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Neutralization of tumor necrosis factor- reverses insulin resistance in skeletal muscle but not adipose tissue

¹Department of Applied Physiology and Kinesiology, University of Florida, Gainesville 32611; ²Malcom Randall Veterans Affairs Medical Center, Gainesville, Florida 32608; and ³Department of Physiology, Louisiana State University Health Science Center, New Orleans, Louisiana 70112

Submitted 3 February 2004 ; accepted in final form 15 June 2004

We examined the possible role of tumor necrosis factor- (TNF-) as a mediator of insulin resistance in maturing male Sprague-Dawley rats. Rats were treated either with goat anti-murine TNF- IgG (anti-TNF-) or goat nonimmune IgG (NI) for 7 days. Vascular catheters were implanted, and rats were fasted overnight before hyperinsulinemic euglycemic clamp (HUC) studies were performed. TNF- neutralization increased the rate of glucose infusion required to maintain euglycemia by 68%. Insulin-stimulated glucose transport into individual tissues was measured after bolus administration of 2-deoxy-[¹⁴C]glucose during HUC. Anti-TNF- administration increased glucose transport in muscles composed predominantly of fast-twitch fibers: white gastrocnemius muscle (68% increase) and tibialis anterior muscle (64% increase). There were nonsignificant trends for increased glucose transport in the slow-twitch soleus muscle and in the mixed-fiber red gastrocnemius muscle. Glucose transport was unchanged in visceral and subcutaneous fat. Anti-TNF treatment did not alter body weight, muscle mass, or fat mass. Anti-TNF- did not alter the distribution of the 17-kDa and 26-kDa forms of TNF- in either muscle or fat. However, anti-TNF- treatment caused an 50% reduction in the secretion of TNF- bioactivity in vitro by explants of visceral and subcutaneous fat. We conclude that TNF- neutralization reversed insulin resistance substantially in fast-twitch muscle and may have done so in other muscles, while having little effect in fat. TNF- neutralization was accompanied by reduced TNF- bioactivity without tissue depletion of TNF- protein.

glucose transport; muscle fiber type; soluble tumor necrosis factor-; membrane tumor necrosis factor-

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