Horm Metab Res 2011; 43(11): 801-808
DOI: 10.1055/s-0031-1287783
Humans, Clinical
© Georg Thieme Verlag KG Stuttgart · New York

Systemic Blockade of TNF-α does not Improve Insulin Resistance in Humans

I. Ferraz-Amaro
1   Servicio de Reumatología, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain
,
M. Arce-Franco
1   Servicio de Reumatología, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain
,
J. Muñiz
2   IMETISA, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain
,
J. López-Fernández
3   Servicio de Endocrinología, La Laguna, Santa Cruz de Tenerife, Spain
4   Departamento de Medicina, Facultad de Medicina, Universidad de La Laguna, La Laguna, Santa Cruz de Tenerife, Spain
,
V. Hernández-Hernández
1   Servicio de Reumatología, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain
,
A. Franco
5   Laboratorio de Inmunología, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain
,
J. Quevedo
6   Servicio de Reumatología, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canarias, Spain
,
J. Martínez-Martín
7   Servicio de Endocrinología, Hospital Universitario Dr. Negrin, Las Palmas de Gran Canarias, Spain
,
F. Díaz-González
1   Servicio de Reumatología, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain
4   Departamento de Medicina, Facultad de Medicina, Universidad de La Laguna, La Laguna, Santa Cruz de Tenerife, Spain
› Author Affiliations
Further Information

Publication History

received 03 July 2011

accepted 26 August 2011

Publication Date:
18 October 2011 (online)

Abstract

The purpose of this study was to determine whether long-term modulation of inflammatory activity by tumor necrosis factor (TNF)-α inhibitors has some influence on insulin resistance (IR). 16 active rheumatoid arthritis (RA) patients without CV risk factors treated with anti-TNF-α agents were included in this study. RA activity by disease activity score 28, IR by HOMA2-IR, body composition by impedance analysis, physical activity by accelerometry, abdominal fat distribution by magnetic resonance imaging, and serum level of key adipokines by ELISA were measured at baseline and during a 1-year follow-up period. Patient body mass index increased significantly (26.94±3.88 vs. 28.06±4.57 kg/m2, p=0.02) after 1 year of treatment. Body composition, in terms of fat and fat-free mass, remained unchanged except for a significant elevation in body cell mass (25.50±4.60 vs. 26.60±3.17 kg, p=0.02). Basal levels of IR in the RA patients included in this study were significantly higher than healthy controls (1.6±0.8 vs. 1.11±0.56, p=0.011) but did not change during the follow-up. Nor did basal concentrations of adiponectin, visfatin, leptin, ghrelin, resistin, and apelin in response to anti-TNF-α treatment; only retinol-binding protein 4, showed a significant increase (51.7±32.7 vs. 64.9±28.4 μg/ml, p=0.03) at the end of the study. IR, adiposity distribution, and serum levels of most adipokines are not significantly affected by long-term inhibition of TNF-α in RA patients. Our data suggest that although systemic blockade of TNF-α exerts an anticachectic effect in RA patients, it does not seem to play a major role in IR.

 
  • References

  • 1 Libby P. Role of inflammation in atherosclerosis associated with rheumatoid arthritis. Am J Med 2008; 121: S21-S31
  • 2 Sokka T, Abelson B, Pincus T. Mortality in rheumatoid arthritis: 2008 update. Clin and Exp Rheumatol 2008; 26: S35-S61
  • 3 Zhang H, Park Y, Wu J, Chen X, Lee S, Yang J, Dellsperger KC, Zhang C. Role of TNF-alpha in vascular dysfunction. Clin Sci (Lond) 2009; 116: 219-230
  • 4 Cawthorn WP, Sethi JK. TNF-alpha and adipocyte biology. FEBS Lett 2008; 582: 117-131
  • 5 Klareskog L, van der Heijde D, de Jager JP, Gough A, Kalden J, Malaise M, Martin Mola E, Pavelka K, Sany J, Settas L, Wajdula J, Pedersen R, Fatenejad S, Sanda M. Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomised controlled trial. Lancet 2004; 363: 675-681
  • 6 Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, Smolen J, Emery P, Harriman G, Feldmann M, Lipsky P. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999; 354: 1932-1939
  • 7 Weinblatt ME, Keystone EC, Furst DE, Moreland LW, Weisman MH, Birbara CA, Teoh LA, Fischkoff SA, Chartash EK. Adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003; 48: 35-45
  • 8 Kaplan MJ. Do tumor-necrosis-factor inhibitors prevent first cardiovascular events in patients with rheumatoid arthritis?. Nat Clin Pract Rheumatol 2005; 1: 74-75
  • 9 Listing J, Strangfeld A, Kekow J, Schneider M, Kapelle A, Wassenberg S, Zink A. Does tumor necrosis factor alpha inhibition promote or prevent heart failure in patients with rheumatoid arthritis?. Arthritis Rheum 2008; 58: 667-677
  • 10 Barnabe C, Martin BJ, Ghali WA. Systematic review and meta-analysis: Anti-tumor necrosis factor alpha therapy and cardiovascular events in rheumatoid arthritis. Arthritis Care Res 2011; 63: 522-529
  • 11 DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14: 173-194
  • 12 Shahin D, Eltoraby E, Mesbah A, Houssen M. Insulin resistance in early untreated rheumatoid arthritis patients. Clin Biochem 2010; 43: 661-665
  • 13 Bregenzer N, Hartmann A, Strauch U, Scholmerich J, Andus T, Bollheimer LC. Increased insulin resistance and beta cell activity in patients with Crohn’s disease. Inflamm Bowel Dis 2006; 12: 53-56
  • 14 Gonzalez-Gay MA, De Matias JM, Gonzalez-Juanatey C, Garcia-Porrua C, Sanchez-Andrade A, Martin J, Llorca J. Anti-tumor necrosis factor-alpha blockade improves insulin resistance in patients with rheumatoid arthritis. Clin Exp Rheumatol 2006; 24: 83-86
  • 15 Oguz FM, Oguz A, Uzunlulu M. The effect of infliximab treatment on insulin resistance in patients with rheumatoid arthritis. Acta Clin Belg 2007; 62: 218-222
  • 16 Seriolo B, Ferrone C, Cutolo M. Longterm anti-tumor necrosis factor-alpha treatment in patients with refractory rheumatoid arthritis: relationship between insulin resistance and disease activity. J Rheumatol 2008; 35: 355-357
  • 17 Tam LS, Tomlinson B, Chu TT, Li TK, Li EK. Impact of TNF inhibition on insulin resistance and lipids levels in patients with rheumatoid arthritis. Clin Rheumatol 2007; 26: 1495-1498
  • 18 Lo J, Bernstein LE, Canavan B, Torriani M, Jackson MB, Ahima RS, Grinspoon SK. Effects of TNF-alpha neutralization on adipocytokines and skeletal muscle adiposity in the metabolic syndrome. Am J Physiol Endocrinol Metab 2007; 293: E102-E109
  • 19 Martinez-Abundis E, Reynoso-von Drateln C, Hernandez-Salazar E, Gonzalez-Ortiz M. Effect of etanercept on insulin secretion and insulin sensitivity in a randomized trial with psoriatic patients at risk for developing type 2 diabetes mellitus. Arch Dermatol Res 2007; 299: 461-465
  • 20 Rosenvinge A, Krogh-Madsen R, Baslund B, Pedersen BK. Insulin resistance in patients with rheumatoid arthritis: effect of anti-TNFalpha therapy. Scand J Rheumatol 2007; 36: 91-96
  • 21 Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315-324
  • 22 Prevoo ML, van’t Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight-joint counts. Development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995; 38: 44-48
  • 23 Fransen J, van Riel PL. The Disease Activity Score and the EULAR response criteria. Clin Exp Rheumatol 2005; 23: S93-S99
  • 24 Powell SM, Jones DI, Rowlands AV. Technical variability of the RT3 accelerometer. Med Sci Sports Exerc 2003; 35: 1773-1778
  • 25 Kyle UG, Bosaeus I, De Lorenzo AD, Deurenberg P, Elia M, Gomez JM, Heitmann BL, Kent-Smith L, Melchior JC, Pirlich M, Scharfetter H, Schols AM, Pichard C. Bioelectrical impedance analysis – part I: review of principles and methods. Clin Nutr 2004; 23: 1226-1243
  • 26 Kyle UG, Bosaeus I, De Lorenzo AD, Deurenberg P, Elia M, Manuel Gomez J, Lilienthal Heitmann B, Kent-Smith L, Melchior JC, Pirlich M, Scharfetter H, MWJS A, Pichard C. Bioelectrical impedance analysis-part II: utilization in clinical practice. Clin Nutr 2004; 23: 1430-1453
  • 27 Thomas EL, Saeed N, Hajnal JV, Brynes A, Goldstone AP, Frost G, Bell JD. Magnetic resonance imaging of total body fat. J Appl Physiol 1998; 85: 1778-1785
  • 28 Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care 2004; 27: 1487-1495
  • 29 Mojiminiyi OA, Abdella NA. Effect of homeostasis model assessment computational method on the definition and associations of insulin resistance. Clin Chem Lab Med 2010; 48: 1629-1634
  • 30 Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR, Wason CJ, Oberbach A, Jansson PA, Smith U, Kahn BB. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med 2006; 354: 2552-2563
  • 31 Muniyappa R, Lee S, Chen H, Quon MJ. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab 2008; 294: E15-E26
  • 32 Everhart JE, Lok AS, Kim HY, Morgan TR, Lindsay KL, Chung RT, Bonkovsky HL, Ghany MG. Weight-related effects on disease progression in the hepatitis C antiviral long-term treatment against cirrhosis trial. Gastroenterology 2009; 137: 549-557
  • 33 Bingley PJ, Mahon JL, Gale EA. Insulin resistance and progression to type 1 diabetes in the European Nicotinamide Diabetes Intervention Trial (ENDIT). Diabetes Care 2008; 31: 146-150
  • 34 Claesson M, Birgander LS, Jansson JH, Lindahl B, Burell G, Asplund K, Mattsson C. Cognitive-behavioural stress management does not improve biological cardiovascular risk indicators in women with ischaemic heart disease: a randomized-controlled trial. J Int Med 2006; 260: 320-331
  • 35 Dessein PH, Joffe BI. Insulin resistance and impaired beta cell function in rheumatoid arthritis. Arthritis Rheumat 2006; 54: 2765-2775
  • 36 Kiortsis DN, Mavridis AK, Vasakos S, Nikas SN, Drosos AA. Effects of infliximab treatment on insulin resistance in patients with rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis 2005; 64: 765-766
  • 37 Hecht A, Ma S, Porszasz J, Casaburi R. Methodology for using long-term accelerometry monitoring to describe daily activity patterns in COPD. COPD 2009; 6: 121-129
  • 38 Klassen L, Schachter C, Scudds R. An exploratory study of two measures of free-living physical activity for people with multiple sclerosis. Clin Rehabil 2008; 22: 260-271
  • 39 Summers GD, Deighton CM, Rennie MJ, Booth AH. Rheumatoid cachexia: a clinical perspective. Rheumatology (Oxford) 2008; 47: 1124-1131
  • 40 Marcora SM, Chester KR, Mittal G, Lemmey AB, Maddison PJ. Randomized phase 2 trial of anti-tumor necrosis factor therapy for cachexia in patients with early rheumatoid arthritis. Am J Clin Nutr 2006; 84: 1463-1472
  • 41 Metsios GS, Stavropoulos-Kalinoglou A, Douglas KM, Koutedakis Y, Nevill AM, Panoulas VF, Kita M, Kitas GD. Blockade of tumour necrosis factor-alpha in rheumatoid arthritis: effects on components of rheumatoid cachexia. Rheumatology (Oxford) 2007; 46: 1824-1827
  • 42 Serelis J, Kontogianni MD, Katsiougiannis S, Bletsa M, Tektonidou MG, Skopouli FN. Effect of anti-TNF treatment on body composition and serum adiponectin levels of women with rheumatoid arthritis. Clin Rheumatol 2008; 27: 795-797
  • 43 Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest 2000; 106: 473-481
  • 44 Dittmar M, Reber H. New equations for estimating body cell mass from bioimpedance parallel models in healthy older Germans. Am J Physiol Endocrinol Metab 2001; 281: E1005-E1014
  • 45 Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA. Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001; 86: 1930-1935
  • 46 Gonzalez-Gay MA, Llorca J, Garcia-Unzueta MT, Gonzalez-Juanatey C, De Matias JM, Martin J, Redelinghuys M, Woodiwiss AJ, Norton GR, Dessein PH. High-grade inflammation, circulating adiponectin concentrations and cardiovascular risk factors in severe rheumatoid arthritis. Clin Exp Rheumatol 2008; 26: 596-603
  • 47 Harle P, Sarzi-Puttini P, Cutolo M, Straub RH. No change of serum levels of leptin and adiponectin during anti-tumour necrosis factor antibody treatment with adalimumab in patients with rheumatoid arthritis. Ann Rheum Dis 2006; 65: 970-971
  • 48 Popa C, Netea MG, de Graaf J, van den Hoogen FH, Radstake TR, Toenhake-Dijkstra H, van Riel PL, van der Meer JW, Stalenhoef AF, Barrera P. Circulating leptin and adiponectin concentrations during tumor necrosis factor blockade in patients with active rheumatoid arthritis. J Rheumatol 2009; 36: 724730
  • 49 Gonzalez-Gay MA, Garcia-Unzueta MT, Berja A, Vazquez-Rodriguez TR, Gonzalez-Juanatey C, de Matias JM, Martin J, Dessein PH, Llorca J. Anti-tumour necrosis factor alpha therapy modulates ghrelin in patients with severe rheumatoid arthritis. Ann Rheum Dis 2008; 67: 1644-1646
  • 50 Gonzalez-Gay MA, Garcia-Unzueta MT, Gonzalez-Juanatey C, Miranda-Filloy JA, Vazquez-Rodriguez TR, De Matias JM, Martin J, Dessein PH, Llorca J. Anti-TNF-alpha therapy modulates resistin in patients with rheumatoid arthritis. Clin Exp Rheumatol 2008; 26: 311-316
  • 51 Hector J, Schwarzloh B, Goehring J, Strate TG, Hess UF, Deuretzbacher G, Hansen-Algenstaedt N, Beil FU, Algenstaedt P. TNF-alpha alters visfatin and adiponectin levels in human fat. Horm Metab Res 2007; 39: 250-255
  • 52 Matsui H, Tsutsumi A, Sugihara M, Suzuki T, Iwanami K, Kohno M, Goto D, Matsumoto I, Ito S, Sumida T. Visfatin (pre-B cell colony-enhancing factor) gene expression in patients with rheumatoid arthritis. Ann Rheum Dis 2008; 67: 571-572
  • 53 Cho YM, Youn BS, Lee H, Lee N, Min SS, Kwak SH, Lee HK, Park KS. Plasma retinol-binding protein-4 concentrations are elevated in human subjects with impaired glucose tolerance and type 2 diabetes. Diabetes Care 2006; 29: 2457-2461
  • 54 Sell H, Eckel J. Regulation of retinol binding protein 4 production in primary human adipocytes by adiponectin, troglitazone and TNF-alpha. Diabetologia 2007; 50: 2221-2223
  • 55 Seriolo B, Paolino S, Ferrone C, Cutolo M. Effects of etanercept or infliximab treatment on lipid profile and insulin resistance in patients with refractory rheumatoid arthritis. Clin Rheumatol 2007; 26: 1799-1800