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

Objective. In prior reports, individuals with rheumatoid arthritis (RA) exhibited increased insulin resistance. However, those studies were limited by either suboptimal assessment methods for insulin sensitivity or a failure to account for important determinants such as adiposity and lack of physical activity. Our objectives were to carefully assess, compare, and determine predictors of skeletal muscle insulin sensitivity in RA, accounting for adiposity and physical activity. Methods. Thirty-nine individuals with established (seropositive or erosions) and treated RA and 39 controls matched for age, sex, race, body mass index, and physical activity underwent a frequently sampled intravenous glucose tolerance test to determine insulin sensitivity. Inflammation, body composition, and physical activity were assessed with systemic cytokine measurements, computed tomography scans, and accelerometry, respectively. Exclusions were diabetes, cardiovascular disease, medication changes within 3 months, and prednisone use over 5 mg/day. This investigation was powered to detect a clinically significant, moderate effect size for insulin sensitivity difference. Results. Despite elevated systemic inflammation [interleukin (IL)-6, IL-18, tumor necrosis factor-α; p < 0.05 for all], persons with RA were not less insulin sensitive [SI geometric mean (SD): RA 4.0 (2.4) vs 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 insulin sensitivity was independently associated with increased abdominal and thigh adiposity, but not with cytokines, disease activity, duration, disability, or disease-modifying medication use. Conclusion. In established and treated RA, traditional risk factors, specifically excess adiposity, play more of a role in predicting skeletal muscle insulin sensitivity than do systemic inflammation or other disease-related factors.

[1]  J. Eckel,et al.  Adipose tissue and its role in organ crosstalk , 2014, Acta physiologica.

[2]  L. El-Kadre,et al.  Interleukin-6 and obesity: the crosstalk between intestine, pancreas and liver , 2013, Current opinion in clinical nutrition and metabolic care.

[3]  P. Neufer,et al.  Lipid-induced mitochondrial stress and insulin action in muscle. , 2012, Cell metabolism.

[4]  W. Lems,et al.  Glucose tolerance, insulin sensitivity and β-cell function in patients with rheumatoid arthritis treated with or without low-to-medium dose glucocorticoids , 2011, Annals of the rheumatic diseases.

[5]  R. DeFronzo,et al.  Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes , 2009, Diabetes Care.

[6]  C. Berne,et al.  Glucose intolerance in patients with chronic inflammatory diseases is normalized by glucocorticoids. , 2009, Acta medica Scandinavica.

[7]  T. Pincus,et al.  Inflammation-associated insulin resistance: differential effects in rheumatoid arthritis and systemic lupus erythematosus define potential mechanisms. , 2008, Arthritis and rheumatism.

[8]  X. Papademetris,et al.  The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome , 2007, Proceedings of the National Academy of Sciences.

[9]  Mark A Hlatky,et al.  Clinical Utility of the Stanford Brief Activity Survey in Men and Women With Early-Onset Coronary Artery Disease , 2007, Journal of cardiopulmonary rehabilitation and prevention.

[10]  G. Gaesser,et al.  NIH ImageJ and Slice‐O‐Matic Computed Tomography Imaging Software to Quantify Soft Tissue , 2007, Obesity.

[11]  B. Pedersen,et al.  Insulin resistance in patients with rheumatoid arthritis: effect of anti‐TNFα therapy , 2007 .

[12]  B. Joffe,et al.  Editorial: should we evaluate insulin sensitivity in rheumatoid arthritis? , 2005, Seminars in arthritis and rheumatism.

[13]  S. Gabriel,et al.  Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis: a population-based cohort study. , 2005, Arthritis and rheumatism.

[14]  S. Studenski,et al.  Co-morbidity adjustment for functional outcomes in community-dwelling older adults , 2002, Clinical rehabilitation.

[15]  K. Ellis.  Human body composition: in vivo methods. , 2000, Physiological reviews.

[16]  R. N. Bergman,et al.  Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study , 1992, The Lancet.

[17]  G. Paolisso,et al.  Evidence for peripheral impaired glucose handling in patients with connective tissue diseases. , 1991, Metabolism: clinical and experimental.

[18]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[19]  H. Lithell,et al.  Impaired glucose handling in active rheumatoid arthritis: relationship to peripheral insulin resistance. , 1988, Metabolism: clinical and experimental.

[20]  Y. Z. Ider,et al.  Quantitative estimation of insulin sensitivity. , 1979, The American journal of physiology.

[21]  R. Imrich,et al.  Chronic inflammation and low-dose glucocorticoid effects on glucose metabolism in premenopausal females with rheumatoid arthritis free of conventional metabolic risk factors. , 2013, Physiological research.

[22]  J. Fries,et al.  The Stanford Health Assessment Questionnaire: a review of its history, issues, progress, and documentation. , 2003, The Journal of rheumatology.

[23]  M. Prevoo,et al.  Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. , 1995, Arthritis and rheumatism.