TNF-α acutely inhibits vascular effects of physiological but not high insulin or contraction

Abstract

TNF-α is elevated in many states of insulin resistance, and acutely administered TNF-α in vivo inhibits insulin-mediated hemodynamic effects and glucose uptake in muscle. In this study, we assess whether the inhibitory effects of TNF-α are affected by insulin dose or muscle contraction. Whole body glucose infusion rate (GIR), femoral blood flow (FBF), hindleg vascular resistance, hindleg glucose uptake (HGU), 2-deoxyglucose uptake into muscles of the lower leg (R′g) and hindleg metabolism of infused 1-methylxanthine (1-MX), a measure of capillary recruitment, were determined. Three groups were studied with and without infusion of TNF-α: euglycemic insulin-clamped, one-leg field-stimulated (2 Hz, 0.1 ms at 30 V), and saline-infused control anesthetized rats. Insulin infusions were 3, 10, or 30 mU · kg-1 · min-1 for 2 h. 1-MX metabolism was maximally increased by all three doses of insulin. GIR, HGU, and R′g were maximal at 10 mU and FBF was maximal at 30 mU of insulin. Contraction increased FBF, HGU, and 1-MX. TNF-α (0.5 μg · kg-1 · h-1) totally blocked the 3 and 10 mU insulin-mediated increases in FBF and 1-MX, and partly blocked GIR, HGU, and R′g. None of the increases due to twitch contraction was affected by TNF-α, and only the increase in FBF due to 30 mU of insulin was partly affected. We conclude that muscle capillary recruitment and glucose uptake due to high levels of insulin or muscle contraction under twitch stimuli at 2 Hz are resistant to TNF-α. These findings may have implications for ameliorating muscle insulin resistance resulting from increased plasma TNF-α and for the differing mechanisms by which contraction and insulin recruit capillary flow in muscle.

Tumor Necrosis Factor-α Induces Skeletal Muscle Insulin Resistance in Healthy Human Subjects via Inhibition of Akt Substrate 160 Phosphorylation

“…The effect of low-grade systemic TNF-␣ concentration on blood flow in humans is unknown. TNF-␣ and insulin oppose each other, such that insulin action is most vulnerable to TNF-␣-mediated inhibition when insulin concentrations are low (as in the present study) and least vulnerable when insulin concentrations are high (38). In rats, an acute in vivo TNF-␣ infusion completely blocked the hemodynamic effects of insulin on blood flow and capillary recruitment, and it inhibited skeletal muscle glucose uptake (31).…”

Tumor necrosis factor-α directly stimulates the overproduction of hepatic apolipoprotein B100-containing VLDL via impairment of hepatic insulin signaling

“…The venous catheter was then used for the infusion of glucose (20%) and insulin (3 mU/kg per min). TNF-␣ was dissolved in saline and administered at a dosage shown to be sufficient to effectively inhibit insulin action (66,67). During the euglycemic clamp, blood glucose concentrations were measured every 10 min, and the euglycemia was maintained at around 4.2 Ϯ 0.1 mM of baseline.…”

Reciprocal Relationships Between Insulin Resistance and Endothelial Dysfunction

“…128 In addition, infusion of TNF-␣ in rats blunts femoral artery blood flow and inhibits glucose uptake in response to insulin, whereas contractile-induced blood flow and glucose uptake are unaffected. 129 Impairment in insulin-stimulated capillary recruitment (in addition to changes in total blood flow) may also play an important role in insulin resistance. 130,131 In genetically obese insulin-resistant Zucker fatty rats compared with lean Zucker rats, capillary recruitment and glucose uptake in skeletal muscle are significantly impaired in response to insulin.…”