METHODS Sudoscan measures electrochemical skin conductance (ESC) of hands and feet through reverse iontophoresis. We evaluated 83 DM patients with and without DN and 210 healthy controls (HCs). Neuropathy Impairment Score-Lower Legs (NIS-LL), quantitative autonomic function testing (QAFT), and quantitative sensory testing (QST) were performed. Symptomatic pain was recorded using a visual analog scale. Receiver-operator characteristic (ROC) curves were calculated to evaluate the efficacy of Sudoscan in detecting DN compared with traditional modalities. RESULTS Diabetes patients with DN had significantly worse ESCs of feet and hands than DM patients without DN and HCs (respectively, 56.3±3 vs. 75.9±5.5 and 84.4±0.9 [P<0.0001] for feet and 51.9±2.4 vs. 67.5±4.3 and 73.1±0.8 [P<0.0001] for hands). Increasing NIS-LL scores were associated with decreasing ESC values. ESCs correlated significantly with clinical (NIS-LL), somatic (QST), and autonomic (QAFT) measures of neuropathy and with pain scores. ROC curve analysis showed significant results for both hands and feet ESC (area under the curve of 0.86 and 0.88, respectively; P<0.0001) with sensitivity of 78% and specificity of 92% for feet to detect DN. CONCLUSIONS Sudoscan is a promising, sensitive tool to detect neuropathy in patients with DM. This is a very simple, easy-to-perform test that can be done in the clinical setting in 3-5 min.
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Affiliation(s)
- Carolina M Casellini
- Strelitz Diabetes Center for Endocrine and Metabolic Disorders and the Neuroendocrine Unit , Department of Medicine, Eastern Virginia Medical School
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Juranek JK, Kothary P, Mehra A, Hays A, Brannagan TH, Schmidt AM. Increased expression of the receptor for advanced glycation end-products in human peripheral neuropathies. Brain Behav 2013; 3:701-9. [PMID: 24363972 PMCID: PMC3868174 DOI: 10.1002/brb3.176] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Revised: 08/07/2013] [Accepted: 08/08/2013] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Diabetic neuropathy and idiopathic neuropathy are among the most prevalent neuropathies in human patients. The molecular mechanism underlying pathological changes observed in the affected nerve remains unclear but one candidate molecule, the receptor for advanced glycation end-products (RAGE), has recently gained attention as a potential contributor to neuropathy. Our previous studies revealed that RAGE expression is higher in porcine and murine diabetic nerve, contributing to the inflammatory mechanisms leading to diabetic neuropathy. Here, for the first time, we focused on the expression of RAGE in human peripheral nerve. METHODS Our study utilized de-identified human sural nerve surplus obtained from 5 non-neuropathic patients (control group), 6 patients with long-term mild-to-moderate diabetic neuropathy (diabetic group) and 5 patients with mild-to-moderate peripheral neuropathy of unknown etiology (idiopathic group). By using immunofluorescent staining and protein immunoblotting we studied the expression and colocalization patterns of RAGE and its ligands: carboxymethyllysine (CML), high mobility group box 1 (HMBG1) and mammalian Diaphanous 1 (mDia1) in control and neuropathic nerves. RESULTS We found that in a normal, healthy human nerve, RAGE is expressed in almost 30% of all nerve fibers and that number is higher in pathological states such as peripheral neuropathy. We established that the levels of RAGE and its pro-inflammatory ligands, CML and HMBG1, are higher in both idiopathic and diabetic nerve, while the expression of the RAGE cytoplasmic domain-binding partner, mDia1 is similar among control, diabetic, and idiopathic nerve. The highest number of double stained nerve fibers was noted for RAGE and CML: ∼76% (control), ∼91% (idiopathic) and ∼82% (diabetic) respectively. CONCLUSIONS Our data suggest roles for RAGE and its inflammatory ligands in human peripheral neuropathies and lay the foundation for further, more detailed and clinically oriented investigation involving these proteins and their roles in disorders of the human peripheral nerve.
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Affiliation(s)
- Judyta K Juranek
- Department of Surgery, Columbia University Medical Center New York, New York ; Diabetes Research Program, Department of Medicine, NYU Medical Center New York, New York
| | - Pratik Kothary
- Department of Surgery, Columbia University Medical Center New York, New York ; Diabetes Research Program, Department of Medicine, NYU Medical Center New York, New York
| | - Alka Mehra
- Infectious Diseases Center, Department of Medicine, NYU Medical Center New York, New York
| | - Arthur Hays
- Department of Pathology, Columbia University Medical Center New York, New York
| | - Thomas H Brannagan
- Department of Neurology, Columbia University Medical Center New York, New York
| | - Ann Marie Schmidt
- Department of Surgery, Columbia University Medical Center New York, New York ; Diabetes Research Program, Department of Medicine, NYU Medical Center New York, New York
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Abstract
Charcot neuroarthropathy is a limb-threatening, destructive process that occurs in patients with neuropathy associated with medical diseases such as diabetes mellitus. Clinicians' treating diabetic patients should be vigilant in recognizing the early signs of acute Charcot neuroarthropathy, such as pain, warmth, edema, or pathologic fracture in a neuropathic foot. Early detection and prompt treatment can prevent joint and bone destruction, which, if untreated, can lead to morbidity and high-level amputation. A high degree of suspicion is necessary. Once the early signs have been detected, prompt immobilization and offloading are important. Treatment should be determined on an individual basis, and it must be determined whether a patient can be treated conservatively or will require surgical intervention when entering the chronic phase. If diagnosed early, medical and conservative measures only will be required. Surgery is indicated for patients with severe or unstable deformities that, if untreated, will result in major amputations. A team approach that includes a foot and ankle surgeon, a diabetologist, a physiotherapist, a medical social councilor, and, most importantly, the patient and immediate family members is vital for successful management of this serious condition.
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Affiliation(s)
- Ajit Kumar Varma
- Professor, Department of Endocrinology, Diabetic Lower Limb and Podiatric Surgery, Amrita Institute of Medical Sciences and Research Center, Ponekkara, Kerala, India.
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Parson HK, Nguyen VT, Orciga MA, Boyd AL, Casellini CM, Vinik AI. Contact heat-evoked potential stimulation for the evaluation of small nerve fiber function. Diabetes Technol Ther 2013; 15:150-7. [PMID: 23298343 DOI: 10.1089/dia.2012.0202] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
BACKGROUND Small fiber peripheral neuropathy (SFN) is emerging as a common complication in diabetes. Currently there are few, not easily available methods of determining the integrity of small nerve fibers. This study was designed to determine the utility of a noninvasive technique, contact heat-evoked potential stimulation (CHEPS), on the identification of SFN and compare it with standardized measures of diabetic peripheral neuropathy (DPN). SUBJECTS AND METHODS We evaluated 31 healthy controls and 30 participants with type 2 diabetes and DPN using neurologic examination, nerve conduction studies (NCS), autonomic function tests, quantitative sensory tests (QSTs), and CHEPS. Contact heat was administered to the thenar eminence, volar and dorsal forearms, lower back, and distal lower limb. Evoked potentials were recorded from the skull vertex. Latencies and amplitudes were determined. RESULTS Intrapeak amplitude (IA) values were significantly reduced in the DPN group at the lower back (44.93±6.5 vs. 23.87±3.36 μV; P<0.01), lower leg (15.87±1.99 vs. 11.68±1.21 μV; P<0.05), and dorsal forearm (29.89±8.86 vs. 14.96±1.61 μV; P<0.05). Pooled data from both groups showed that IA values at different sites significantly correlated with clinical neurologic scores, NCS, QSTs, and autonomic function. Receiver operator characteristic curve analysis, used to evaluate the performance of CHEPS in detecting nerve dysfunction, was most significant for IA at the lower back (area under the curve, 0.778;±SE, 0.06; 95% confidence interval, 0.654-0.875; P<0.0001). CONCLUSIONS This study suggests that CHEPS is a novel, noninvasive technique able to detect impairment of small nerve fiber function from skin to cerebral cortex, providing an objective measure of C and Aδ nerve dysfunction.
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Affiliation(s)
- Henri K Parson
- Strelitz Diabetes Center for Endocrine and Metabolic Disorders, Department of Medicine, Eastern Virginia Medical School, Norfolk, Virginia 23510, USA
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Vinik AI, Erbas T, Casellini CM. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Investig 2013; 4:4-18. [PMID: 23550085 PMCID: PMC3580884 DOI: 10.1111/jdi.12042] [Citation(s) in RCA: 219] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2012] [Accepted: 11/14/2012] [Indexed: 12/16/2022] Open
Abstract
One of the most overlooked of all serious complications of diabetes is cardiovascular autonomic neuropathy. There is now clear evidence that suggests activation of inflammatory cytokines in diabetic patients and that these correlate with abnormalities in sympathovagal balance. Dysfunction of the autonomic system predicts cardiovascular risk and sudden death in patients with type 2 diabetes. It also occurs in prediabetes, providing opportunities for early intervention. Simple tests that can be carried out at the bedside with real-time output of information - within the scope of the practicing physician - facilitate diagnosis and allow the application of sound strategies for management. The window of opportunity for aggressive control of all the traditional risk factors for cardiovascular events or sudden death with intensification of therapy is with short duration diabetes, the absence of cardiovascular disease and a history of severe hypoglycemic events. To this list we can now add autonomic dysfunction and neuropathy, which have become the most powerful predictors of risk for mortality. It seems prudent that practitioners should be encouraged to become familiar with this information and apply risk stratification in clinical practice. Several agents have become available for the correction of functional defects in the autonomic nervous system, and restoration of autonomic balance is now possible.
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Affiliation(s)
- Aaron I Vinik
- The Strelitz Diabetes Research Center and Neuroendocrine Unit, The Department of Medicine and Pathology/Anatomy/Neurobiology, Eastern Virginia Medical School Norfolk, Virginia, USA
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Tahrani AA, Zeng W, Shakher J, Piya MK, Hughes S, Dubb K, Stevens MJ. Cutaneous structural and biochemical correlates of foot complications in high-risk diabetes. Diabetes Care 2012; 35:1913-8. [PMID: 22751961 PMCID: PMC3424985 DOI: 10.2337/dc11-2076] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Impairment of skin quality may contribute to diabetic foot ulceration (DFU). Our goal was to determine whether high-risk patients exhibited specific skin structural and metabolic deficits that could predispose to foot complications. RESEARCH DESIGN AND METHODS A total of 46 patients comprising 9 diabetic control subjects, 16 with diabetic peripheral neuropathy (DPN) alone, and 21 with recurrent DFUs (including 9 with Charcot neuroarthropathy [CNA]) were recruited and compared with 14 nondiabetic control (NDC) subjects. DPN was assessed using the Michigan Neuropathy Screening Instrument (MNSI). Skin punch biopsies (3 mm) were performed on upper and lower leg skin for measurements of intraepidermal nerve fiber density (IENFD), structural analysis, type 1 procollagen abundance, tissue degrading matrix metalloproteinases (MMPs), and poly(ADP-ribose) (PAR) immunoreactivity. RESULTS MNSI scores were comparable across DPN groups. IENFD was decreased by diabetes and DPN but did not differ between neuropathic groups. Skin structural deficit scores were elevated in all neuropathic subjects, particularly in the DFU group. Type 1 procollagen abundance was reduced in DFU subjects 387 ± 256 units (mean ± 1 SD) compared with NDC subjects (715 ± 100, P < 0.001). MMP-1 and MMP-2 were activated by diabetes. PAR immunoreactivity was increased in DFU (particularly in the CNA group; P < 0.01) compared with other DPN subjects. CONCLUSIONS Increased PAR, reduced type 1 procollagen abundance, and impaired skin structure are associated with foot complications in diabetes. The potential of therapies that improve skin quality to reduce DFU needs to be investigated.
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Ramasamy R, Yan SF, Schmidt AM. The diverse ligand repertoire of the receptor for advanced glycation endproducts and pathways to the complications of diabetes. Vascul Pharmacol 2012; 57:160-7. [PMID: 22750165 DOI: 10.1016/j.vph.2012.06.004] [Citation(s) in RCA: 116] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2012] [Revised: 06/20/2012] [Accepted: 06/21/2012] [Indexed: 02/06/2023]
Abstract
The multi-ligand receptor RAGE was discovered on account of its ability to bind and transduce the cell stress-provoking signals of advanced glycation endproducts (AGEs). The finding that RAGE also bound pro-inflammatory molecules set the stage for linking RAGE and inflammation to the pathogenesis of diabetic macro- and microvascular complications. In this review, we focus on the roles of RAGE and its ligands in diabetes complications. We recount the findings from mice, rats, swine and human subjects suggesting that RAGE action potently contributes to vascular, inflammatory and end-organ stress and damage in types 1 and 2 diabetes. We detail the efforts to track ligands and RAGE in human subjects with diabetes to address if this axis may be a biomarker reflective of the state of the diabetic complications. Lastly, we suggest specific strategies to tackle AGE-ligand-RAGE interactions as potential therapeutic targets for diabetes and its complications.
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Affiliation(s)
- Ravichandran Ramasamy
- Diabetes Research Program, Division of Endocrinology, Department of Medicine, New York University School of Medicine, New York, NY 10016, United States
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Pop-Busui R. What do we know and we do not know about cardiovascular autonomic neuropathy in diabetes. J Cardiovasc Transl Res 2012; 5:463-78. [PMID: 22644723 DOI: 10.1007/s12265-012-9367-6] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2012] [Accepted: 04/12/2012] [Indexed: 12/16/2022]
Abstract
Cardiovascular autonomic neuropathy (CAN) in diabetes is generally overlooked in practice, although awareness of its serious consequences is emerging. Challenges in understanding the complex, dynamic changes in the modulation of the sympathetic/parasympathetic systems' tone and their interactions with physiologic mechanisms regulating the control of heart rate, blood pressure, and other cardiovascular functions in the presence of acute hyper-or-hypoglycemic stress, other stressors or medication, and challenges with sensitive evaluations have contributed to lower CAN visibility compared with other diabetes complications. Yet, CAN is a significant cause of morbidity and mortality, due to a high-risk of cardiac arrhythmias, silent myocardial ischemia and sudden death. While striving for aggressive risk factor control in diabetes practice seemed intuitive, recent reports of major clinical trials undermine established thinking concerning glycemic control and cardiovascular risk. This review covers current understanding and gaps in that understanding of the clinical implications of CAN and prevention and treatment of CAN.
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Affiliation(s)
- Rodica Pop-Busui
- Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
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Suder NC, Wukich DK. Prevalence of diabetic neuropathy in patients undergoing foot and ankle surgery. Foot Ankle Spec 2012; 5:97-101. [PMID: 22322102 DOI: 10.1177/1938640011434502] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION The aim of this prospective study was to determine the prevalence of neuropathy in diabetic patients undergoing foot and ankle surgery. It was hypothesized that the prevalence of diabetic neuropathy is higher among patients who undergo foot and ankle surgery compared with historical rates of neuropathy in diabetic patients in general. METHODS During a consecutive 42-month period, patient data were prospectively entered for 1859 consecutive patients undergoing foot and ankle surgery. Among the subjects, 394 had been previously diagnosed with diabetes mellitus (DM), and the remaining 1465 did not have DM. RESULTS The prevalence of neuropathy in patients with and without DM was 77.2% (304 of 394 patients) and 11.7% (172 of 1465 patients), respectively. Patients with diabetic neuropathy were older, had poorer glycemic control, had higher serum creatinine levels, and reported more significant tobacco use than diabetic patients without neuropathy. CONCLUSION Nearly 80% of diabetic patients undergoing foot and ankle surgery at a large academic medical center had diabetic neuropathy. Preoperative recognition of this morbid complication of DM is important to appropriately stratify those diabetic patients into a high-risk category.
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Affiliation(s)
- Natalie C Suder
- UPMC Comprehensive Foot and Ankle Center, Pittsburgh, PA 15203, USA
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Larson SAM, Burns PR. The pathogenesis of Charcot neuroarthropathy: current concepts. Diabet Foot Ankle 2012; 3:DFA-3-12236. [PMID: 22396834 PMCID: PMC3284308 DOI: 10.3402/dfa.v3i0.12236] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2011] [Revised: 12/16/2011] [Accepted: 12/19/2011] [Indexed: 12/13/2022]
Abstract
The pathogenesis of Charcot neuroarthropathy (CN) has been poorly understood by clinicians and scientists alike. Current researchers have made progress toward understanding the cause of CN and possible treatment options. The authors review the current literature on the pathogenesis of this debilitating disorder and attempt to explain the roles of inflammation, bone metabolism, and advanced glycation end products.
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Affiliation(s)
- Shelly A M Larson
- Podiatric Medicine and Surgery Residency Program, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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Abstract
Bad bedfellows - autonomic dysfunction, inflammation, and diabetes! Are they related? How? Evidence suggests the activation of inflammatory cytokines like IL-6 and TNFα in newly diagnosed type 2 diabetes and that the inflammatory change correlates with abnormalities in sympathovagal balance. Dysfunction of the autonomic system predicts cardiovascular risk and sudden death in patients with type 2 diabetes. It occurs in prediabetes, providing opportunities for early intervention. The importance of recognizing autonomic dysfunction as a predictor of morbidity and mortality with intensification of treatment suggests that all patients with type 2 diabetes at onset, and those with type 1 diabetes after 5 years should be screened for autonomic imbalance. These tests can be performed at the bedside with real time output of information - within the scope of the practicing physician - facilitates diagnosis and allows the application of sound strategies for management. The window of opportunity for aggressive control of all the traditional risk factors for cardiovascular events or sudden death with intensification of therapy is with short duration diabetes, the absence of cardiovascular disease, and a history of severe hypoglycemic events. To this list we can now add autonomic dysfunction and neuropathy, which have become the most powerful predictors of risk for mortality. It seems prudent that practitioners should be encouraged to become familiar with this information and apply risk stratification in clinical practice. After all, how difficult is it to ask patients "do you have numb feet?" and to determine their heart rate variability - it could be lifesaving. Ultimately methods to reset the hypothalamus and the inflammatory cascade are needed if we are to impact the care of patients with this compendium of conditions.
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Affiliation(s)
- Aaron I Vinik
- Department of Medicine, Eastern Virginia Medical School, Strelitz Diabetes and Neuroendocrine Center, Division of Endocrinology and Metabolism Norfolk, VA, USA.
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47
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Affiliation(s)
- Aaron Vinik
- From the Strelitz Diabetes Center, Eastern Virginia Medical School, Norfolk, Virginia
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