TNF-alpha acutely inhibits vascular effects of physiological but not high insulin or contraction.
TNF-alpha is elevated in many states of insulin resistance, and acutely administered TNF-alpha in vivo inhibits insulin-mediated hemodynamic effects and glucose uptake in muscle. In this study, we assess whether the inhibitory effects of TNF-alpha 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-alpha: 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 x kg-1 x min-1 for 2 h x 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-alpha (0.5 microg x kg-1 x 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-alpha, 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-alpha. These findings may have implications for ameliorating muscle insulin resistance resulting from increased plasma TNF-alpha and for the differing mechanisms by which contraction and insulin recruit capillary flow in muscle.
Zhang
Lei
L
Department of Biochemistry, University of Tasmania, Hobart 7001, Australia.
Wheatley
Catherine M
CM
Richards
Stephen M
SM
Barrett
Eugene J
EJ
Clark
Michael G
MG
Rattigan
Stephen
S
D000818:Animals; D000963:Antimetabolites / Q000493:pharmacokinetics; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D003847:Deoxyglucose / Q000493:pharmacokinetics; D004347:Drug Interactions; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000502:physiology; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014970:Xanthines / Q000493:pharmacokinetics
D000963:Antimetabolites; D000970:Antineoplastic Agents; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D014409:Tumor Necrosis Factor-alpha; D014970:Xanthines; C053085:1-methylxanthine; D003847:Deoxyglucose