Subclinical Inflammation and Diabetic Polyneuropathy

Herder, Christian; Lankisch, Mark; Ziegler, Dan; Rathmann, Wolfgang; Köenig, Wolfgang; Illig, Thomas; Döring, Angela; Thorand, Barbara; Holle, Rolf; Giani, Guido; Martin, Stéphan; Meisinger, Christa

doi:10.2337/dc08-2011

Cited by 103 publications

(94 citation statements)

References 15 publications

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“…In that study, patients with painful neuropathy had higher circulating levels of CRP and sICAM-1, whereas no differences were found for TNF-a, and IL-6 was not measured (10). The difference compared with our study regarding CRP is interesting given that we previously found associations between CRP and the MNSI score in a sample of diabetic patients (17), but not in the general older population (13), which suggests differences in risk factors of DSPN with respect to diabetic status. One study reported an association between TNF-a plasma levels and neuropathic pain in patients with type 2 diabetes, but the analysis was not adjusted for any confounding variables (18).…”

Section: Discussioncontrasting

confidence: 51%

“…The population-based sample and the adjustment for multiple confounding variables represent strengths of our analysis. The population-based approach is relevant because DSPN without and with pain also affects a considerable proportion of nondiabetic individuals among the older population, as previously reported (3,6,17) and reviewed (2). A detailed analysis of this intriguing finding is beyond the scope of this study.…”

Section: Discussionmentioning

confidence: 92%

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Differential Association Between Biomarkers of Subclinical Inflammation and Painful Polyneuropathy: Results From the KORA F4 Study

et al. 2014

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OBJECTIVEInflammatory processes have been implicated in the pathogenesis of painful neuropathy in rodents, but the relationship between inflammatory biomarkers and painful distal sensorimotor polyneuropathy (DSPN) has not been assessed in population-based studies. Therefore, we investigated whether circulating levels of seven pro-and anti-inflammatory immune mediators were associated with painful DSPN in older individuals in a large population-based study. RESEARCH DESIGN AND METHODSThe study population consisted of individuals with painless (n = 337) and painful DSPN (n = 54) from a source population (n = 1,047) of men and women aged 61-82 years who participated in the German KORA F4 survey (2006)(2007)(2008). We measured circulating levels of seven immune mediators and assessed their associations with the presence of painful DSPN using multiple logistic regression models. RESULTSAfter adjustment for age and sex, we found positive associations between serum concentrations of the cytokine interleukin (IL)-6 and the soluble intercellular adhesion molecule (sICAM)-1 and painful DSPN (P = 0.004 and P = 0.005, respectively), whereas no associations were observed for C-reactive protein, IL-18, tumor necrosis factor-a, adiponectin, and IL-1 receptor antagonist (IL-1RA, P = 0.07-0.38). Associations between IL-6 and sICAM-1 and painful DSPN remained significant after additional adjustment for waist circumference, height, hypertension, cholesterol, smoking, alcohol intake, physical activity, history of myocardial infarction and/or stroke, presence of other neurological conditions, and use of nonsteroidal anti-inflammatory drugs (P = 0.005 and P = 0.016, respectively). CONCLUSIONSPainful DSPN is linked to systemic subclinical and vascular inflammation in the older population independent of anthropometric, lifestyle, and metabolic confounders.

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Section: Discussioncontrasting

confidence: 51%

Section: Discussionmentioning

confidence: 92%

Differential Association Between Biomarkers of Subclinical Inflammation and Painful Polyneuropathy: Results From the KORA F4 Study

et al. 2014

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“…After an injury, such as those triggered by hyperglycaemia or modified LDLs, intracellular cascades can be activated in Schwann cells, including nuclear translocation of NF-κB and consequent expression of various cytokines and chemokines, similar to the scenario after traumatic nerve damage. These events contribute to Wallerian degeneration and emphasize the potential involvement of Schwann cells in the subclinical inflammation that is observed in patients with type 2 diabetes and is detectable as increased circulating levels of C-reactive protein and IL-6, which are consistently associated with polyneuropathy 95 . Furthermore, via production of cytokines and chemokines, Schwann cells might contribute to immune cell recruitment 4,96 and nerve inflammation in diabetes.…”

Section: Oxidative Stress and Mitochondrial Dysfunctionmentioning

confidence: 87%

Schwann cell interactions with axons and microvessels in diabetic neuropathy

et al. 2017

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The incidence of diabetes mellitus has increased dramatically over the past two to three decades. According to the International Diabetes Federation Diabetes Atlas, 415 million people worldwide had diabetes in 2015, and this number is expected to grow by 5% annually, predominantly as a result of increasing prevalence of type 2 diabetes. Furthermore, an estimated 100 million Europeans and 80 million Americans have impaired glucose tolerance or prediabetes. Few people die from acute diabetes in countries with comprehensive health care systems, but the disease is inflicting a huge medical, social and economic burden on society owing to the need for lifelong treatment of its systemic consequences and the insidious development of multi-organ damage.Peripheral neuropathy (BOXES 1,2) is a common but often neglected complication of long-term diabetes, and the lack of treatment options reflects an incomplete understanding of the pathogenic mechanisms. Hyperglycaemia is generally accepted as the primary pathogenic insult in type 1 and type 2 diabetic neuropathy, although roles are emerging for other factors, such as impaired insulin signalling, hypertension and dyslipidaemia (particularly for type 2 diabetes), which might precede overt hyperglycaemia 1 . Many preclinical studies, and occasional clinical studies, have indicated that diabetic neuropathy -like diabetic nephropathy and retinopathy -results from microvascular disease, with a focus on axonal degeneration as a consequence of ischaemia and/or hypoxia. This mechanism, however, is likely to be only one aspect of a more complex pathogenesis.The earliest descriptions of pathology in diabetic neuropathy indicated that Schwannopathy accompanied axonal degeneration. The majority of clinical and basic research in diabetic neuropathy since then has focused on the effects on neurons. However, accumulating data from research into the development and regeneration of the PNS has identified Schwann cells as equally indispensable components that maintain neuronal structure and function, nourish axons, and promote survival and growth upon injury. The early reports from 1979 that demonstrated morphological changes in Schwann cells in human diabetic neuropathy 2 are now supported by an increased awareness of molecular alterations in Schwann cells during diabetes 3 . Schwann cells express a wide range of receptors and, when they sense insults or danger signals, they upregulate synthesis and secretion of factors that stimulate neuroprotection, regrowth and remyelination, or factors that aggravate disease phenotypes 4 . The most recent studies have demonstrated that Schwann cells regulate many aspects of axonal function, so that disruption of their metabolism by diabetes results in the accumulation of neurotoxic intermediates and compromises production of neuronal support factors, contributing to axonal degeneration, endothelial dysfunction and diabetic neuropathy. Abstract | The prevalence of diabetes worldwide is at pandemic levels, with the number of patients increasing by 5% annu...

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“…Several population-based studies conducted in different KORA cohorts have documented associations between markers of systemic subclinical inflammation and the presence of DSPN [89][90][91][92]. In the KORA F3 cohort, high levels of C-reactive protein (CRP) and interleukin 6 (IL-6) were positively associated with the presence and severity of DSPN [92].…”

Section: Inflammationmentioning

confidence: 99%

“…In the KORA F3 cohort, high levels of C-reactive protein (CRP) and interleukin 6 (IL-6) were positively associated with the presence and severity of DSPN [92]. In the KORA F4 cohort, serum concentrations of the anti-inflammatory IL-1 receptor antagonist (IL-1RA), IL-6, IL-18, and soluble intercellular adhesion molecule-1 (sICAM-1) were positively associated with the severity of neuropathic deficits, suggesting that DSPN is linked to proinflammatory and anti-inflammatory, possibly compensatory, processes in the older general population [91].…”

Section: Inflammationmentioning

confidence: 99%

Risk Factors and Comorbidities in Diabetic Neuropathy: An Update 2015

2015

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■ AbstractDistal symmetric sensorimotor polyneuropathy (DSPN) is the most common neurological manifestation in diabetes. Major risk factors of DSPN include diabetes duration, hyperglycemia, and age, followed by prediabetes, hypertension, dyslipidemia, and obesity. Height, smoking, insulin resistance, hypoinsulinemia, and others represent an additional risk. Importantly, hyperglycemia, hypertension, dyslipidemia, obesity, and smoking are modifiable. Stringent glycemic control has been shown to be effective in type 1, but not to the same extent in type 2 diabetes. Antilipidemic treatment, especially with fenofibrate, and multi-factorial intervention have produced encouraging results, but more experience is necessary. The major comorbidities of DSPN are depression, autonomic neuropathy, peripheral artery disease, cardiovascular disease, nephropathy, retinopathy, and medial arterial calcification. Knowledge of risk factors and comorbidities has the potential to enrich the therapeutic strategy in clinical practice as part of the overall medical care for patients with neuropathy. This article provides an updated overview of DSPN risk factors and comorbidities.

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Subclinical Inflammation and Diabetic Polyneuropathy

Cited by 103 publications

References 15 publications

Differential Association Between Biomarkers of Subclinical Inflammation and Painful Polyneuropathy: Results From the KORA F4 Study

Differential Association Between Biomarkers of Subclinical Inflammation and Painful Polyneuropathy: Results From the KORA F4 Study

Schwann cell interactions with axons and microvessels in diabetic neuropathy

Risk Factors and Comorbidities in Diabetic Neuropathy: An Update 2015

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