Applied nutritional investigationDisability in patients with multiple sclerosis: Influence of insulin resistance, adiposity, and oxidative stress
Introduction
Multiple sclerosis (MS) is a chronic inflammatory and progressive immune-mediated disease of central nervous system (CNS), mainly characterized by a selective and coordinated inflammatory destruction of the myelin sheath, with damage to the axon [1]. Accumulating data indicate that oxidative stress plays a major role in the pathogenesis of MS. Reactive oxygen species (ROS) may play a key role in the disease development by contributing to myelin and oligodendroglia degeneration, the pathological hallmarks of MS [2], [3]. Additionally, we previously demonstrated that individuals with MS have persistent oxidative stress, even when the disease remained in clinical remission, and that oxidative stress may play an important role in the physiopathology of disability progression as evaluated by the Expanded Disability Status Scale (EDSS) [3].
Approximately half of all individuals with MS develop cognitive impairments, and the severity of these conditions predicts their quality of life [4], [5]. Hyperinsulinemia has been suggested to be associated with cognitive impairments in neurodegenerative disorders such as Alzheimer’s disease and MS [6], and the role of insulin in the CNS has emerged as a novel field of research [7]. Systemic chronic inflammation has been proposed to exert a prominent role in the pathogenesis of insulin resistance (IR) [8]. Additionally, oxidative stress and IR are closer associated and much evidence has shown that oxidative stress can lead to IR by promoting the expression of several proinflammatory cytokines, which can reduce insulin sensitivity [9]. Moreover, insulin abnormalities may increase inflammatory responses, oxidative stress [10] and could exacerbate cognitive impairments in individuals with MS [5]. Additionally, insulin has a central role in immunity and can act as a neurotransmissor [5].
Experimental autoimmune encephalomyelitis (EAE) has been extensively used as an animal model for humans with MS [11]. Insights from EAE suggest that T cells are activated in the periphery and migrate into the CNS, resulting in elevated levels of proinflammatory cytokines, activated glia, and increased production of free radical species [11], [12]. It has been shown that peroxisome proliferator-activated receptor-γ (PPARγ), is expressed in the spinal cord inflammatory infiltrate in EAE. Interestingly, PPARγ agonists, such as thiazolidinediones, antidiabetic agents that decrease IR, significantly reduce disease severity [12], [13].
To date, scarce information is available about the association of metabolic comorbidities and disability in individuals with MS. One study [14] showed that vascular comorbidities, such as diabetes, hypertension, hypercholesterolemia, and peripheral vascular disease were independently associated with an increased risk for disability. Another study [15] reported that worsening disability was associated with higher low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs) in patients with MS.
Our group has performed some studies on the development of IR and the metabolic syndrome in chronic inflammatory diseases [16], [17] and these reports have found an important role of oxidative stress in the development and maintenance of these conditions. Previously, it also was verified that an association exists between disability and oxidative stress in patients with MS, but IR was not measured in that study [3].
IR and adiposity are important pathophysiological mechanisms related to atherosclerosis [18], but until now, we are not aware of any study that has evaluated the association of IR and adiposity with disability in patients with MS. Additionally, IR prevalence in individuals with MS, to our knowledge, has not been determined yet. Our hypothesis was that IR and adiposity would be associated with disability in patients with MS. Therefore, the aims of the present study were threefold: to report the prevalence of IR in individuals with MS; to verify differences in metabolic and inflammatory biomarkers, and oxidative stress in individuals with MS with or without IR; and to assess whether IR and adiposity are associated with EDSS in these individuals.
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Participants
The protocol was approved by the Institutional Research Ethics Committees of the State University of Londrina, Londrina, Paraná, Southern Brazil. All individuals invited to participate in the study were informed in detail about the research and a written consent form was obtained. The study consecutively included 110 patients with MS and 175 healthy volunteers. Control participants and MS patients were matched by age, sex, ethnicity, smoking, and body mass index (BMI).
The patients with MS were
Results
The clinical characteristics of the patients with MS are shown in Table 1. Among these patients, 98 (89.1%) presented RR-MS and only 12 (10.9%) presented SP-MS. With regard to the therapy, 81 (73.6%) were treated with IFN-β1a or 1b and 16 (14.5%) were treated with glatiramer acetate. The duration of the disease ranged from 2 to 10 y (median 7 y). The EDSS scores ranged from 1 to 4.5 (median 2.5).
The demographic, anthropometric, and metabolic characteristics in patients with MS and healthy
Discussion
Patients with MS exhibited higher prevalence (40%) of IR and presented 2.48 times more chance for developing IR compared with healthy individuals. Patients with MS and IR had higher disability shown by EDSS than those patients without IR. Additionally, IR and adiposity were associated with EDSS. These findings suggest that IR and adiposity may be involved with the progression of disability in MS.
Of note, patients with MS presented higher IR than controls, whereas BMI and WC did not show any
Conclusion
This is the first study to demonstrate an increase IR prevalence and the association between IR and adiposity with disability assessed by EDSS in individuals with MS. More studies are warranted to elucidate the mechanisms by which IR and adiposity could contribute to the progression and disability in patients with MS.
Acknowledgments
This study was supported by grants obtained from the Institutional Program for Scientific Initiation Scholarship (PIBIC) of the National Council for Scientific and Technological Development (CNPq); State University of Londrina (PROPPG); and Bayer HealthCare. The authors acknowledge the State University of Londrina, the University Hospital of the State University of Londrina, and HUTEC for their technical and administrative support.
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Cited by (0)
SRO was responsible for the conception and design of the study, laboratory analysis, and interpretation of data. ANCS was involved with the conception and design of the study, interpretation of data, revision of the manuscript, and approval of the final version of the manuscript. APK, ERDA, and HKM: were responsible for laboratory analysis. JL and DRK-M were involved with the clinical evaluation of MS patients (EDSS). ID and EMVR revised the manuscript and approved the final version of the manuscript. The authors declare there are no conflicts of interest.