Effect of lowering tumour necrosis factor-α on vascular endothelial function in Type II diabetes

Abstract

Tumour necrosis factor-alpha (TNF alpha) is a mediator of reactive oxygen species, which are implicated in endothelial dysfunction and atherosclerosis. Type II diabetes is associated with endothelial dysfunction and elevated circulating TNF alpha. We hypothesized that reducing serum levels of TNFalpha, using pentoxifylline, would improve endothelial function. Thirteen subjects [age 58+/-2 (S.E.M.) years] with Type II diabetes (disease duration 74+/-13 months) undertook a randomized, crossover study of 8 weeks pentoxifylline and 8 weeks placebo. Endothelium-dependent and-independent vasodilation in resistance arteries was assessed via bilateral forearm venous occlusion plethysmography during intra-brachial infusions of acetylcholine (ACh), sodium nitroprusside (SNP) and N(G)-monomethyl-L-arginine (L-NMMA). High-resolution ultrasound of the brachial artery in response to ischaemia was used to determine endothelium-dependent conduit vessel flow-mediated dilation (FMD), and endothelium-independent conduit function was assessed by sublingual administration of glyceryl trinitrate (GTN). Serum concentrations of TNF alpha were also determined. Pentoxifylline lowered serum TNF alpha from 4.1+/-0.7 to 2.9+/-0.6 pg x ml(-1) (P=0.001). Forearm blood flow (FBF) responses at each dose of ACh did not differ with treatment (P=0.4). Similarly, FBF responses to SNP (P=0.8) and L-NMMA (P=0.2) did not differ. There was also no significant difference in brachial artery diameter during FMD (P=0.2) or GTN administration (P=0.06). Despite lowering serum TNF alpha concentration, pentoxifylline at a dose of 400 mg three times a day for 8 weeks did not improve vascular function in either conduit or resistance vessels in this group of Type II diabetic subjects.

Gait characteristics in people with type 2 diabetes mellitus

“…Whatever the mechanism of endothelial cell damage in the peripheral circulation (Bilsborough et al 2002), in the present investigation there is indication of gait impairment independent of muscle strength and sensory loss in the foot. This was especially seen in turns.…”

Effect of pentoxifylline on semen parameters, reproductive hormones, and seminal plasma antioxidant capacity in men with idiopathic infertility: a randomized double-blind placebo-controlled study

“…PTX also downregulates the production of tumor necrosis factor-alpha (TNF-a). This cytokine induces an increase in hydrogen peroxide production from mitochondria [49,50]. Therefore, PTX is a potent antioxidant, which reduces oxidative stress at cell level.…”

Tumor Necrosis Factor/Sphingosine-1-Phosphate Signaling Augments Resistance Artery Myogenic Tone in Diabetes

“…As a reported cause of insulin resistance (42) and diabetes complications (43), several small clinical trials have targeted TNF in diabetes (44)(45)(46)(47). The vast majority of these investigations primarily focused on blood glucose control and insulin sensitivity as clinical end points (44)(45)(46); a few of these trials indirectly assessed vasodilator responses via forearm perfusion (46,47).…”

“…The vast majority of these investigations primarily focused on blood glucose control and insulin sensitivity as clinical end points (44)(45)(46); a few of these trials indirectly assessed vasodilator responses via forearm perfusion (46,47). Although anti-TNF therapy successfully lowers inflammatory markers (e.g., C-reactive protein), it largely fails to improve any other defined clinical end point.…”