Adipose Depots, Not Disease-related Factors, Account for Skeletal Muscle Insulin Sensitivity in Established and Treated Rheumatoid Arthritis

Abstract

Objectives In prior reports, individuals with rheumatoid arthritis (RA) exhibited increased insulin resistance. However, these studies were limited by either suboptimal assessment methods for insulin sensitivity or a failure to account for important determinants, adiposity and physical activity. Our objectives were to carefully assess, compare and determine predictors of skeletal muscle insulin sensitivity (SI) in RA, accounting for adiposity and physical activity. Methods Thirty-nine individuals with established (seropositive or erosions) and treated RA and 39 age, gender, race, BMI, and physical activity-matched controls underwent a frequently-sampled intravenous glucose tolerance test to determine SI. Inflammation, body composition, and physical activity were assessed with systemic cytokine measurements, CT scans, and accelerometry, respectively. Exclusions were diabetes, cardiovascular disease, medication changes within three months, and prednisone use over 5 mg/d. This investigation was powered to detect a clinically significant, moderate effect size for SI difference. Results Despite elevated systemic inflammation (interleukin (IL)-6, IL-18, tumor necrosis factor-alpha; P<0.05 for all), persons with RA were not less insulin sensitive (SI geometric mean (SD): RA 4.0 (2.4) versus Control 4.9 (2.1)*10−5 min−1/[pmol/l]; P=0.39). Except for visceral adiposity being slightly greater in controls (P=0.03), there were no differences in body composition or physical activity. Lower SI was independently associated with increased abdominal and thigh adiposity, but not with cytokines, disease activity, duration, disability, or disease modifying medication use. Conclusions In established and treated RA, traditional risk factors, specifically excess adiposity, play more of a role in predicting skeletal muscle insulin sensitivity than systemic inflammation or other disease-related factors.

Cachexia and adiposity in rheumatoid arthritis. Relevance for disease management and clinical outcomes

“…For both men and women, being over the 75th percentile of VF increased the risk of high fasting glucose and metabolic syndrome [27]. In another study in established treated RA, visceral adiposity was associated with insulin resistance, but was not more prevalent in RA than in controls [30]. Conversely, in another study the HOMA-IR, that expressed insulin resistance, was not modified in RA [31].…”

Molecular alterations in skeletal muscle in rheumatoid arthritis are related to disease activity, physical inactivity, and disability

“…Exclusions included current pregnancy, type 2 diabetes mellitus, and known coronary artery disease. Further specific details on questionnaires and measurement protocols have previously been described [5]. This study was in compliance with the Helsinki Declaration and was approved by the Duke University Institutional Review Board.…”

“…Assessments of both groups included questionnaires, physical exams for disease status, fasting blood collection, intravenous glucose tolerance tests for insulin sensitivity, 7 days of accelerometer-measured physical activity, computed tomography (CT) imaging of abdomen and thigh, and vastus lateralis muscle biopsies [5]. Disability (health assessment questionnaire-disability index (HAQ-DI) and co-morbidities (co-morbidity index) were assessed by previously published questionnaires [6, 7].…”

“…Disease activity assessed by the disease activity score in 28 joints (DAS-28) was determined from a patient-completed visual analog scale, physician-determined numbers of tender and swollen joints, and erythrocyte sedimentation rate [8]. Plasma concentrations of inflammatory markers and cytokines were determined by immunoassay [5] and nuclear magnetic resonance (NMR) spectroscopy (GlycA) [9]. Insulin sensitivity was determined using Bergman’s minimal model [10] and concentrations of glucose and insulin (glucose: Beckman-CoulterDXC600; insulin: electrochemiluminscent assay from Meso Scale Discovery) at each of 29 time points during the intravenous glucose tolerance test.…”

Is Visceral Fat the Missing Link in the Relationship Between Inflammation and Insulin Resistance in RA?

“…In this issue of The Journal, AbouAssi and colleagues present a meticulous and thorough evaluation of insulin sensitivity in 39 patients with RA and 39 control subjects matched for not only age and sex, but also for BMI and physical activity 15 . Insulin sensitivity was quantified by frequently sampled intravenous glucose tolerance test (FSIVGTT).…”