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Sloan G, Donatien P, Privitera R, Shillo P, Caunt S, Selvarajah D, Anand P, Tesfaye S. Vascular and nerve biomarkers in thigh skin biopsies differentiate painful from painless diabetic peripheral neuropathy. FRONTIERS IN PAIN RESEARCH 2024; 5:1485420. [PMID: 39512388 PMCID: PMC11543357 DOI: 10.3389/fpain.2024.1485420] [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: 08/23/2024] [Accepted: 10/08/2024] [Indexed: 11/15/2024] Open
Abstract
Background Identifying distinct mechanisms and biomarkers for painful diabetic peripheral neuropathy (DPN) is required for advancing the treatment of this major global unmet clinical need. We previously provided evidence in calf skin biopsies that disproportion between reduced sensory small nerve fibers and increased blood vessels may distinguish painful from non-painful DPN. We proposed that overexposure of the reduced nerve fibers in DPN to increased hypoxemia-induced vasculature and related algogenic factors, e.g., nerve growth factor (NGF), leads to neuropathic pain. To further investigate this proposed mechanism, we have now studied more proximal thigh skin biopsies, to see if the same disproportion between increased vasculature and decreased nerve fibers generally differentiates painful DPN from painless DPN. Methods A total of 28 subjects with type 2 diabetes (T2DM) and 13 healthy volunteers (HV) underwent detailed clinical and neurophysiological assessments, based on the neuropathy composite score of the lower limbs [NIS(LL)] plus 7 tests. T2DM subjects were subsequently divided into three groups: painful DPN (n = 15), painless DPN (n = 7), and no DPN (n = 6). All subjects underwent skin punch biopsy from the upper lateral thigh 20 cm below the anterior iliac spine. Results Skin biopsies showed decreased PGP 9.5-positive intraepidermal nerve fiber (IENF) density in both painful DPN (p < 0.0001) and painless DPN (p = 0.001). Vascular marker von Willebrand Factor (vWF) density was markedly increased in painful DPN vs. other groups, including painless DPN (p = 0.01). There was a resulting significant decrease in the ratio of intraepidermal nerve fiber density to vasculature and PGP9.5 to vWF, in painful DPN vs. painless DPN (p = 0.05). These results were similar in pattern to those observed in these HV and T2DM groups previously in distal calf biopsies; however, the increase in vWF was much higher and nerve fiber density much lower in the calf than thigh for painful DPN. Thigh skin vWF density was significantly correlated with several metabolic (waist/hip ratio, HbA1c), clinical (e.g., pain score), and neurophysiological measures. Conclusion This study supports our proposal that increased dermal vasculature, and its disproportionate ratio to reduced nociceptors, may help differentiate painful DPN from painless DPN. This disproportion is greater in the distal calf than the proximal thigh skin; hence, neuropathic pain in DPN is length-dependent and first localized to the distal lower limbs, mainly feet.
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Affiliation(s)
- Gordon Sloan
- Division of Clinical Medicine, University of Sheffield, Sheffield, United Kingdom
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Philippe Donatien
- Peripheral Neuropathy Unit, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Rosario Privitera
- Peripheral Neuropathy Unit, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Pallai Shillo
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Sharon Caunt
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Dinesh Selvarajah
- Division of Clinical Medicine, University of Sheffield, Sheffield, United Kingdom
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Praveen Anand
- Peripheral Neuropathy Unit, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Solomon Tesfaye
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
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Yum Y, Park S, Nam YH, Yoon J, Song H, Kim HJ, Lim J, Jung SC. Therapeutic Effect of Schwann Cell-Like Cells Differentiated from Human Tonsil-Derived Mesenchymal Stem Cells on Diabetic Neuropathy in db/db Mice. Tissue Eng Regen Med 2024; 21:761-776. [PMID: 38619758 PMCID: PMC11187028 DOI: 10.1007/s13770-024-00638-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/23/2024] [Accepted: 03/12/2024] [Indexed: 04/16/2024] Open
Abstract
BACKGROUND Diabetic neuropathy (DN) is the most common complication of diabetes, and approximately 50% of patients with this disease suffer from peripheral neuropathy. Nerve fiber loss in DN occurs due to myelin defects and is characterized by symptoms of impaired nerve function. Schwann cells (SCs) are the main support cells of the peripheral nervous system and play important roles in several pathways contributing to the pathogenesis and development of DN. We previously reported that human tonsil-derived mesenchymal stem cells differentiated into SCs (TMSC-SCs), named neuronal regeneration-promoting cells (NRPCs), which cells promoted nerve regeneration in animal models with peripheral nerve injury or hereditary peripheral neuropathy. METHODS In this study, NRPCs were injected into the thigh muscles of BKS-db/db mice, a commonly used type 2 diabetes model, and monitored for 26 weeks. Von Frey test, sensory nerve conduction study, and staining of sural nerve, hind foot pad, dorsal root ganglia (DRG) were performed after NRPCs treatment. RESULTS Von Frey test results showed that the NRPC treatment group (NRPC group) showed faster responses to less force than the vehicle group. Additionally, remyelination of sural nerve fibers also increased in the NRPC group. After NRPCs treatment, an improvement in response to external stimuli and pain sensation was expected through increased expression of PGP9.5 in the sole and TRPV1 in the DRG. CONCLUSION The NRPCs treatment may alleviate DN through the remyelination and the recovery of sensory neurons, could provide a better life for patients suffering from complications of this disease.
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Affiliation(s)
- Yoonji Yum
- Department of Biochemistry, College of Medicine, Ewha Womans University, 25 Magokdong-ro-2-gil, Gangseo-gu, Seoul, 07804, Republic of Korea
| | - Saeyoung Park
- Department of Biochemistry, College of Medicine, Ewha Womans University, 25 Magokdong-ro-2-gil, Gangseo-gu, Seoul, 07804, Republic of Korea
| | - Yu Hwa Nam
- Department of Biochemistry, College of Medicine, Ewha Womans University, 25 Magokdong-ro-2-gil, Gangseo-gu, Seoul, 07804, Republic of Korea
| | - Juhee Yoon
- Department of Biochemistry, College of Medicine, Ewha Womans University, 25 Magokdong-ro-2-gil, Gangseo-gu, Seoul, 07804, Republic of Korea
| | - Hyeryung Song
- Department of Biochemistry, College of Medicine, Ewha Womans University, 25 Magokdong-ro-2-gil, Gangseo-gu, Seoul, 07804, Republic of Korea
| | - Ho Jin Kim
- Cellatoz Therapeutics Lnc., 17, Pangyo-ro 228beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13487, Republic of Korea
| | - Jaeseung Lim
- Cellatoz Therapeutics Lnc., 17, Pangyo-ro 228beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do, 13487, Republic of Korea
| | - Sung-Chul Jung
- Department of Biochemistry, College of Medicine, Ewha Womans University, 25 Magokdong-ro-2-gil, Gangseo-gu, Seoul, 07804, Republic of Korea.
- Graduate Program in System Health Science and Engineering, Ewha Womans University, 25 Magokdong-ro-2-gil, Gangseo-gu, Seoul, 07804, Republic of Korea.
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Liu J, Lin Y, Huang Y, Yang Q, Li X, Ye Y, Zheng B, Song W. Efficacy and safety of acupuncture for painful diabetic neuropathy: a systematic review and meta-analysis. Front Neurol 2024; 15:1402458. [PMID: 38903165 PMCID: PMC11188462 DOI: 10.3389/fneur.2024.1402458] [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: 04/03/2024] [Accepted: 05/16/2024] [Indexed: 06/22/2024] Open
Abstract
Background Painful diabetic neuropathy (PDN) is a common chronic neurological complication of diabetes mellitus. Medications are often used to relieve pain, but with significant side effects. Acupuncture is now a component of pragmatic and integrative treatment for PDN. An increasing number of relevant randomized controlled trials have been published in recent years, but a comprehensive meta-analysis has not yet been performed. The aim of this paper is to verify the effectiveness and safety of acupuncture for PDN by meta-analysis and trial sequential analysis (TSA). Methods All participants in this study should have had a PDN diagnosis and the trial group was treated with acupuncture. Eight databases, including EMbase, PubMed, Web of science, Cochrane Library, China Biology Medicine disc (CBM), China National Knowledge Infrastructure (CNKI), Wanfang and Chongqing VIP (CQVIP) were retrieved from inception to 5 April 2023. Meta-analysis was conducted utilizing RevMan 5.3 and Stata 15.0. TSA was performed to assess the adequacy of sample size for the outcomes. Results A total of 36 studies, comprising 2,739 PDN patients, were included. Among them, 1,393 patients were assigned to the trial group and 1,346 patients were treated in the control group. Outcomes covers the primary indicator Total effective rate (RR = 1.42, 95%CI [1.34, 1.52], p < 0.00001), with 21 studies reported, Pain intensity (SMD = -1.27, 95%CI [-1.58, -0.95], p < 0.00001), with 23 studies reported, and other outcomes, including motor nerve conduction velocity (MCV; MD = 3.58, 95%CI [2.77, 4.38], p < 0.00001), sensory nerve conduction velocity (SCV; MD = 3.62, 95%CI [2.75, 4.49], p < 0.00001), Depression score (SMD = -1.02, 95%CI [1.58, 0.46]), Toronto clinical scoring system (TCSS; MD = -2.41, 95%CI [-3.37, -1.45], p < 0.00001), Quality of life (SMD = 1.06, 95%CI [0.66, 1.46]), traditional Chinese medicine (TCM) syndrome score (MD = -4.99, 95%CI [-6.79, -3.18], p < 0.00001), suggesting that acupuncture have an ameliorating effect on PDN in various respect. Egger's test revealed publication bias for four outcomes. TSA showed that as for Total effective rate, Pain Intensity, MCV and SCV, the number of included studies was sufficient to support the conclusions. Conclusion Acupuncture demonstrates significant effectiveness in improving PDN outcomes, including Total effective rate, Pain intensity, MCV, SCV, Depression score, TCSS, Quality of life, TCM syndrome score. But the Adverse events rate is no different in trail group and control group. The publication bias presented in Total effective rate, Pain intensity, MCV and SCV can be remedied by Trim and filling method. Systematic review registration Prospero, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=477295.
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Affiliation(s)
- Jiaming Liu
- The Second Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yueqi Lin
- The Second Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yuheng Huang
- The Second Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Qingyi Yang
- The Second Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Xiaojie Li
- The Second Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Yinglan Ye
- The Second Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Bohui Zheng
- The Second Clinical Medical School of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China
| | - Wei Song
- The Second Clinical College of Guangzhou University of Chinese Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, Guangdong, China
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Kissoon NR, LeMahieu AM, Stoltenberg AD, Bendel MA, Lamer TJ, Watson JC, Sletten DM, Singer W. Quantitative assessment of painful diabetic peripheral neuropathy after high-frequency spinal cord stimulation: a pilot study. PAIN MEDICINE (MALDEN, MASS.) 2023; 24:S41-S47. [PMID: 37833046 DOI: 10.1093/pm/pnad087] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 05/08/2023] [Accepted: 06/22/2023] [Indexed: 10/15/2023]
Abstract
OBJECTIVE Randomized trials have demonstrated efficacy of spinal cord stimulation (SCS) for treatment of painful diabetic neuropathy (PDN). Preliminary data suggested that treatment of PDN with high-frequency SCS resulted in improvements on neurological examination. The purpose of the present study was to explore whether patients with PDN treated with high-frequency SCS would have improvements in lower-extremity peripheral nerve function. DESIGN Prospective cohort study in an outpatient clinical practice at a tertiary care center. METHODS Patients with PDN were treated with high-frequency SCS and followed up for 12 months after SCS implantation with clinical outcomes assessments of pain intensity, neuropathic symptoms, and neurological function. Small-fiber sudomotor function was assessed with the quantitative sudomotor axon reflex test (QSART), and large-fiber function was assessed with nerve conduction studies (NCS). Lower-extremity perfusion was assessed with laser Doppler flowmetry. RESULTS Nine patients completed 12-month follow-up visits and were observed to have improvements in lower-extremity pain, weakness, and positive sensory symptoms. Neuropathy impairment scores were improved, and 2 patients had recovery of sensory responses on NCS. A reduction in sweat volume on QSART was observed in the proximal leg but not at other sites. No significant differences were noted in lower-extremity perfusion or NCS as compared with baseline. CONCLUSIONS The improvement in pain relief was concordant with improvement in neuropathy symptoms. The findings from this study provide encouraging preliminary data in support of the hypothesis of a positive effect of SCS on peripheral neuropathy, but the findings are based on small numbers and require further evaluation. TRIAL REGISTRATION ClinicalTrials.gov ID NCT03769675.
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Affiliation(s)
- Narayan R Kissoon
- Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, United States
- Department of Neurology, Mayo Clinic, Rochester, MN 55905, United States
| | - Allison M LeMahieu
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN 55905, United States
| | - Anita D Stoltenberg
- Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, United States
| | - Markus A Bendel
- Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, United States
| | - Tim J Lamer
- Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, United States
| | - James C Watson
- Department of Anesthesiology, Mayo Clinic, Rochester, MN 55905, United States
| | - David M Sletten
- Department of Neurology, Mayo Clinic, Rochester, MN 55905, United States
| | - Wolfgang Singer
- Department of Neurology, Mayo Clinic, Rochester, MN 55905, United States
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Busa P, Kuthati Y, Huang N, Wong CS. New Advances on Pathophysiology of Diabetes Neuropathy and Pain Management: Potential Role of Melatonin and DPP-4 Inhibitors. Front Pharmacol 2022; 13:864088. [PMID: 35496279 PMCID: PMC9039240 DOI: 10.3389/fphar.2022.864088] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/14/2022] [Indexed: 12/14/2022] Open
Abstract
Pre-diabetes and diabetes are growing threats to the modern world. Diabetes mellitus (DM) is associated with comorbidities such as hypertension (83.40%), obesity (90.49%), and dyslipidemia (93.43%), creating a substantial burden on patients and society. Reductive and oxidative (Redox) stress level imbalance and inflammation play an important role in DM progression. Various therapeutics have been investigated to treat these neuronal complications. Melatonin and dipeptidyl peptidase IV inhibitors (DPP-4i) are known to possess powerful antioxidant and anti-inflammatory properties and have garnered significant attention in the recent years. In this present review article, we have reviewed the recently published reports on the therapeutic efficiency of melatonin and DPP-4i in the treatment of DM. We summarized the efficacy of melatonin and DPP-4i in DM and associated complications of diabetic neuropathy (DNP) and neuropathic pain. Furthermore, we discussed the mechanisms of action and their efficacy in the alleviation of oxidative stress in DM.
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Affiliation(s)
- Prabhakar Busa
- Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan
| | - Yaswanth Kuthati
- Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan
| | - Niancih Huang
- Department of Anesthesiology, Tri-Service General Hospital, Taipei, Taiwan
- Grauate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
| | - Chih-Shung Wong
- Department of Anesthesiology, Cathay General Hospital, Taipei, Taiwan
- Department of Anesthesiology, Tri-Service General Hospital, Taipei, Taiwan
- Grauate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan
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Shillo P, Yiangou Y, Donatien P, Greig M, Selvarajah D, Wilkinson ID, Anand P, Tesfaye S. Nerve and Vascular Biomarkers in Skin Biopsies Differentiate Painful From Painless Peripheral Neuropathy in Type 2 Diabetes. FRONTIERS IN PAIN RESEARCH 2022; 2:731658. [PMID: 35295465 PMCID: PMC8915761 DOI: 10.3389/fpain.2021.731658] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 09/13/2021] [Indexed: 01/19/2023] Open
Abstract
Painful diabetic peripheral neuropathy can be intractable with a major impact, yet the underlying pain mechanisms remain uncertain. A range of neuronal and vascular biomarkers was investigated in painful diabetic peripheral neuropathy (painful-DPN) and painless-DPN and used to differentiate painful-DPN from painless-DPN. Skin biopsies were collected from 61 patients with type 2 diabetes (T2D), and 19 healthy volunteers (HV). All subjects underwent detailed clinical and neurophysiological assessments. Based on the neuropathy composite score of the lower limbs [NIS(LL)] plus seven tests, the T2D subjects were subsequently divided into three groups: painful-DPN (n = 23), painless-DPN (n = 19), and No-DPN (n = 19). All subjects underwent punch skin biopsy, and immunohistochemistry used to quantify total intraepidermal nerve fibers (IENF) with protein gene product 9.5 (PGP9.5), regenerating nerve fibers with growth-associated protein 43 (GAP43), peptidergic nerve fibers with calcitonin gene-related peptide (CGRP), and blood vessels with von Willebrand Factor (vWF). The results showed that IENF density was severely decreased (p < 0.001) in both DPN groups, with no differences for PGP9.5, GAP43, CGRP, or GAP43/PGP9.5 ratios. There was a significant increase in blood vessel (vWF) density in painless-DPN and No-DPN groups compared to the HV group, but this was markedly greater in the painful-DPN group, and significantly higher than in the painless-DPN group (p < 0.0001). The ratio of sub-epidermal nerve fiber (SENF) density of CGRP:vWF showed a significant decrease in painful-DPN vs. painless-DPN (p = 0.014). In patients with T2D with advanced DPN, increased dermal vasculature and its ratio to nociceptors may differentiate painful-DPN from painless-DPN. We hypothesized that hypoxia-induced increase of blood vessels, which secrete algogenic substances including nerve growth factor (NGF), may expose their associated nociceptor fibers to a relative excess of algogens, thus leading to painful-DPN.
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Affiliation(s)
- Pallai Shillo
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Yiangos Yiangou
- Peripheral Neuropathy Unit, Hammersmith Hospital, Imperial College London, London, United Kingdom
| | - Philippe Donatien
- Peripheral Neuropathy Unit, Hammersmith Hospital, Imperial College London, London, United Kingdom
| | - Marni Greig
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Dinesh Selvarajah
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
| | - Iain D Wilkinson
- Academic Unit of Radiology, University of Sheffield, Sheffield, United Kingdom
| | - Praveen Anand
- Peripheral Neuropathy Unit, Hammersmith Hospital, Imperial College London, London, United Kingdom
| | - Solomon Tesfaye
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom
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Sloan G, Alam U, Selvarajah D, Tesfaye S. The Treatment of Painful Diabetic Neuropathy. Curr Diabetes Rev 2022; 18:e070721194556. [PMID: 34238163 DOI: 10.2174/1573399817666210707112413] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 02/18/2021] [Accepted: 03/08/2021] [Indexed: 11/22/2022]
Abstract
Painful diabetic peripheral neuropathy (painful-DPN) is a highly prevalent and disabling condition, affecting up to one-third of patients with diabetes. This condition can have a profound impact resulting in a poor quality of life, disruption of employment, impaired sleep, and poor mental health with an excess of depression and anxiety. The management of painful-DPN poses a great challenge. Unfortunately, currently there are no Food and Drug Administration (USA) approved disease-modifying treatments for diabetic peripheral neuropathy (DPN) as trials of putative pathogenetic treatments have failed at phase 3 clinical trial stage. Therefore, the focus of managing painful- DPN other than improving glycaemic control and cardiovascular risk factor modification is treating symptoms. The recommended treatments based on expert international consensus for painful- DPN have remained essentially unchanged for the last decade. Both the serotonin re-uptake inhibitor (SNRI) duloxetine and α2δ ligand pregabalin have the most robust evidence for treating painful-DPN. The weak opioids (e.g. tapentadol and tramadol, both of which have an SNRI effect), tricyclic antidepressants such as amitriptyline and α2δ ligand gabapentin are also widely recommended and prescribed agents. Opioids (except tramadol and tapentadol), should be prescribed with caution in view of the lack of definitive data surrounding efficacy, concerns surrounding addiction and adverse events. Recently, emerging therapies have gained local licenses, including the α2δ ligand mirogabalin (Japan) and the high dose 8% capsaicin patch (FDA and Europe). The management of refractory painful-DPN is difficult; specialist pain services may offer off-label therapies (e.g. botulinum toxin, intravenous lidocaine and spinal cord stimulation), although there is limited clinical trial evidence supporting their use. Additionally, despite combination therapy being commonly used clinically, there is little evidence supporting this practise. There is a need for further clinical trials to assess novel therapeutic agents, optimal combination therapy and existing agents to determine which are the most effective for the treatment of painful-DPN. This article reviews the evidence for the treatment of painful-DPN, including emerging treatment strategies such as novel compounds and stratification of patients according to individual characteristics (e.g. pain phenotype, neuroimaging and genotype) to improve treatment responses.
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Affiliation(s)
- Gordon Sloan
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
| | - Uazman Alam
- Department of Cardiovascular and Metabolic Medicine and the Pain Research Institute, Institute of Life Course and Medical Sciences, University of Liverpool, and Liverpool University Hospital, NHS Foundation Trust, Liverpool, UK
- Division of Diabetes, Endocrinology and Gastroenterology, Institute of Human Development, University of Manchester, Manchester, UK
| | - Dinesh Selvarajah
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
- Department of Oncology and Human Metabolism, University of Sheffield, Sheffield, UK
| | - Solomon Tesfaye
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, NHS Foundation Trust, Sheffield, UK
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Sloan G, Selvarajah D, Tesfaye S. Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy. Nat Rev Endocrinol 2021; 17:400-420. [PMID: 34050323 DOI: 10.1038/s41574-021-00496-z] [Citation(s) in RCA: 210] [Impact Index Per Article: 52.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/15/2021] [Indexed: 02/08/2023]
Abstract
Diabetic sensorimotor peripheral neuropathy (DSPN) is a serious complication of diabetes mellitus and is associated with increased mortality, lower-limb amputations and distressing painful neuropathic symptoms (painful DSPN). Our understanding of the pathophysiology of the disease has largely been derived from animal models, which have identified key potential mechanisms. However, effective therapies in preclinical models have not translated into clinical trials and we have no universally accepted disease-modifying treatments. Moreover, the condition is generally diagnosed late when irreversible nerve damage has already taken place. Innovative point-of-care devices have great potential to enable the early diagnosis of DSPN when the condition might be more amenable to treatment. The management of painful DSPN remains less than optimal; however, studies suggest that a mechanism-based approach might offer an enhanced benefit in certain pain phenotypes. The management of patients with DSPN involves the control of individualized cardiometabolic targets, a multidisciplinary approach aimed at the prevention and management of foot complications, and the timely diagnosis and management of neuropathic pain. Here, we discuss the latest advances in the mechanisms of DSPN and painful DSPN, originating both from the periphery and the central nervous system, as well as the emerging diagnostics and treatments.
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Affiliation(s)
- Gordon Sloan
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Dinesh Selvarajah
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
- Department of Oncology and Human Metabolism, University of Sheffield, Sheffield, UK
| | - Solomon Tesfaye
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
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Abstract
Neuropathy is a common complication of long-term diabetes that impairs quality of life by producing pain, sensory loss and limb amputation. The presence of neuropathy in both insulin-deficient (type 1) and insulin resistant (type 2) diabetes along with the slowing of progression of neuropathy by improved glycemic control in type 1 diabetes has caused the majority of preclinical and clinical investigations to focus on hyperglycemia as the initiating pathogenic lesion. Studies in animal models of diabetes have identified multiple plausible mechanisms of glucotoxicity to the nervous system including post-translational modification of proteins by glucose and increased glucose metabolism by aldose reductase, glycolysis and other catabolic pathways. However, it is becoming increasingly apparent that factors not necessarily downstream of hyperglycemia can also contribute to the incidence, progression and severity of neuropathy and neuropathic pain. For example, peripheral nerve contains insulin receptors that transduce the neurotrophic and neurosupportive properties of insulin, independent of systemic glucose regulation, while the detection of neuropathy and neuropathic pain in patients with metabolic syndrome and failure of improved glycemic control to protect against neuropathy in cohorts of type 2 diabetic patients has placed a focus on the pathogenic role of dyslipidemia. This review provides an overview of current understanding of potential initiating lesions for diabetic neuropathy and the multiple downstream mechanisms identified in cell and animal models of diabetes that may contribute to the pathogenesis of diabetic neuropathy and neuropathic pain.
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Lysophosphatidic Acid Receptor 1- and 3-Mediated Hyperalgesia and Hypoalgesia in Diabetic Neuropathic Pain Models in Mice. Cells 2020; 9:cells9081906. [PMID: 32824296 PMCID: PMC7465054 DOI: 10.3390/cells9081906] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 08/08/2020] [Accepted: 08/13/2020] [Indexed: 12/28/2022] Open
Abstract
Lysophosphatidic acid (LPA) signaling is known to play key roles in the initiation and maintenance of various chronic pain models. Here we examined whether LPA signaling is also involved in diabetes-induced abnormal pain behaviors. The high-fat diet (HFD) showing elevation of blood glucose levels and body weight caused thermal, mechanical hyperalgesia, hypersensitivity to 2000 or 250 Hz electrical-stimulation and hyposensitivity to 5 Hz stimulation to the paw in wild-type (WT) mice. These HFD-induced abnormal pain behaviors and body weight increase, but not elevated glucose levels were abolished in LPA1−/− and LPA3−/− mice. Repeated daily intrathecal (i.t.) treatments with LPA1/3 antagonist AM966 reversed these abnormal pain behaviors. Similar abnormal pain behaviors and their blockade by daily AM966 (i.t.) or twice daily Ki16425, another LPA1/3 antagonist was also observed in db/db mice which show high glucose levels and body weight. Furthermore, streptozotocin-induced similar abnormal pain behaviors, but not elevated glucose levels or body weight loss were abolished in LPA1−/− and LPA3−/− mice. These results suggest that LPA1 and LPA3 play key roles in the development of both type I and type II diabetic neuropathic pain.
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Corneal confocal microscopy detects small nerve fibre damage in patients with painful diabetic neuropathy. Sci Rep 2020; 10:3371. [PMID: 32099076 PMCID: PMC7042367 DOI: 10.1038/s41598-020-60422-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 02/11/2020] [Indexed: 12/28/2022] Open
Abstract
Neuropathic pain is believed to arise from damage to nociceptive C fibres in diabetic neuropathy (DN). We have utilised corneal confocal microscopy (CCM) to quantify the severity of small nerve fibre damage in relation to the severity of neuropathic pain and quality of life (QoL) in patients with and without painful DN. 30 controls and patients with painful (n = 78) and painless (n = 62) DN underwent assessment of large and small nerve fibre function, CCM, neuropathic symptoms (small fibre neuropathy symptom inventory questionnaire, neuropathic pain scale) and QoL (SF-36, pre-R-ODS and hospital anxiety and depression scale). Patients with painful compared to painless DN, had comparable neurophysiology and vibration perception, but lower corneal nerve fibre density (20.1 ± 0.87 vs. 24.13 ± 0.91, P = 0.005), branch density (44.4 ± 3.31 vs. 57.74 ± 3.98, P = 0.03), length (19.61 ± 0.81 vs. 22.77 ± 0.83, P = 0.01), inferior whorl length (18.03 ± 1.46 vs. 25.1 ± 1.95, P = 0.005) and cold sensation threshold (21.35 ± 0.99 vs. 26.08 ± 0.5, P < 0.0001) and higher warm sensation threshold (43.7 ± 0.49 vs. 41.37 ± 0.51, P = 0.004) indicative of small fibre damage. There was a significant association between all CCM parameters and the severity of painful neuropathic symptoms, depression score and QoL. CCM identifies small nerve fibre loss, which correlates with the severity of neuropathic symptoms and reduced QoL in patients with painful diabetic neuropathy.
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Borire AA, Issar T, Kwai NC, Visser LH, Simon NG, Poynten AM, Kiernan MC, Krishnan AV. Sonographic assessment of nerve blood flow in diabetic neuropathy. Diabet Med 2020; 37:343-349. [PMID: 31338857 DOI: 10.1111/dme.14085] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/22/2019] [Indexed: 12/16/2022]
Abstract
AIMS To undertake sonographic assessment of nerve blood flow in people with Type 2 diabetes and correlate the findings with neuropathy severity scores and electrophysiological measurements. METHODS Median and tibial nerve ultrasound scans were undertaken in 75 people with diabetes and 30 aged-matched controls without diabetes, using a high-resolution linear probe at non-entrapment sites. Nerve blood flow was quantified using power Doppler techniques to obtain the vessel score and the maximum perfusion intensity. Neuropathy severity was assessed using a total neuropathy score. RESULTS Diabetic nerves had higher rates of nerve blood flow detection (28%) compared to the control group (P < 0.0001). Significant correlations were found between nerve blood flow measurements and nerve size (P <0.001), reported sensory symptoms (P < 0.05) and neuropathy severity scores (P < 0.001). The cohort with diabetes had significantly larger median (8.5 ± 0.3 mm2 vs 7.2 ± 0.1 mm2 ; P < 0.05) and tibial nerves (18.0 ± 0.9 mm2 vs 12.8 ± 0.5 mm2 ; P < 0.05) compared with controls. CONCLUSION Peripheral nerve hypervascularity is detectable by ultrasonography in moderate to severe diabetic neuropathy with prominent sensory dysfunction.
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Affiliation(s)
- A A Borire
- Prince of Wales Clinical School, University of New South Wales, Sydney, Australia
| | - T Issar
- Prince of Wales Clinical School, University of New South Wales, Sydney, Australia
| | - N C Kwai
- School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
| | - L H Visser
- St Elisabeth Ziekenhuis, Tilburg, Netherlands
| | - N G Simon
- St Vincent's Clinical School, University of New South Wales, Sydney, Australia
| | - A M Poynten
- Department of Endocrinology, Prince of Wales Hospital, Randwick, Australia
| | - M C Kiernan
- Brain and Mind Centre, University of Sydney and Institute of Clinical Neurosciences, Royal Prince Alfred Hospital, Sydney, NSW, Australia
| | - A V Krishnan
- Prince of Wales Clinical School, University of New South Wales, Sydney, Australia
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Shillo P, Sloan G, Greig M, Hunt L, Selvarajah D, Elliott J, Gandhi R, Wilkinson ID, Tesfaye S. Painful and Painless Diabetic Neuropathies: What Is the Difference? Curr Diab Rep 2019; 19:32. [PMID: 31065863 PMCID: PMC6505492 DOI: 10.1007/s11892-019-1150-5] [Citation(s) in RCA: 89] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW The prevalence of diabetes mellitus and its chronic complications are increasing to epidemic proportions. This will unfortunately result in massive increases in diabetic distal symmetrical polyneuropathy (DPN) and its troublesome sequelae, including disabling neuropathic pain (painful-DPN), which affects around 25% of patients with diabetes. Why these patients develop neuropathic pain, while others with a similar degree of neuropathy do not, is not clearly understood. This review will look at recent advances that may shed some light on the differences between painful and painless-DPN. RECENT FINDINGS Gender, clinical pain phenotyping, serum biomarkers, brain imaging, genetics, and skin biopsy findings have been reported to differentiate painful- from painless-DPN. Painful-DPN seems to be associated with female gender and small fiber dysfunction. Moreover, recent brain imaging studies have found neuropathic pain signatures within the central nervous system; however, whether this is the cause or effect of the pain is yet to be determined. Further research is urgently required to develop our understanding of the pathogenesis of pain in DPN in order to develop new and effective mechanistic treatments for painful-DPN.
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Affiliation(s)
- Pallai Shillo
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Glossop Road, Sheffield, S10 2JF UK
| | - Gordon Sloan
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Glossop Road, Sheffield, S10 2JF UK
| | - Marni Greig
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Glossop Road, Sheffield, S10 2JF UK
| | - Leanne Hunt
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Glossop Road, Sheffield, S10 2JF UK
| | - Dinesh Selvarajah
- Department of Oncology and Human Metabolism, University of Sheffield, Sheffield, UK
| | - Jackie Elliott
- Department of Oncology and Human Metabolism, University of Sheffield, Sheffield, UK
| | - Rajiv Gandhi
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Glossop Road, Sheffield, S10 2JF UK
| | | | - Solomon Tesfaye
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Glossop Road, Sheffield, S10 2JF UK
- Department of Oncology and Human Metabolism, University of Sheffield, Sheffield, UK
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14
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Sloan G, Shillo P, Selvarajah D, Wu J, Wilkinson ID, Tracey I, Anand P, Tesfaye S. A new look at painful diabetic neuropathy. Diabetes Res Clin Pract 2018; 144:177-191. [PMID: 30201394 DOI: 10.1016/j.diabres.2018.08.020] [Citation(s) in RCA: 114] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023]
Abstract
The prevalence of diabetes mellitus and its chronic complications continue to increase alarmingly. Consequently, the massive expenditure on diabetic distal symmetrical polyneuropathy (DSPN) and its sequelae, will also likely rise. Up to 50% of patients with diabetes develop DSPN, and about 20% develop neuropathic pain (painful-DSPN). Painful-DSPN can cast a huge burden on sufferers' lives with increased rates of unemployment, mental health disorders and physical co-morbidities. Unfortunately, due to limited understanding of the mechanisms leading to painful-DSPN, current treatments remain inadequate. Recent studies examining the pathophysiology of painful-DSPN have identified maladaptive alterations at the level of both the peripheral and central nervous systems. Additionally, genetic studies have suggested that patients with variants of voltage gated sodium channels may be more at risk of developing neuropathic pain in the presence of a disease trigger such as diabetes. We review the recent advances in genetics, skin biopsy immunohistochemistry and neuro-imaging, which have the potential to further our understanding of the condition, and identify targets for new mechanism based therapies.
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Affiliation(s)
- Gordon Sloan
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust & Academic Unit of Radiology, University of Sheffield, Sheffield, United Kingdom
| | - Pallai Shillo
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust & Academic Unit of Radiology, University of Sheffield, Sheffield, United Kingdom
| | - Dinesh Selvarajah
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust & Academic Unit of Radiology, University of Sheffield, Sheffield, United Kingdom
| | - Jing Wu
- Department of Endocrinology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Iain D Wilkinson
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust & Academic Unit of Radiology, University of Sheffield, Sheffield, United Kingdom
| | - Irene Tracey
- FMRIB, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom
| | - Praveen Anand
- Peripheral Neuropathy Unit, Centre for Clinical Translation, Imperial College London, Hammersmith Hospital, London, United Kingdom
| | - Solomon Tesfaye
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust & Academic Unit of Radiology, University of Sheffield, Sheffield, United Kingdom.
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van Beek M, Geurts JW, Slangen R, Schaper NC, Faber CG, Joosten EA, Dirksen CD, van Dongen RT, van Kuijk SMJ, van Kleef M. Severity of Neuropathy Is Associated With Long-term Spinal Cord Stimulation Outcome in Painful Diabetic Peripheral Neuropathy: Five-Year Follow-up of a Prospective Two-Center Clinical Trial. Diabetes Care 2018; 41:32-38. [PMID: 29109298 DOI: 10.2337/dc17-0983] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 09/25/2017] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Evidence from prospective studies for long-term treatment efficacy of spinal cord stimulation (SCS) in painful diabetic peripheral neuropathy (PDPN) is not available. We report prospective data on the effect of SCS on pain ratings, treatment success and failure, and complications during a 5-year follow-up in patients with PDPN. RESEARCH DESIGN AND METHODS Patients with PDPN (n = 48) were included in this prospective multicenter study. The Michigan Diabetic Neuropathy Score (MDNS) was used to assess the severity of neuropathy. Numerical rating scale (NRS) score for pain, Patient's Global Impression of Change (PGIC), and treatment success (50% reduction of NRS score or significant PGIC) during 5 years of follow-up were evaluated. Complications of SCS were reported, and associations between baseline characteristics and SCS trial success or failure during a 5-year follow-up were investigated by using survival analyses. RESULTS Treatment success was observed in 55% of patients after 5 years. Median duration of SCS treatment was 60 months (minimum 1 month, maximum 60 months), and 80% of patients with a permanent implant still used their SCS device after 5 years. Higher MDNS was associated with treatment failure during the 5-year follow-up (hazard ratio 3.9 [95% CI 1.3-11.6]; P = 0.014). CONCLUSIONS SCS is successful in reducing chronic pain symptoms in the lower extremities of patients with PDPN up to 5 years after initiation of treatment. Furthermore, 80% of patients with PDPN still use their SCS device after 5 years. Moreover, the severity of neuropathy is associated with a higher chance of long-term treatment failure during a 5-year follow-up.
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Affiliation(s)
- Maarten van Beek
- Department of Anesthesiology and Pain Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - José W Geurts
- Department of Anesthesiology and Pain Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands.,Department of Anesthesiology, Rijnstate Hospital, Arnhem, the Netherlands
| | - Rachel Slangen
- Department of Anesthesiology and Pain Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Nicolaas C Schaper
- Department of Internal Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Catharina G Faber
- Department of Neurology, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Elbert A Joosten
- Department of Anesthesiology and Pain Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands
| | - Carmen D Dirksen
- Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre+, Maastricht, the Netherlands.,Care and Public Health Research Institute School for Public Health and Primary Care, Maastricht University, Maastricht, the Netherlands
| | - Robert T van Dongen
- Department of Anesthesiology, Pain, and Palliative Care, Radboud University Medical Centre, Nijmegen, the Netherlands
| | - Sander M J van Kuijk
- Department of Clinical Epidemiology and Medical Technology Assessment, Maastricht University Medical Centre+, Maastricht, the Netherlands
| | - Maarten van Kleef
- Department of Anesthesiology and Pain Medicine, Maastricht University Medical Centre, Maastricht, the Netherlands
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16
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van Beek M, van Kleef M, Linderoth B, van Kuijk SMJ, Honig WM, Joosten EA. Spinal cord stimulation in experimental chronic painful diabetic polyneuropathy: Delayed effect of High-frequency stimulation. Eur J Pain 2016; 21:795-803. [PMID: 27891705 PMCID: PMC5412908 DOI: 10.1002/ejp.981] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/22/2016] [Indexed: 12/12/2022]
Abstract
Background Spinal cord stimulation (SCS) has been shown to provide pain relief in painful diabetic polyneuropathy (PDPN). As the vasculature system plays a great role in the pathophysiology of PDPN, a potential beneficial side‐effect of SCS is peripheral vasodilation, with high frequency (HF) SCS in particular. We hypothesize that HF‐SCS (500 Hz), compared with conventional (CON) or low frequency (LF)‐SCS will result in increased alleviation of mechanical hypersensitivity in chronic experimental PDPN. Methods Diabetes was induced in 8‐week‐old female Sprague–Dawley rats with an intraperitoneal injection of 65 mg/kg of streptozotocin (n = 44). Rats with a significant decrease in mechanical withdrawal response to von Frey filaments over a period of 20 weeks were implanted with SCS electrodes (n = 18). Rats were assigned to a cross‐over design with a random order of LF‐, CON‐, HF‐ and sham SCS and mechanical withdrawal thresholds were assessed with von Frey testing. Results Compared with sham treatment, the average 50% WT score for 5 Hz was 4.88 g higher during stimulation (p = 0.156), and 1.77 g higher post‐stimulation (p = 0.008). CON‐SCS resulted in 50% WT scores 5.7 g, and 2.51 g higher during (p = 0.064) and after stimulation (p < 0.004), respectively. HF‐SCS started out with an average difference in 50% WT score compared with sham of 1.87 g during stimulation (p = 0.279), and subsequently the steepest rise to a difference of 5.47 g post‐stimulation (p < 0.001). Conclusions We demonstrated a delayed effect of HF‐SCS on mechanical hypersensitivity in chronic PDPN animals compared with LF‐, or CON‐SCS. Significance This study evaluates the effect of SCS frequency (5–500 Hz) on mechanical hypersensitivity in the chronic phase of experimental PDPN. High frequency (500 Hz) – SCS resulted in a delayed effect‐ on pain‐related behavioural outcome in chronic PDPN.
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Affiliation(s)
- M van Beek
- Department of Translational Neuroscience, School of Mental Health and Neuroscience, Maastricht University, The Netherlands.,Pain Management and Research Center, Department of Anesthesiology, MUMC+, Maastricht, The Netherlands
| | - M van Kleef
- Pain Management and Research Center, Department of Anesthesiology, MUMC+, Maastricht, The Netherlands
| | - B Linderoth
- Pain Management and Research Center, Department of Anesthesiology, MUMC+, Maastricht, The Netherlands.,Department of Clinical Neuroscience, (Functional Neurosurgery), Karolinska Institutet, Stockholm, Sweden
| | - S M J van Kuijk
- Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA), MUMC+, Maastricht, The Netherlands
| | - W M Honig
- Department of Translational Neuroscience, School of Mental Health and Neuroscience, Maastricht University, The Netherlands
| | - E A Joosten
- Department of Translational Neuroscience, School of Mental Health and Neuroscience, Maastricht University, The Netherlands.,Pain Management and Research Center, Department of Anesthesiology, MUMC+, Maastricht, The Netherlands
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Brock C, Brock B, Pedersen AG, Drewes AM, Jessen N, Farmer AD. Assessment of the cardiovascular and gastrointestinal autonomic complications of diabetes. World J Diabetes 2016; 7:321-332. [PMID: 27625746 PMCID: PMC4999648 DOI: 10.4239/wjd.v7.i16.321] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Revised: 04/08/2016] [Accepted: 06/03/2016] [Indexed: 02/05/2023] Open
Abstract
The global prevalence of diabetes mellitus is increasing; arguably as a consequence of changes in diet, lifestyle and the trend towards urbanization. Unsurprisingly, the incidence of both micro and macrovascular complications of diabetes mirrors this increasing prevalence. Amongst the complications with the highest symptom burden, yet frequently under-diagnosed and sub-optimally treated, is diabetic autonomic neuropathy, itself potentially resulting in cardiovascular autonomic neuropathy and gastrointestinal (GI) tract dysmotility. The aims of this review are fourfold. Firstly to provide an overview of the pathophysiological processes that cause diabetic autonomic neuropathy. Secondly, to discuss both the established and emerging cardiometric methods for evaluating autonomic nervous system function in vivo. Thirdly, to examine the tools for assessing pan-GI and segmental motility and finally, we will provide the reader with a summary of putative non-invasive biomarkers that provide a pathophysiological link between low-grade neuro inflammation and diabetes, which may allow earlier diagnosis and intervention, which in future may improve patient outcomes.
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18
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Schreiber AK, Nones CFM, Reis RC, Chichorro JG, Cunha JM. Diabetic neuropathic pain: Physiopathology and treatment. World J Diabetes 2015; 6:432-444. [PMID: 25897354 PMCID: PMC4398900 DOI: 10.4239/wjd.v6.i3.432] [Citation(s) in RCA: 265] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2014] [Revised: 11/26/2014] [Accepted: 02/09/2015] [Indexed: 02/05/2023] Open
Abstract
Diabetic neuropathy is a common complication of both type 1 and type 2 diabetes, which affects over 90% of the diabetic patients. Although pain is one of the main symptoms of diabetic neuropathy, its pathophysiological mechanisms are not yet fully known. It is widely accepted that the toxic effects of hyperglycemia play an important role in the development of this complication, but several other hypotheses have been postulated. The management of diabetic neuropathic pain consists basically in excluding other causes of painful peripheral neuropathy, improving glycemic control as a prophylactic therapy and using medications to alleviate pain. First line drugs for pain relief include anticonvulsants, such as pregabalin and gabapentin and antidepressants, especially those that act to inhibit the reuptake of serotonin and noradrenaline. In addition, there is experimental and clinical evidence that opioids can be helpful in pain control, mainly if associated with first line drugs. Other agents, including for topical application, such as capsaicin cream and lidocaine patches, have also been proposed to be useful as adjuvants in the control of diabetic neuropathic pain, but the clinical evidence is insufficient to support their use. In conclusion, a better understanding of the mechanisms underlying diabetic neuropathic pain will contribute to the search of new therapies, but also to the improvement of the guidelines to optimize pain control with the drugs currently available.
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19
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Pathogenesis of painful diabetic neuropathy. PAIN RESEARCH AND TREATMENT 2014; 2014:412041. [PMID: 24891949 PMCID: PMC4026988 DOI: 10.1155/2014/412041] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 03/31/2014] [Accepted: 04/15/2014] [Indexed: 12/13/2022]
Abstract
The prevalence of diabetes is rising globally and, as a result, its associated complications are also rising. Painful diabetic neuropathy (PDN) is a well-known complication of diabetes and the most common cause of all neuropathic pain. About one-third of all diabetes patients suffer from PDN. It has a huge effect on a person's daily life, both physically and mentally. Despite huge advances in diabetes and neurology, the exact mechanism of pain causation in PDN is still not clear. The origin of pain could be in the peripheral nerves of the central nervous system. In this review, we discuss various possible mechanisms of the pathogenesis of pain in PDN. We discuss the role of hyperglycaemia in altering the physiology of peripheral nerves. We also describe central mechanisms of pain.
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20
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Sensory correlates of pain in peripheral neuropathies. Clin Neurophysiol 2014; 125:1048-58. [DOI: 10.1016/j.clinph.2013.09.038] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2013] [Revised: 08/26/2013] [Accepted: 09/30/2013] [Indexed: 01/04/2023]
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Dixit S, Maiya AG, Shastry BA. Effect of aerobic exercise on peripheral nerve functions of population with diabetic peripheral neuropathy in type 2 diabetes: a single blind, parallel group randomized controlled trial. J Diabetes Complications 2014; 28:332-9. [PMID: 24507164 DOI: 10.1016/j.jdiacomp.2013.12.006] [Citation(s) in RCA: 73] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Revised: 12/08/2013] [Accepted: 12/20/2013] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To evaluate the effect of moderate intensity aerobic exercise (40%-60% of Heart Rate Reserve (HRR)) on diabetic peripheral neuropathy. METHODS A parallel-group, randomized controlled trial was carried out in a tertiary health care setting, India. The study comprised of experimental (moderate intensity aerobic exercise and standard care) and control groups (standard care). Population with type 2 diabetes with clinical neuropathy, defined as a minimum score of seven on the Michigan Diabetic Neuropathy Score (MDNS), was randomly assigned to experimental and control groups by computer generated random number tables. RANOVA was used for data analysis (p<0.05 was significant). RESULTS A total of 87 patients with DPN were evaluated in the study. After randomization there were 47 patients in the control group and 40 patients in the experimental group. A comparison of two groups using RANOVA for anthropometric measures showed an insignificant change at eight weeks. For distal peroneal nerve's conduction velocity there was a significant difference in two groups at eight weeks (p<0.05), Degrees of freedom (Df)=1, 62, F=5.14, and p=0.03. Sural sensory nerve at eight weeks showed a significant difference in two groups for conduction velocity, Df =1, 60, F=10.16, and p=0.00. Significant differences in mean scores of MDNS were also observed in the two groups at eight weeks (p value significant<0.05). CONCLUSION Moderate intensity aerobic exercises can play a valuable role to disrupt the normal progression of DPN in type 2 diabetes.
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Affiliation(s)
- Snehil Dixit
- Department of Physiotherapy, School of Allied Health Sciences (SOAHS), Manipal University, Manipal, 576104, Karnataka, India.
| | - Arun G Maiya
- Department of Physiotherapy, School of Allied Health Sciences (SOAHS), Manipal University, Manipal, 576104, Karnataka, India
| | - B A Shastry
- Department of Medicine, Kasturba Hospital, Manipal University, Manipal, 576104, Karnataka, India
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Abstract
Although a number of the diabetic neuropathies may result in painful symptomatology, this review focuses on the most common: chronic sensorimotor distal symmetrical polyneuropathy (DSPN). It is estimated that 15-20% of diabetic patients may have painful DSPN, but not all of these will require therapy. In practice, the diagnosis of DSPN is a clinical one, whereas for longitudinal studies and clinical trials, quantitative sensory testing and electrophysiological assessment are usually necessary. A number of simple numeric rating scales are available to assess the frequency and severity of neuropathic pain. Although the exact pathophysiological processes that result in diabetic neuropathic pain remain enigmatic, both peripheral and central mechanisms have been implicated, and extend from altered channel function in peripheral nerve through enhanced spinal processing and changes in many higher centers. A number of pharmacological agents have proven efficacy in painful DSPN, but all are prone to side effects, and none impact the underlying pathophysiological abnormalities because they are only symptomatic therapy. The two first-line therapies approved by regulatory authorities for painful neuropathy are duloxetine and pregabalin. α-Lipoic acid, an antioxidant and pathogenic therapy, has evidence of efficacy but is not licensed in the U.S. and several European countries. All patients with DSPN are at increased risk of foot ulceration and require foot care, education, and if possible, regular podiatry assessment.
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Affiliation(s)
- Solomon Tesfaye
- Diabetes Research Unit, Sheffield Teaching Hospitals, Royal Hallamshire Hospital, Sheffield, U.K
| | - Andrew J.M. Boulton
- Institute for Endocrinology and Diabetes, University of Manchester, Manchester, U.K
| | - Anthony H. Dickenson
- Neuroscience, Physiology and Pharmacology, University College London, London, U.K
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Abstract
Painful diabetic polyneuropathy (PDPN) is generally considered a variant of diabetic polyneuropathy (DPN) but the identification of distinctive aspects that characterize painful compared with painless DPN has however been addressed in many studies, mainly with the purpose of better understanding the mechanisms of neuropathic pain in the scenario of peripheral nerve damage of DPN, of determining risk markers for pain development, and also of recognizing who might respond to treatments. This review is aimed at examining available literature dealing with the issue of similarities and differences between painful and painless DPN in an attempt to respond to the question of whether painful and painless DPN are the same disease or not and to address the conundrum of why some people develop the insensate variety of DPN whilst others experience distressing pain. Thus, from the perspective of comparing painful with painless forms of DPN, this review considers the clinical correlates of PDPN, its distinctive framework of symptoms, signs, and nerve functional and structural abnormalities, the question of large and small fiber involvement, the peripheral pain mechanisms, the central processing of pain and some new insights into the pathogenesis of pain in peripheral polyneuropathies and PDPN.
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Affiliation(s)
- Vincenza Spallone
- Endocrinology, Department of Systems Medicine, University of Tor Vergata, Via Montpellier 1, 00133, Rome, Italy.
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Skapare E, Konrade I, Liepinsh E, Strele I, Makrecka M, Bierhaus A, Lejnieks A, Pirags V, Dambrova M. Association of reduced glyoxalase 1 activity and painful peripheral diabetic neuropathy in type 1 and 2 diabetes mellitus patients. J Diabetes Complications 2013; 27:262-7. [PMID: 23351995 DOI: 10.1016/j.jdiacomp.2012.12.002] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Revised: 11/30/2012] [Accepted: 12/08/2012] [Indexed: 12/31/2022]
Abstract
AIMS The present study was undertaken to investigate the relationship between glyoxalase 1 (Glo1) enzyme activity and painful diabetic neuropathy (DN) in patients with diabetes mellitus. METHODS Glo1 activity and biochemical markers were determined in blood samples from 108 patients with type 1 diabetes, 109 patients with type 2 diabetes, and 132 individuals without diabetes as a control. Painful and painless peripheral DN was assessed and multivariate regression analysis was used to determine independent association of Glo1 activity with occurrence of painful DN. RESULTS In patients with type 1 and type 2 diabetes mellitus and painful DN compared to patients with painless DN, Glo1 activity was significantly reduced by 12 and 14%, respectively. The increase in Glo1 activity was significantly associated with reduced occurrence of painful DN after adjusting for confounders by multivariate analysis. CONCLUSIONS Our results demonstrate for the first time that Glo1 activity is lower in patients with both types of diabetes mellitus who were diagnosed with painful DN. These data support the hypothesis that Glo1 activity modulates the phenotype of DN and warrant further investigation into the role of Glo1 in DN.
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Affiliation(s)
- Elina Skapare
- Latvian Institute of Organic Synthesis, Laboratory of Pharmaceutical Pharmacology, Riga, Latvia.
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Pluijms WA, van Kleef M, Honig WM, Janssen SP, Joosten EA. The effect of spinal cord stimulation frequency in experimental painful diabetic polyneuropathy. Eur J Pain 2013; 17:1338-46. [PMID: 23609991 DOI: 10.1002/j.1532-2149.2013.00318.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/26/2013] [Indexed: 01/07/2023]
Abstract
BACKGROUND Spinal cord stimulation (SCS) has been shown to be an effective treatment for painful diabetic polyneuropathy (PDP). An increase of efficacy is needed since only 67% of patients benefit from SCS. This study aimed to develop an animal model for SCS in PDP and study the effect of various stimulation frequencies on the functional outcome. As the pathophysiology of PDP is complex, including vasoconstriction and nerve injury, the frequency of SCS may result in different outcomes. METHODS Diabetes mellitus was induced by an intraperitoneal injection of streptozotocin in 8-week-old female Sprague-Dawley rats (n=76; glucose >15 mmol/L; n=51). A SCS device was implanted at level Th13 4 weeks later. SCS of the dorsal columns was applied for 30 min and the effect on mechanical hypersensitivity was evaluated. RESULTS Mechanical hypersensitivity developed in 26 rats, which were included (low-frequency, n=6; mid-frequency, n=8; high frequency, n=9; and sham, n=3). SCS of the dorsal columns was applied for 40 min, and the effect on mechanical hypersensitivity was evaluated. In all treatment groups, SCS resulted in reversal of mechanical hypersensitivity and a clinically relevant reduction was achieved in 70% of animals. No differences in efficacy were found between the different treatment groups. CONCLUSIONS The pain-relieving effect of SCS in PDP was studied in an experimental model. Our study shows that SCS on mechanical hypersensitivity in PDP rats is equally effective when applied at low, mid and high frequency.
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Affiliation(s)
- W A Pluijms
- Pain Management and Research Center, Department of Anesthesiology, Maastricht University Hospital, The Netherlands
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Yoo M, Sharma N, Pasnoor M, Kluding PM. Painful Diabetic Peripheral Neuropathy: Presentations, Mechanisms, and Exercise Therapy. ACTA ACUST UNITED AC 2013; Suppl 10. [PMID: 25360348 PMCID: PMC4211105 DOI: 10.4172/2155-6156.s10-005] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Diabetic peripheral neuropathy (DPN) is a frequent complication of diabetes and a major cause of morbidity and increased mortality. It is typically characterized by significant deficits in tactile sensitivity, vibration sense, lower-limb proprioception, and kinesthesia. Painful diabetic neuropathy (P-DPN) is a common phenotype of DPN that affects up to one-third of the general diabetic population. P-DPN has been shown to be associated with significant reductions in overall quality of life, increased levels of anxiety and depression, sleep impairment, and greater gait variability. The purpose of this review is to examine proposed mechanisms of P-DPN, summarize current treatment regimen, and assess exercise as a potential therapy for P-PDN. Although exercise has been shown to be an effective therapeutic modality for diabetes, its specific effects on DPN and especially the painful phenotype have not been sufficiently investigated in current literature. Several rodent models and clinical trials have presented promising results in this area, and warrant further investigations examining the effect of exercise on P-DPN.
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Affiliation(s)
- Min Yoo
- Department of Physical Therapy and Rehabilitation Science, University of Kansas Medical Center, USA
| | - Neena Sharma
- Department of Physical Therapy and Rehabilitation Science, University of Kansas Medical Center, USA
| | - Mamatha Pasnoor
- Department of Neurology, University of Kansas Medical Center, USA
| | - Patricia M Kluding
- Department of Physical Therapy and Rehabilitation Science, University of Kansas Medical Center, USA
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Transplantation of bone marrow-derived mononuclear cells improves mechanical hyperalgesia, cold allodynia and nerve function in diabetic neuropathy. PLoS One 2011; 6:e27458. [PMID: 22125614 PMCID: PMC3220696 DOI: 10.1371/journal.pone.0027458] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2011] [Accepted: 10/17/2011] [Indexed: 01/19/2023] Open
Abstract
Relief from painful diabetic neuropathy is an important clinical issue. We have previously shown that the transplantation of cultured endothelial progenitor cells or mesenchymal stem cells ameliorated diabetic neuropathy in rats. In this study, we investigated whether transplantation of freshly isolated bone marrow-derived mononuclear cells (BM-MNCs) alleviates neuropathic pain in the early stage of streptozotocin-induced diabetic rats. Two weeks after STZ injection, BM-MNCs or vehicle saline were injected into the unilateral hind limb muscles. Mechanical hyperalgesia and cold allodynia in SD rats were measured as the number of foot withdrawals to von Frey hair stimulation and acetone application, respectively. Two weeks after the BM-MNC transplantation, sciatic motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), sciatic nerve blood flow (SNBF), mRNA expressions and histology were assessed. The BM-MNC transplantation significantly ameliorated mechanical hyperalgesia and cold allodynia in the BM-MNC-injected side. Furthermore, the slowed MNCV/SNCV and decreased SNBF in diabetic rats were improved in the BM-MNC-injected side. BM-MNC transplantation improved the decreased mRNA expression of NT-3 and number of microvessels in the hind limb muscles. There was no distinct effect of BM-MNC transplantation on the intraepidermal nerve fiber density. These results suggest that autologous transplantation of BM-MNCs could be a novel strategy for the treatment of painful diabetic neuropathy.
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Chung JO, Cho DH, Chung DJ, Chung MY. Association between Diabetic Polyneuropathy and Cardiovascular Complications in Type 2 Diabetic Patients. Diabetes Metab J 2011; 35:390-6. [PMID: 21977459 PMCID: PMC3178700 DOI: 10.4093/dmj.2011.35.4.390] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2010] [Accepted: 01/13/2011] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Diabetes mellitus is a major independent risk factor for cardiovascular disease (CVD), but high cardiovascular risk in diabetes mellitus patients is not completely explained by clustering traditional risk factors. Recently, associations between diabetic polyneuropathy (DPN) and macrovasculopathy have been suggested. We aimed to assess associations between DPN and cardiovascular complications in type 2 diabetic patients. METHODS Microvascular and cardiovascular complications were evaluated in 1,041 type 2 diabetic patients. RESULTS In patients with DPN, the age, prevalence of hypertension, diabetes duration, systolic blood pressure, pulse pressure, and hemoglobin glycation (HbA1c) levels were significantly higher, while the high density lipoprotein cholesterol (HDL-C) levels were lower than in those without DPN. The prevalence of CVD was higher in patients with DPN. In multivariate analysis, DPN was independently associated with CVD (odds ratio, 1.801; 95% confidence interval, 1.009 to 3.214). CONCLUSION Our results showed that DPN was associated with a high prevalence of cardiovascular disease in type 2 diabetic patients, but further studies are needed to investigate the causative nature of associations between DPN and CVD.
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Affiliation(s)
- Jin Ook Chung
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Dong Hyeok Cho
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Dong Jin Chung
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Min Young Chung
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
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Selvarajah D, Wilkinson ID, Davies J, Gandhi R, Tesfaye S. Central nervous system involvement in diabetic neuropathy. Curr Diab Rep 2011; 11:310-22. [PMID: 21667355 DOI: 10.1007/s11892-011-0205-z] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Diabetic neuropathy is a chronic and often disabling condition that affects a significant number of individuals with diabetes. Long considered a disease of the peripheral nervous system, there is now increasing evidence of central nervous system involvement. Recent advances in neuroimaging methods detailed in this review have led to a better understanding and refinement of how diabetic neuropathy affects the central nervous system. Recognition that diabetic neuropathy is, in part, a disease that affects the whole nervous system is resulting in a critical rethinking of this disorder, opening a new direction for further research.
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Affiliation(s)
- Dinesh Selvarajah
- Diabetes Research Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF, UK
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Selvarajah D, Wilkinson ID, Gandhi R, Griffiths PD, Tesfaye S. Microvascular perfusion abnormalities of the Thalamus in painful but not painless diabetic polyneuropathy: a clue to the pathogenesis of pain in type 1 diabetes. Diabetes Care 2011; 34:718-20. [PMID: 21282344 PMCID: PMC3041213 DOI: 10.2337/dc10-1550] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The pathogenesis of painful diabetic neuropathy (DN) remains undetermined, with both central and peripheral mechanisms implicated. This study investigates whether thalamic perfusion abnormalities occur in painful DN. RESEARCH DESIGN AND METHODS Eighteen subjects with type 1 diabetes (no DN = 6, painful DN = 5, painless DN = 7) and six healthy volunteers (HV) were recruited. Microvascular perfusion characteristics (relative cerebral blood volume [rCBV], flow [rCBF], and transit time [tt(FM)]) of the thalamus and caudate nucleus were assessed using magnetic resonance perfusion imaging. The caudate nucleus was chosen to serve as an in vivo control region. RESULTS Subjects with painful DN had significantly greater thalamic rCBV (means [SD]; painful DN, 228.7 [19.5]; no DN, 202.3 [25.8]; painless DN, 216.5 [65.5]; HV, 181.9 [51.7]; P = 0.04) and the longest tt(FM)(s) (painful DN, 38.4 [3.6]; no DN, 35.3 [13.2]; painless DN, 35.9 [13.7]; HV, 33.7 [14.9]; P = 0.07). There was no significant difference in markers of caudate nucleus perfusion. CONCLUSIONS Painful DN is associated with increased thalamic vascularity. This may provide an important clue to the pathogenesis of pain in DN.
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Affiliation(s)
- Dinesh Selvarajah
- Diabetes Research Department, Royal Hallamshire Hospital, Sheffield, UK.
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Gandhi RA, Marques JLB, Selvarajah D, Emery CJ, Tesfaye S. Painful diabetic neuropathy is associated with greater autonomic dysfunction than painless diabetic neuropathy. Diabetes Care 2010; 33:1585-90. [PMID: 20587724 PMCID: PMC2890363 DOI: 10.2337/dc09-2314] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Although a clear link between diabetic peripheral neuropathy (DPN) and autonomic neuropathy is recognized, the relationship of autonomic neuropathy with subtypes of DPN is less clear. This study aimed to investigate the relationship of autonomic neuropathy with painless and painful DPN. RESEARCH DESIGN AND METHODS Eighty subjects (20 healthy volunteers, 20 with no DPN, 20 with painful DPN, 20 with painless DPN) underwent detailed neurophysiological investigations (including conventional autonomic function tests [AFTs]) and spectral analysis of short-term heart rate variability (HRV), which assesses sympathovagal modulation of the heart rate. Various frequency-domain (including low frequency [LF], high frequency [HF], and total power [TP]) and time-domain (standard deviation of all normal-to-normal R-R intervals [SDNN] and root mean square of successive differences [RMSSD]) parameters were assessed. RESULTS HRV analysis revealed significant differences across the groups in LF, HF, TP, SDNN, and RMSSD (ANOVA P < 0.001). Subgroup analysis showed that compared with painless DPN, painful DPN had significantly lower HF (3.59 +/- 1.08 [means +/- SD] vs. 2.67 +/- 1.56), TP (5.73 +/- 1.28 vs. 4.79 +/- 1.51), and SDNN (2.91 +/- 0.65 vs. 1.62 +/- 3.5), P < 0.05. No significant differences were seen between painless DPN and painful DPN using an AFT. CONCLUSIONS This study shows that painful DPN is associated with significantly greater autonomic dysfunction than painless DPN. These changes are only detected using spectral analysis of HRV (a simple test based on a 5-min electrocardiogram recording), suggesting that it is a more sensitive tool to detect autonomic dysfunction, which is still under-detected in people with diabetes. The greater autonomic dysfunction seen in painful DPN may reflect more predominant small fiber involvement and adds to the growing evidence of its role in the pathophysiology of painful DPN.
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Affiliation(s)
- Rajiv A Gandhi
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield, UK,
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Obrosova IG. Diabetic painful and insensate neuropathy: pathogenesis and potential treatments. Neurotherapeutics 2009; 6:638-47. [PMID: 19789069 PMCID: PMC5084286 DOI: 10.1016/j.nurt.2009.07.004] [Citation(s) in RCA: 208] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2009] [Accepted: 07/09/2009] [Indexed: 12/31/2022] Open
Abstract
Advanced peripheral diabetic neuropathy (PDN) is associated with elevated vibration and thermal perception thresholds that progress to sensory loss and degeneration of all fiber types in peripheral nerve. A considerable proportion of diabetic patients also describe abnormal sensations such as paresthesias, allodynia, hyperalgesia, and spontaneous pain. One or several manifestations of abnormal sensation and pain are described in all the diabetic rat and mouse models studied so far (i.e., streptozotocin-diabetic rats and mice, type 1 insulinopenic BB/Wor and type 2 hyperinsulinemic diabetic BBZDR/Wor rats, Zucker diabetic fatty rats, and nonobese diabetic, Akita, leptin- and leptin-receptor-deficient, and high-fat diet-fed mice). Such manifestations are 1) thermal hyperalgesia, an equivalent of a clinical phenomenon described in early PDN; 2) thermal hypoalgesia, typically present in advanced PDN; 3) mechanical hyperalgesia, an equivalent of pain on pressure in early PDN; 4) mechanical hypoalgesia, an equivalent to the loss of sensitivity to mechanical noxious stimuli in advanced PDN; 5) tactile allodynia, a painful perception of a light touch; and 5) formalin-induced hyperalgesia. Rats with short-term diabetes develop painful neuropathy, whereas those with longer-term diabetes and diabetic mice typically display manifestations of both painful and insensate neuropathy, or insensate neuropathy only. Animal studies using pharmacological and genetic approaches revealed important roles of increased aldose reductase, protein kinase C, and poly(ADP-ribose) polymerase activities, advanced glycation end-products and their receptors, oxidative-nitrosative stress, growth factor imbalances, and C-peptide deficiency in both painful and insensate neuropathy. This review describes recent achievements in studying the pathogenesis of diabetic neuropathic pain and sensory disorders in diabetic animal models and developing potential pathogenetic treatments.
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Affiliation(s)
- Irina G Obrosova
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808, USA.
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A case of insulin neuritis that developed in a patient under regular insulin treatment on increasing the insulin dose. Insulin neuritis: is it a misnomer? J Neurol 2009; 256:274-5. [PMID: 19242646 DOI: 10.1007/s00415-009-0952-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2007] [Revised: 02/22/2008] [Accepted: 03/25/2008] [Indexed: 10/21/2022]
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Abstract
Current therapeutic possibilities can be divided into two groups: the pathogenetically oriented and the symptomatic therapy. One of the most important component of etiology-based treatment is the stabilization of glycemic control. Based on efficacy and safety data benfotiamine and alpha-lipoic acid should be considered as first choices among pathogenetically oriented treatments of diabetic neuropathy. Promising data were published about the aldose reductase inhibitor ranirestat. The symptomatic effect of antiepileptic drugs in diabetic painful neuropathy (DPN) is originated from several possible pharmacological properties. Pregabalin and gabapentin have the highest efficacy and the lowest frequency of adverse events among these drugs. Antidepressants also extensively used for symptomatic treatment in DPN. In the last years several studies were published about the benefial effect of duloxetine. Most likely combination therapy will be frequently applied in the future for the treatment of DPN, the optimal choice could be to combine pathogenetically oriented and symptomatic treatment.
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Affiliation(s)
- Tamás Várkonyi
- First Department of Medicine, University of Szeged, Szeged, Hungary.
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Obrosova IG, Drel VR, Oltman CL, Mashtalir N, Tibrewala J, Groves JT, Yorek MA. Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats. Am J Physiol Endocrinol Metab 2007; 293:E1645-55. [PMID: 17911342 DOI: 10.1152/ajpendo.00479.2007] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Evidence for important roles of the highly reactive oxidant peroxynitrite in diabetic complications is emerging. We evaluated the role of peroxynitrite in early peripheral neuropathy and vascular dysfunction in STZ-diabetic rats. In the first dose-finding study, control and STZ-diabetic rats were maintained with or without the potent peroxynitrite decomposition catalyst Fe(III)tetrakis-2-(N-triethylene glycol monomethyl ether) pyridyl porphyrin (FP15) at 3, 5, or 10 mg.kg(-1).day(-1) in the drinking water for 4 wk after an initial 2 wk without treatment for assessment of early neuropathy. In the second study with similar experimental design, control and STZ-diabetic rats were maintained with or without FP15, 5 mg.kg(-1).day(-1), for vascular studies. Rats with 6-wk duration of diabetes developed motor and sensory nerve conduction velocity deficits, mechanical hyperalgesia, and tactile allodynia in the absence of small sensory nerve fiber degeneration. They also had increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve and dorsal root ganglia. All these variables were dose-dependently corrected by FP15, with minimal differences between the 5 and 10 mg.kg(-1).day(-1) doses. FP15, 5 mg.kg(-1).day(-1), also corrected endoneurial nutritive blood flow and nitrotyrosine, but not superoxide, fluorescence in aorta and epineurial arterioles. Diabetes-induced decreases in acetylcholine-mediated relaxation by epineurial arterioles and coronary and mesenteric arteries, as well as bradykinin-induced relaxation by coronary and mesenteric arteries, were alleviated by FP15 treatment. The findings reveal the important role of nitrosative stress in early neuropathy and vasculopathy and provide the rationale for further studies of peroxynitrite decomposition catalysts in long-term diabetic models.
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Affiliation(s)
- Irina G Obrosova
- Pennington Biomedical Research Center, Louisiana State University, 6400 Perkins Road, Baton Rouge, LA 70808, USA.
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Quattrini C, Harris ND, Malik RA, Tesfaye S. Impaired skin microvascular reactivity in painful diabetic neuropathy. Diabetes Care 2007; 30:655-9. [PMID: 17327336 DOI: 10.2337/dc06-2154] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The pathogenesis of painful diabetic neuropathy (PDN) is not clear. Following our in vivo observations of increased sural nerve epineurial blood flow in patients with PDN, we investigated the cutaneous microcirculation of the foot by laser Doppler flowmetry to determine if the epineurial findings were just confined to the nerve or more widespread in other vascular beds. RESEARCH DESIGN AND METHODS We measured foot skin vasodilator responses to acetylcholine (Ach) and sodium nitroprusside (SNP) and vasoconstrictor responses to sympathetic (deepest possible gasp) stimulation in 5 healthy control subjects, 10 non-neuropathic diabetic (NND) patients, 10 diabetic patients with painless neuropathy (PLDN), and 8 diabetic patients with PDN. RESULTS In PDN, there were significantly reduced responses to Ach (ANOVA P = 0.003) and vasoconstrictor inspiratory gasp (ANOVA P < 0.001) but not to SNP (NS). Post hoc analysis showed significant differences in Ach-induced vasodilation between PDN and nondiabetic control subjects (P < 0.05) as well as between PDN and NND (P < 0.05) but not PDN and PLDN (NS). There were no significant differences for SNP-induced vasodilation. However, there were significant differences in the vasoconstrictor response between PDN and control, NND, and PLDN (P < 0.01). CONCLUSIONS We found an impairment of cutaneous endothelium-related vasodilation and C-fiber-mediated vasoconstriction in PDN. Inappropriate local blood flow regulation may have a role in the pathogenesis of pain in diabetic neuropathy. Prospective studies are required to determine the temporal relationship of these changes in relation to the emergence of neuropathic pain.
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Affiliation(s)
- Cristian Quattrini
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield S10 2JF, UK
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Selvarajah D, Wilkinson ID, Emery CJ, Harris ND, Shaw PJ, Witte DR, Griffiths PD, Tesfaye S. Early involvement of the spinal cord in diabetic peripheral neuropathy. Diabetes Care 2006; 29:2664-9. [PMID: 17130202 DOI: 10.2337/dc06-0650] [Citation(s) in RCA: 121] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The pathogenesis of diabetic peripheral neuropathy (DPN) is poorly understood. We have recently reported a significant reduction in spinal cord cross-sectional area at the stage of clinically detectable DPN. In this study, we investigated whether spinal cord atrophy occurs in early (subclinical) DPN. RESEARCH DESIGN AND METHODS Eighty-one male type 1 diabetic subjects, 24 nondiabetic control subjects, and 8 subjects with hereditary sensory motor neuropathy (HSMN) type 1A underwent detailed clinical and neurophysiological assessments. Diabetic subjects were subsequently divided into three groups based on neuropathy severity (19 with no DPN, 23 with subclinical DPN, and 39 with clinically detectable DPN). All subjects underwent magnetic resonance imaging of the cervical spine and cord area measurements at disc level C2/C3. RESULTS Mean corrected spinal cord area index (SCAI) (corrected for age, height, and weight) was 67.5 mm [95% CI 64.1-70.9] in diabetic subjects without DPN. Those with subclinical (62.4 mm [59.5-65.3]) and clinically detectable DPN (57.2 mm [54.9-59.6]) had lower mean SCAIs compared with subjects with no DPN (P = 0.03 and P < 0.001, respectively). No significant difference was found between diabetic subjects without DPN and nondiabetic control subjects (69.2 mm [66.3-72.0], P = 0.47). Mean SCAIs in subjects with HSMN type 1A (71.07 mm [65.3-76.9]) were not significantly different from those for nondiabetic control subjects and diabetic subjects without DPN. Among diabetic subjects, SCAI was significantly related to sural sensory conduction velocities and the Neuropathy Composite and Symptom Scores. CONCLUSIONS Spinal cord involvement occurs early in DPN. There is also a significant relation between reduction in SCAI and neurophysiological assessments of DPN.
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Affiliation(s)
- Dinesh Selvarajah
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield S10 2JF, U.K
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Jensen TS, Backonja MM, Hernández Jiménez S, Tesfaye S, Valensi P, Ziegler D. New perspectives on the management of diabetic peripheral neuropathic pain. Diab Vasc Dis Res 2006; 3:108-19. [PMID: 17058631 DOI: 10.3132/dvdr.2006.013] [Citation(s) in RCA: 126] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Peripheral neuropathy affects about 30% of people with diabetes mellitus. Between 16% and 26% of diabetes patients experience chronic pain. This may be referred to as diabetic neuropathic pain (DNP) or diabetic peripheral neuropathic pain (DPNP). Minimum requirements for diagnosis of DPNP should include assessment of pain and symptoms and neurological examination, with the accent on sensory examination. Given that depression and other co-morbidities are commonly associated with this condition, a broad approach to management is essential. Lifestyle intervention and optimisation of glycaemic control are recommended as initial steps in management. An evidence-based treatment algorithm for DPNP has been proposed, recommending initial use of either a tricyclic antidepressant, selective serotonin noradrenaline re-uptake inhibitor or alpha-2-delta agonist, depending on patient co-morbidities and contra-indications. Addition of an opioid agonist may be required in the event of inadequate pain control. Irrespective of which treatment is offered, only about one third of patients are likely to achieve more than 50% pain relief. Further research to improve the diagnosis and management of DPNP is needed.
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Affiliation(s)
- Troels S Jensen
- Department of Endocrinology, Diabetology and Nutrition, Hôpital Jean-Verdier APHP Paris-Nord University, Bondy, France.
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Vinik A, Parson H, Ullal J. The role of PPARs in the microvascular dysfunction in diabetes. Vascul Pharmacol 2006; 45:54-64. [PMID: 16784897 DOI: 10.1016/j.vph.2005.11.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2005] [Revised: 11/01/2005] [Accepted: 11/01/2005] [Indexed: 11/19/2022]
Abstract
There is a major defect in skin blood flow (SkBF) in people with type 2 diabetes (T2DM). This defect is associated with relatively normal nitric oxide (NO) production in the skin. The abnormal blood flow cosegregates with hypertension, dyslipidemia, abnormal fatty acid composition, a proinflammatory state, and insulin resistance. Since these covariates are an integral part of the insulin resistance syndrome, we examined the effects of the thiazoledindiones (TZDs) as insulin sensitizers for their ability to correct the abnormal blood flow. The PPARgamma rosiglitazone improved NO production to normal levels, but had a small effect on SKBF. In contrast, pioglitazone had a small effect on skin neurovascular function but a dramatic effect on reducing nitrosative stress. These effects do not appear to be due to the insulin sensitizing properties of these compounds but are associated with a reduction in indices of inflammation, hemodilution, and are likely to be due to one of the many "vascular" effects of TZDs. The role of inflammation in the disordered neurovascular function in diabetes cannot be underplayed and the possible contribution of PPARalpha agonists to alter the inflammatory state needs to be explored further. Since blood flow regulation is mediated by mechanisms other than NO, such as prostaglandins and endothelial derived hyperpolarizing factor, which, in turn, are compromised by the inflammatory state, we anticipate that activation of both the PPARgamma as well as PPARalpha should ameliorate the disordered blood flow in type 2 diabetes. While it now appears that the PPARs may have a major role to play in protection from macrovascular disease, their contribution to amelioration of the microvascular defects in type 2 diabetes has fallen short of spectacular success. In this respect, the combinations of PPARalpha, PPARbeta and PPARgamma may better serve the unique requirements for improving the microvascular defect in diabetes.
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Affiliation(s)
- Aaron Vinik
- Strelitz Diabetes Institute, Eastern Virginia Medical School, Norfolk, VA 23510, United States.
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Vinik AI, Ullal J, Parson HK, Barlow PM, Casellini CM. Pioglitazone treatment improves nitrosative stress in type 2 diabetes. Diabetes Care 2006; 29:869-76. [PMID: 16567830 DOI: 10.2337/diacare.29.04.06.dc05-0517] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The purpose of this study was to determine the effect of 24 weeks of treatment with 45 mg/day pioglitazone on peripheral skin blood flow (SkBF) and skin nitric oxide (NO) production in vivo in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS This was a randomized, parallel, cross-over, double-blind, within- and between-subject study designed to compare vascular responses before and after treatment. We studied 12 subjects with type 2 diabetes (average age 58.6 +/- 30.8 years, HbA(1c) 7.9 +/- 00.4%, BMI 31.3 +/- 1.2 kg/m(2)). SkBF was measured using laser Doppler techniques in response to ischemia reperfusion and local skin warming, and NO production was assessed in vivo using an amperometric NO meter inserted directly into the skin. These measurements were performed before treatment and at 6 and 24 weeks. RESULTS The SkBF response was not significantly improved after 24 weeks in either of the groups. NO production was significantly decreased in the pioglitazone-treated group in the basal condition (area under the curve 6.4 +/- 1.0 vs. 2.8 +/- 0.8, P < 0.01), after local heat stimulation at 40 degrees C (12.9 +/- 2.2 vs. 5.7 +/- 1.7, P < 0.01), and after nociceptor stimulated flow with local heating at 44 degrees C (36.4 +/- 6.3 vs. 16.6 +/- 3.4). Differences were not significant in the placebo-treated group. CONCLUSIONS Treatment of patients with type 2 diabetes with pioglitazone for 24 weeks reduced skin NO production, thus probably reducing nitrosative stress without a demonstrable effect on SkBF. Because nitrosative stress is considered to be a factor in the pathogenesis of neurovascular dysfunction, these findings warrant further investigation.
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Affiliation(s)
- Aaron I Vinik
- Department of Internal Medicine, The Strelitz Diabetes Institutes, Eastern Virginia Medical School, Norfolk, VA 23510, USA.
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Emerick AJ, Richards MP, Kartje GL, Neafsey EJ, Stubbs EB. Experimental diabetes attenuates cerebral cortical-evoked forelimb motor responses. Diabetes 2005; 54:2764-71. [PMID: 16123367 DOI: 10.2337/diabetes.54.9.2764] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Poorly controlled diabetes leads to debilitating peripheral complications, including retinopathy, nephropathy, and neuropathy. Chronic diabetes also impairs the central nervous system (CNS), leading to measurable deficits in cognition, somatosensory, and motor function. The cause of diabetes-associated CNS impairment is unknown. In this study, sustained hyperglycemia resulting from insulin deficiency was shown to contribute to CNS motor dysfunction. Experimental diabetes was induced in rats by streptozotocin (STZ) injection. CNS motor function was assessed by intracortical microstimulation of the sensorimotor cortex. Experimental diabetes significantly (P < 0.01; n = 14) attenuated the number of motor cortical sites eliciting forelimb movements. The net area of the motor cortex representing the forelimb in diabetic rats was significantly reduced (4.0 +/- 0.5 [control] vs. 2.4 +/- 0.4 [STZ] mm(2); P < 0.05). Experimental diabetes attenuated the activation of some, but not all, forelimb motor cortical neurons. Insulin treatment of diabetic rats prevented the attenuation of cortical-evoked forelimb responses. Peripheral nerve-evoked responses were unaffected by this short period of diabetes, suggesting the absence of peripheral nerve dysfunction. This study showed that metabolic imbalance resulting from insulin deficiency elicits a marked attenuation of cortical-evoked motor function. Uncontrolled hyperglycemia, deficiencies of central insulin, or both may contribute to corticospinal motor dysfunction.
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Affiliation(s)
- April J Emerick
- Neurology Service (127), Bldg. 1, Rm. F201, Edward Hines, Jr. VA Hospital, Hines, IL 60141, USA
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Tesfaye S, Chaturvedi N, Eaton SEM, Ward JD, Manes C, Ionescu-Tirgoviste C, Witte DR, Fuller JH. Vascular risk factors and diabetic neuropathy. N Engl J Med 2005; 352:341-50. [PMID: 15673800 DOI: 10.1056/nejmoa032782] [Citation(s) in RCA: 857] [Impact Index Per Article: 42.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Other than glycemic control, there are no treatments for diabetic neuropathy. Thus, identifying potentially modifiable risk factors for neuropathy is crucial. We studied risk factors for the development of distal symmetric neuropathy in 1172 patients with type 1 diabetes mellitus from 31 centers participating in the European Diabetes (EURODIAB) Prospective Complications Study. METHODS Neuropathy was assessed at baseline (1989 to 1991) and at follow-up (1997 to 1999), with a mean (+/-SD) follow-up of 7.3+/-0.6 years. A standardized protocol included clinical evaluation, quantitative sensory testing, and autonomic-function tests. Serum lipids and lipoproteins, glycosylated hemoglobin, and the urinary albumin excretion rate were measured in a central laboratory. RESULTS At follow-up, neuropathy had developed in 276 of 1172 patients without neuropathy at baseline (23.5 percent). The cumulative incidence of neuropathy was related to the glycosylated hemoglobin value and the duration of diabetes. After adjustment for these factors, we found that higher levels of total and low-density lipoprotein cholesterol and triglycerides, a higher body-mass index, higher von Willebrand factor levels and urinary albumin excretion rate, hypertension, and smoking were all significantly associated with the cumulative incidence of neuropathy. After adjustment for other risk factors and diabetic complications, we found that duration of diabetes, current glycosylated hemoglobin value, change in glycosylated hemoglobin value during the follow-up period, body-mass index, and smoking remained independently associated with the incidence of neuropathy. Cardiovascular disease at baseline was associated with double the risk of neuropathy, independent of cardiovascular risk factors. CONCLUSIONS This prospective study indicates that, apart from glycemic control, the incidence of neuropathy is associated with potentially modifiable cardiovascular risk factors, including a raised triglyceride level, body-mass index, smoking, and hypertension.
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Affiliation(s)
- Solomon Tesfaye
- Diabetes Research Unit, Royal Hallamshire Hospital, Sheffield, United Kingdom.
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Jeffcoate WJ, Idris I, Game FL. Erythromelia, or Mitchell's syndrome--new names for unexplained signs of inflammation in distal symmetrical neuropathy in diabetes. Diabet Med 2004; 21:1334-8. [PMID: 15569137 DOI: 10.1111/j.1464-5491.2004.01346.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND Two cases are described in which distal symmetrical sensorimotor neuropathy complicating diabetes was associated with episodes of subacute vasodilation of one or other lower limb, and which were otherwise unexplained. The vasodilation was associated with swelling and stiffness, but was painless and self-limiting. INTERPRETATION It is suggested that this phenomenon results from disordered vasoregulation in diabetic neuropathy, and is linked to the processes which underlie diabetic neuropathic osteoarthropathy (Charcot foot), as well as disorders such as complex regional pain syndrome-1 (CRPS-1, reflex sympathetic dystrophy) and erythromelalgia. CONCLUSIONS As self-limiting vasodilation may be not uncommon in distal symmetrical neuropathies, but unrecognized because the phenomenon has not been named, the terms 'neuropathic erythromelia' or 'Mitchell's syndrome' are proposed. The adoption of either of these names may lead to earlier diagnosis and prevent inappropriate investigation and treatment.
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Affiliation(s)
- W J Jeffcoate
- Foot Ulcer Trials Unit, Department of Diabetes and Endocrinology, City Hospital, Nottingham, UK.
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Sugimoto K, Shoji M, Yasujima M, Suda T, Yagihashi S. Peripheral nerve endoneurial microangiopathy and necrosis in rats with insulinoma. Acta Neuropathol 2004; 108:503-14. [PMID: 15365726 DOI: 10.1007/s00401-004-0915-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2004] [Revised: 07/19/2004] [Accepted: 07/26/2004] [Indexed: 10/26/2022]
Abstract
Peripheral nerve pathology related to chronic hyperinsulinemia and hypoglycemia has yet to be fully explored. Here we conducted a systematic quantitative analysis of morphological alterations in peripheral sensory and motor nerve fibers and endoneurial microvasculature in longstanding insulinoma-carrying rats (I-rats; n=12). Age-matched normal rats (n=6) served as controls. Over the 15-month observation period, two of I-rats developed paresis of the hind limbs when their blood glucose level fell below 1.7 mmol/l. These animals showed a massive myelinated fiber loss associated with active degeneration of residual myelinated fibers and multiple endoneurial microvascular occlusions at the sciatic nerve level. The rest of the non-paretic I-rats showed a decreased density of large myelinated fibers with axonal degeneration in the peroneal nerve and an increased density of small myelinated fibers with preserved morphology in the sural nerve. This was associated with endoneurial microangiopathic changes indicative of endoneurial ischemia/hypoxia in the sciatic and peroneal nerves, and an increase in endoneurial microvascular density in the sciatic and sural nerves. In conjunction with previous data, these findings suggest that the observed increase in endoneurial microvascular density may be a compensatory response to endoneurial ischemia/hypoxia induced by chronic hyperinsulinemia in I-rats without paresis. In conclusion, the present study showed characteristic morphological alterations in peripheral sensory and motor nerve fibers associated with microangiopathy indicative of endoneurial ischemia/hypoxia in the sciatic and peroneal nerves, and provides the first evidence for the occurrence of endoneurial necrosis in the sciatic nerve, to which the hind limb paresis can be ascribed in I-rats.
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Affiliation(s)
- Kazuhiro Sugimoto
- Department of Laboratory Medicine, Hirosaki University School of Medicine, 5 Zaifu-cho, 036-8562 Hirosaki, Japan.
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Shun CT, Chang YC, Wu HP, Hsieh SC, Lin WM, Lin YH, Tai TY, Hsieh ST. Skin denervation in type 2 diabetes: correlations with diabetic duration and functional impairments. ACTA ACUST UNITED AC 2004; 127:1593-605. [PMID: 15128619 DOI: 10.1093/brain/awh180] [Citation(s) in RCA: 256] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Sensory neuropathy is a prominent component of diabetic neuropathy. It is not entirely clear how diabetes influences skin innervation, and whether these changes are correlated with clinical signs and laboratory findings. To investigate these issues, we performed skin biopsies on the distal leg of 38 consecutive type 2 diabetic patients with sensory symptoms in lower limbs (25 males and 13 females, aged 56.2 +/- 9.4 years) and analysed the correlations of intraepidermal nerve fibre (IENF) densities in skin with glycaemic status (duration of diabetes, HbA1C, and fasting and post-prandial glucose levels), and functional parameters of small fibres (warm and cold thresholds) and large fibres (vibratory threshold and parameters of nerve conduction studies). Clinically, 23 patients (60.5%) had signs of small-fibre impairment, and 19 patients (50.0%) had signs of large-fibre impairment. IENF densities were much lower in diabetic patients than in age- and gender-matched controls (1.794 +/- 2.120 versus 9.359 +/- 3.466 fibres/mm, P < 0.0001), and 81.6% (31/38) of diabetic patients had reduced IENF densities. IENF densities were negatively associated with the duration of diabetes (standardized coefficient: -0.422, P = 0.015) by analysis with a multivariate linear regression model. Abnormal results of functional examinations were present in 81.6% (warm threshold), 57.9% (cold threshold), 63.2% (vibratory threshold) and 49% (amplitude of sural sensory action potential) of diabetic patients. Among the three sensory thresholds, the warm threshold temperature had the highest correlation with IENF densities (standardized coefficient: -0.773, P < 0.0001). On nerve conduction studies in lower-limb nerves, there were abnormal responses in 54.1% of sural nerves, and 50.0% of peroneal nerves. Of neurophysiological parameters, the amplitude of the sural sensory action potential had the highest correlation with IENF density (standardized coefficient: 0.739, P < 0.0001). On clinical examination, 15 patients showed no sign of small-fibre impairment, but seven of these patients had reduced IENF densities. In conclusion, small-fibre sensory neuropathy presenting with reduced IENF densities and correlated elevation of warm thresholds is a major manifestation of type 2 diabetes. In addition, the extent of skin denervation increases with diabetic duration.
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Affiliation(s)
- Chia-Tung Shun
- Department of Pathology, National Taiwan University Hospital, Taipei
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Bierhaus A, Humpert PM, Rudofsky G, Wendt T, Morcos M, Hamann A, Nawroth PP. New treatments for diabetic neuropathy: pathogenetically oriented treatment. Curr Diab Rep 2003; 3:452-8. [PMID: 14611740 DOI: 10.1007/s11892-003-0007-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Although there is clear evidence from experimental diabetic neuropathy (DN) models that the multiple pathways involved in neuronal degeneration cause overproduction of reactive oxygen species, oxidative stress, and cellular dysfunction, therapeutic approaches addressing these mechanisms have not yet provided a basis for a successful treatment of patients with DN. This review discusses the current knowledge on the pathomechanisms of unchecked reactive oxygen species accumulation, implications for specific treatment, and the need for carefully designed experimental studies and clinical trials closing the gap between promising results in experimental DN and its implementation into a pathogenetically oriented treatment.
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