Metabolic and Vascular Effects of Tumor Necrosis Factor-α Blockade with Etanercept in Obese Patients with Type 2 Diabetes

Abstract

Objective: The pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) impairs insulin action in insulin-sensitive tissues, such as fat, muscle and endothelium, and causes endothelial dysfunction. We hypothesized that TNF-α blockade with etanercept could reverse vascular and metabolic insulin resistance. Method and Results: Twenty obese patients with type 2 diabetes were randomized to etanercept treatment (25 mg subcutaneously twice weekly for 4 weeks) or used as controls in an open parallel study. Forearm blood flow and glucose uptake were measured during intra-arterial infusions of serotonin, sodium nitroprusside and insulin co-infused with serotonin. β-Cell function was assessed with oral and intra-venous glucose tolerance tests and whole-body insulin sensitivity by hyperinsulinemic euglycemic clamps. Plasma levels of C-reactive protein and interleukin-6 decreased significantly with etanercept (C-reactive protein from 9.9 ± 3.1 to 4.8 ± 1.4 mg l^–1, p = 0.04; interleukin-6 from 3.1 ± 0.4 to 1.9 ± 0.2 ng l^–1, p = 0.03). Vasodilatory responses to serotonin and sodium nitroprusside infusions remained unchanged. Insulin effect on vasodilatation and on whole-body and forearm glucose uptake remained unchanged as well. β-Cell function tended to improve. Conclusion: Although short-term etanercept treatment had a significant beneficial effect on systemic inflammatory markers, no improvement of vascular or metabolic insulin sensitivity was observed.

Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes

“…However, TNF-α antagonism has not demonstrated significant improvement on insulin sensitivity in patients with metabolic syndrome [76] or T2DM [77,78], but these pilot studies were probably underpowered as they were conducted on a short-time period in a limited number of patients. Further longer and bigger studies are warranted, especially because TNF-α antagonism treatment in non-diabetic patients with rheumatoid polyarthritis improves their insulin sensitivity [79].…”

Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?

“…Further pharmacological agents inhibiting inflammatory signaling such as etanercept, which inhibits TNFa, and chaperone proteins, which inhibit ER stress, were used in obese patients with insulin resistance and resulted in metabolic benefits (Dominguez et al, 2005;Ozcan et al, 2006). However, Dominguez and coworkers revealed only benefit on b-cell function with etanercept treatment, suggesting that it may not be a valuable treatment for NAFLD.…”

Adipose tissue macrophages inhibit adipogenesis of mesenchymal precursor cells via wnt-5a in humans

“…6 On a molecular level, in murine cell culture models and mice, adipose tissue development and function has been shown to be altered by the proinflammatory cytokine tumour necrosis factor-a. 7 However, in human subjects treated with the anti-tumour necrosis factor-a antibody adalimumab 8 or the soluble tumour necrosis factor-a receptor etanercept, 9 insulin sensitivity was not significantly improved. These findings might suggest that in the human organism, macrophages affect adipose tissue biology via different bioactive molecules.…”