J Appl Physiol 102: 818-a-819-a, 2007;
doi:10.1152/japplphysiol.01208c.2006
8750-7587/07 $8.00
POINT-COUNTERPOINT
REBUTTAL FROM DR. MOONEY
As anticipated, Drs. Pedersen and Febbraio do not view IL-6 as a bad guy in insulin action. Let's examine their argument. Acute IL-6 infusions in healthy adults have little or no effect on hepatic glucose metabolism while promoting utilization in skeletal muscle. The critical limitation of these infusion studies, however, is that they do not replicate the chronic elevation of IL-6 in obesity-associated insulin resistance. To date, no human studies adequately address chronic effects of IL-6 on insulin action. A polymorphism in the human IL-6 gene promoter at –174 may chronically affect circulating IL-6 and alter risk of insulin resistance and diabetes, but conclusions are conflicting. My colleagues cite one study (8) to support their arguments, but the report actually concludes that the C-174C genotype alone is not associated with diabetic risk. In another recent study, the G-174G genotype was associated with increased plasma IL-6 and reduced insulin sensitivity (2). My colleagues also cite human studies with IL-6 receptor blocking antibodies (1, 4, 9), but the articles actually make no mention of glucose levels. Unfortunately, no clinical studies with these antibodies have analyzed glucose metabolism.
Without definitive human studies, an understanding of the effects of chronic IL-6 must come from animal and in vitro studies. Depletion of circulating IL-6 in obese mice improved hepatic insulin responsiveness but had no effect in lean mice (7). This supports the conclusion that IL-6 is an important mediator of obesity-associated insulin resistance and is more than the marker of obesity that my colleagues contend (3). This is further supported by Kern et al. (6) who demonstrated that circulating IL-6 levels correlate with insulin resistance independent of BMI.
Finally, tissue-specific differences in response to IL-6 may underlie the two faces of IL-6. My colleagues link IL-6-dependent activation of AMP kinase in L6 myotubes to beneficial metabolic effects of IL-6 in skeletal muscle (6). Interestingly, they had questioned in vitro approaches, particularly those using supraphysiological IL-6 concentrations, yet 100 ng/ml IL-6 was used in their study. We have shown IL-6- dependent inhibition of insulin signaling and increased expression of SOCS-3, a potential mediator of insulin resistance, in hepatocytes in response to fivefold less IL-6 (10). Additionally, IL-6 induces little SOCS-3 in myotubes and is not an effective activator of AMP kinase in liver (5). This supports the conclusion that the liver is a major site for IL-6-dependent dysregulation of insulin action while skeletal muscle may not be a target for this effect.
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Copyright © 2007 by the American Physiological Society.
