Tumor Necrosis Factor-α Antagonism Improves Vasodilation During Hyperinsulinemia in Metabolic Syndrome

Abstract

OBJECTIVE -Obesity is associated with chronic inflammation due to overproduction of proinflammatory cytokines, including tumor necrosis factor (TNF)-␣. We assessed the effects of TNF-␣ neutralization by infliximab on vascular reactivity during hyperinsulinemia in obesity-related metabolic syndrome. RESEARCH DESIGN AND METHODS-Vascular responses to intra-arterial infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in patients with metabolic syndrome, before and after administration of infliximab.RESULTS -Patients had blunted vasodilator responses to ACh and SNP during hyperinsulinemia compared with control subjects; a potentiation of the responsiveness to both ACh and SNP, however, was observed in patients following infliximab. The antioxidant vitamin C improved the vasodilator response to ACh in patients with metabolic syndrome, but its effect was not further enhanced by concurrent administration of infliximab.CONCLUSIONS -TNF-␣ neutralization ameliorates vascular reactivity in metabolic syndrome during hyperinsulinemia, likely in relation to decreased oxidative stress, thereby suggesting an involvement of inflammatory cytokines in vascular dysfunction of these patients. Diabetes Care 31:1439-1441, 2008C entral obesity is associated with lowgrade, chronic inflammation, which might affect insulin action and thus contribute to both insulin resistance and vascular dysfunction characteristic of metabolic syndrome. Among various inflammatory cytokines, tumor necrosis factor (TNF)-␣ seems to play an important role in the pathophysiology of insulin resistance. However, no clear link has been established between the vascular pathology of metabolic syndrome and a particular inflammatory cytokine in humans. This study, therefore, assessed the effects of TNF-␣ neutralization by the monoclonal antibody infliximab on vascular reactivity during hyperinsulinemia in metabolic syndrome. RESEARCH DESIGN ANDMETHODS -A total of 16 patients with metabolic syndrome (National Cholesterol Education Program Adult Treatment Panel [NCEP ATP] III criteria) and 13 healthy control subjects, approximately matched for sex and age, were recruited for this study. In all patients, waist circumference was Ͼ102 cm in male subjects and Ͼ88 cm in female subjects, thus indicating central obesity. Studies consisted of infusion of drugs into the brachial artery and measurement of forearm blood flow responses by means of straingauge plethysmography. In Study 1, control subjects and 10 patients with metabolic syndrome received infusion of regular insulin (0.2 mU ⅐ kg Ϫ1 ⅐ min Ϫ1 ); after 45 min of insulin infusion, doseresponse curves to graded doses of acetylcholine (ACh) (release of endogenous NO) and sodium nitroprusside (SNP) (exogenous NO donor) were obtained. Thereafter, while keeping insulin infusion constant, patients with metabolic syndrome received infusion of infliximab (200 g/min for 45 min) and doseresponse curves to ACh and SNP were repeated. In Study 2, to assess whether the effect of infliximab on vascular response...

Fish oil supplementation improves endothelial function in normoglycemic offspring of patients with type 2 diabetes

“…These observations are consistent with recent findings from our group that the TNF-α-neutralizing effect of infliximab is associated with increased endothelial function evaluated by intra-arterial infusion of acetylcholine in subjects with metabolic syndrome, and in particular those with increased insulin resistance [28]. …”

Vascular Generation of Tumor Necrosis Factor-α Reduces Nitric Oxide Availability in Small Arteries From Visceral Fat of Obese Patients

“…Recent reports have investigated a possible link between TNF-␣ and obesity-related vascular dysfunction, because the vasculature represents an important target for this cytokine (21). Tesauro et al (22) documented that infliximab ameliorated peripheral vascular dysfunction during hyperinsulinemia in obese patients by an antioxidant activity. More recently, a potential specific role of inflammation from perivascular adipose tissue in the pathogenesis of vascular dysfunction has been investigated.…”

Insights into the molecular mechanisms of diabetes-induced endothelial dysfunction: focus on oxidative stress and endothelial progenitor cells

“…TNF-a activates p47 phosphorylation at Ser379 by PKC which induces a conformational change that allows binding with both p22 and TRAF4, and stimulates its membrane translocation as well as the downstream activation of ERK1/2, p38 MAPK, and JNK [111]. Furthermore, TNF-a antagonist (infliximab) was successful in alleviating ED in metabolic syndrome patients [112]. However, other studies using different TNF-a antagonist (etanercept) failed to show similar results [113].…”