PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of annrheumdAnnals of the Rheumatic DiseasesCurrent TOCInstructions for authors
 
Ann Rheum Dis. Apr 2007; 66(4): 558–559.
PMCID: PMC1856029
Improved insulin sensitivity by anti‐TNFα antibody treatment in patients with rheumatic diseases
Frank C Huvers, Calin Popa, Mihai G Netea, Frank H J van den Hoogen, and Cees J Tack
Frank C Huvers, Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Calin Popa, Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Mihai G Netea, Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Frank H J van den Hoogen, Department of Rheumatology, Sint Maartenskliniek, Nijmegen, The Netherlands
Cees J Tack, Department of General Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
Correspondence to: Dr C Popa
Department of Rheumatology, Radboud University Nijmegen Medical Centre, P O Box 9101, Nijmegen 6500 HB, The Netherlands; c.popa@aig.umcn.nl
Accepted October 10, 2006.
Insulin resistance is a key factor in the pathogenesis of the metabolic syndrome and type 2 diabetes, but the underlying mechanisms remain poorly understood. Adipocytokines, including tumour necrosis factor α (TNFα), interleukin 6, leptin and adiponectin,1,2 are increasingly recognised as important regulators of both insulin sensitivity, as well as inflammation, and a dysregulation of their levels and/or functions has been shown in both obesity and rheumatoid arthritis.3 Further investigations have substantiated the important negative effects of TNFα on insulin‐mediated glucose uptake and the development of insulin resistance.4 In this study, the influence of therapeutic TNFα blockade on insulin sensitivity was investigated in regularly treated patients with rheumatic diseases.
A group of eight patients who were non‐diabetic and having various chronic inflammatory disorders (table 11)) were investigated in an open prospective study design. Patients were attending the outpatient clinic of the Sint Maartenskliniek in Nijmegen and entered the study after giving their written informed consent. The regional medical ethical committee approved the study. Patients started the treatment with infliximab (3 mg/kg) and were followed up over a period of 6 weeks. During this interval, the additional antirheumatic drugs remained unchanged. Table 11 gives the patient characteristics. Hyperinsulinaemic–euglycaemic clamps were performed as described in detail elsewhere5,6 before each anti‐TNF infusion, and the M value was used to quantify insulin sensitivity.5,6 At baseline, two patients with rheumatoid arthritis had both a higher fasting glucose concentration and a slight decrease in insulin sensitivity, and an additional four had low‐insulin sensitivity. This suggests that our group of patients were characterised by insulin resistance, which is in line with previous reports.3 Although, TNFα neutralisation was previously reported to fail to improve insulin sensitivity in obese non‐insulin dependent patients with diabetes,7 in this study, it improved insulin sensitivity in seven patients (5.09 (6.24) at baseline vs 6.56 (8.97) after 6 weeks, p = 0.05), restored insulin sensitivity within the normal ranges in three patients, whereas TNF neutralisation slightly worsened insulin sensitivity in one patient (fig 1A1A)) who had ankylosing spondylitis and manifestations of peripheral arthritis (table 11).). Our findings are in line with previous studies, which reported that anti‐TNF agents corrected disturbances in glucose metabolism in patients with rheumatoid arthritis.8,9 To our knowledge, our study is the first to apply hyperinsulinaemic–euglycaemic clamps, the gold standard method for assessing insulin sensitivity, in documenting this effect.
Table thumbnail
Tabel 1 Characteristics of study participants
figure ar62323.f1
Figure 1 (A) Effects of anti‐tumour necrosis factor (TNF) therapy on insulin sensitivity. M values were calculated as the average glucose infusion rate during the last 30 min, the plateau phase, of the clamp.5,6 The lowest limit (more ...)
During our study, except for one patient who later turned out to have Whipple's disease, TNFα neutralisation was accompanied by a considerable decrease in DAS28 and ESR (table 11).). We therefore hypothesised that the suppression of the inflammatory cascade might be responsible for the improvement of observed insulin sensitivity.4 However, no significant correlation between disease activity or other inflammatory markers and insulin sensitivity at both time points could be detected. Interestingly, the improvement in insulin sensitivity correlated negatively with the baseline BMI (r = −0.83, p = 0.01) in our study (fig 1B1B).). This finding was unexpected and an explanation for that is currently under investigation in our laboratory.
In conclusion, using the hyperinsulinaemic–euglycaemic clamp technique, we found that TNFα blockade in patients with chronic inflammatory conditions improves insulin sensitivity, which is likely to be mainly due to the reduction of the inflammatory status. This change may decrease long‐term cardiovascular risk in rheumatoid arthritis.
Footnotes
Competing interests: None declared.
1. Wallen K E, Hotamisligil G S. Inflammation, stress, and diabetes. J Clin Invest 2005. 1151111–1119.1119. [PMC free article] [PubMed]
2. Fantuzzi G. Adipose tissue, adipokines, and inflammation. J Allergy Clin Immunol 2005. 115911–919.919. [PubMed]
3. Svenson K L G, Lundqvist G, Wide L., Hällgren Impaired glucose handling in active rheumatoid arthritis: relationship to the secretion of insulin and counter‐regulatory hormones. Metabolism 1987. 36940–943.943. [PubMed]
4. Uysal K T, Wiesbrock S M, Marino M W, Hotamisligi G S. Protection from obesity‐induced insulin resistance in mice lacking TNF‐alpha function. Nature 1997. 389610–614.614. [PubMed]
5. Keijzers G B, de Galan B E, Tack C J, Smits P. Caffeine can decrease insulin sensitivity in humans. Diabetes care 2002. 25364–369.369. [PubMed]
6. Tack C J, Ong M K, Lutterman J A, Smits P. Insulin‐induced vasodilatation and endothelial function in obesity/insulin resistance. Effects of troglitazone. Diabetologia 1998. 41569–576.576. [PubMed]
7. Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R. Effects of an engineered human anti‐TNF‐alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 1996. 45881–885.885. [PubMed]
8. Yazdani‐Biuki B, Stelzl H, Brezinschek H P, Hermann J, Mueller T, Krippl et al Improvement of insulin sensitivity in insulin resistant subjects during prolonged treatment with anti‐TNF‐α antibody infliximab. Eur J Clin Invest 2004. 34641–642.642. [PubMed]
9. Kiortsis D N, Mavridis A K, Vasakos S, Nikas S N, Drosos A A. Effects of infliximab treatment on insulin resistance in patients with rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis 2005. 64765–766.766. [PMC free article] [PubMed]
Articles from Annals of the Rheumatic Diseases are provided here courtesy of
BMJ Group