Division of Rheumatology, Yale University, New Haven, CT, USAUnited States
Instructor, Mount Auburn Hospital and Harvard University, Cambridge, MA, USAUnited States
Internal Medicine, New York Medical College, Valhalla, NY, USAUnited States
Attending Physician, Middlesex Hospital Endocrinology, Middletown, CT, USAUnited States
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Insulin resistance is a key feature of obesity, metabolic syndrome, and Type 2 Diabetes Mellitus (T2DM). Inflammation and insulin resistance are closely linked with each other. I. Tumor necrosis factor-α (TNF-α) has been found to impair the insulin sensitivity and promote insulin resistance through multiple actions on the insulin sensitive tissues. Inflammatory cyto-kines such as TNF, Interleukin (IL)-6, IL-1 and IL-8 may inhibit insulin signaling.1 Hotamisligil et al2 did the pioneering work in 1993 confirming the link between TNF-α and insulin resis-tance in mice. Animal studies have confirmed that the TNF-α interferes with phosphorylation cascades of the insulin receptor beta subunit and insulin receptor substrate-1, thereby alter-ing the transmembrane signaling that is essential for insulin action in various insulin sensitive tissues.3-5 Also TNF-α causes depletion of GLUT 4, the insulin sensitive glucose transporter in adipocytes and muscles.2,6,7 A intravenous administration of a recombinant TNF-α receptor antibody resulted in improvement in insulin sensitivity2 and dramatic reductions in plasma in-sulin, glucose, and non-esterified fatty acid levels5 in obese, as compared with lean rats.
Hypothesis Tumor Necrosis Factor Inhibitors May * *Corresponding author Improve Glycemic Control in Patients Abhijeet Danve, MD Assistant Clinical Professor Division of Rheumatology Rheumatoid Arthritis and Concomitant Yale University, New Haven CT 06067, USA Type 2 Diabetes Mellitus E-mail: abhijeet.danve@yale.edu Volume 1 : Issue 2 1* 2 3 4 Abhijeet Danve, MD ; Shivtej Sehra, MD ; Divya jaykumar, MD ; Supriya Kulkarni, MD Article Ref. #: 1000ORHOJ1106 1Division of Rheumatology, Yale University, New Haven, CT, USA Article History 2 Instructor, Mount Auburn Hospital and Harvard University, Cambridge, MA, USA th Received: August 15th, 2016 3 st Internal Medicine, New York Medical College, Valhalla, NY, USA Accepted: September 1 , 2016 th 4Attending Physician, Middlesex Hospital Endocrinology, Middletown, CT, USA Published: September 6 , 2016 Citation Insulin resistance is a key feature of obesity, metabolic syndrome, and Type 2 Diabetes Danve A, Sehra S, Jaykumar D, Mellitus (T2DM). Inflammation and insulin resistance are closely linked with each other. I. Kulkarni S. Tumor necrosis factor in- hibitors may improve glycemic control Tumor necrosis factor-α (TNF-α) has been found to impair the insulin sensitivity and promote in patients rheumatoid arthritis and insulin resistance through multiple actions on the insulin sensitive tissues. Inflammatory cyto- concomitant diabetes mellitus.Osteol kines such as TNF, Interleukin (IL)-6, IL-1 and IL-8 may inhibit insulin signaling. Hotamisligil Rheumatol Open J. 2016; 1(2): 17-19. 2 et al did the pioneering work in 1993 confirming the link between TNF-α and insulin resis- doi: 10.17140/ORHOJ-1-106 tance in mice. Animal studies have confirmed that the TNF-α interferes with phosphorylation cascades of the insulin receptor beta subunit and insulin receptor substrate-1, thereby alter- ing the transmembrane signaling that is essential for insulin action in various insulin sensitive 3-5 tissues.3-5 Also TNF-α causes depletion of GLUT 4, the insulin sensitive glucose transporter 2,6,7 in adipocytes and muscles. A intravenous administration of a recombinant TNF-α receptor antibody resulted in improvement in insulin sensitivity2 and dramatic reductions in plasma in- sulin, glucose, and non-esterified fatty acid levels5 in obese, as compared with lean rats. These findings suggested that TNF-α inhibitors (TNFi) could be used for the treatment of T2DM. But initial two human clinical trials of anti TNF-α antibodies for treatment T2DM 8,9 failed to show statistically significant improvement in insulin sensitivity.8,9 These studies how- ever had few limitations; they had short duration of treatment, small number of patients and were underpowered.
Short-term treatment with etanercept over 4 weeks was associated with beneficial ef- fect on reduction of the inflammatory markers, but no improvement in vascular or metabolic insulin sensitivity in 20 adult patients with T2DM in an open labeled study.10 In 2011, a pro- spective study of 40 patients of metabolic syndrome without diabetes, prolonged therapy with etanercept for 6 months clearly showed improved fasting glucose, increased the ratio of high molecular weight to total adiponectin, and decreased soluble intercellular adhesion molecule-1 (sICAM-1) . In another study TNF-α antagonism with etanercept was associated with reduction in glucose level and increase in the proportion of high molecular weight adiponectin in obese patient’s metabolic syndrome.11 Copyright © 2016 Danve A. This is an open Rheumatoid Arthritis (RA) is autoimmune inflammatory disease involving joints and access article distributed under the extra-particular tissues. T2DM patients are at increased risk of developing RA. A large nation- Creative Commons Attribution 4.0 wide population based case control study showed elevated risk of RA in female Taiwanese International License (CC BY 4.0), 12 patients with T2DM. Similarly, patients with RA are also at increased risk of developing dia- which permits unrestricted use, distribution, and reproduction in betes.13 There is a direct correlation between the degree of impaired glucose handling and the any medium, provided the original severity of the inflammatory activity in patients with RA. Dessein and colleagues14 reported an work is properly cited.
increased prevalence of insulin resistance as assessed by the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) and the Quantitative Insulin itant T2DM are more likely to have difficult to control diabe- Sensitivity Check Index (QUICKI) in patients with inflammato- tes by virtue of increased insulin resistance caused by elevated ry arthritis, including RA, spondyloarthritis, and undifferentiat- TNF-α levels. Anti-TNF therapy should lead to improved insulin ed inflammatory arthritis, as compared to in healthy controls. In resistance and improved diabetes control. There is no large study this study, insulin resistance was associated with several markers available to evaluate the effect of TNF inhibitor therapy on the of inflammation, including TNF-α, interleukin (IL)-6, Erythro- control of the concomitant diabetes in patients with rheumatic cyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP), diseases. We hypothesize that patients with RA and concomi- and measures of disease activity and damage. Moreover, in this tant T2DM who are on TNFi have better controlled diabetes as series of patients with RA insulin resistance was associated with compared to those who are on conventional DMARDS. We also coronary calcifications as well. These results point towards the hypothesize that patients with RA and DM on TNFi have lower role of insulin resistance and inflammation in the pathogenesis risk of cardiovascular disease as compared to those on tradi- of coronary atherosclerosis in RA.15 Circulating TNF-α is also tional DMARDS by virtue of control of inflammatory activity an important mediator of endothelial dysfunction and has been in both DM and RA. We look forward for prospective studies in implicated in increased cardiovascular risk in patients with this interesting area of research.
CONFLICT OF INTEREST TNF-α is the major cytokine involved in the immu- nopathogenesis of RA. Excellent response to TNFi therapy has The authors declare they have no conflicts of interest.
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