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J Appl Physiol 102: 818, 2007; doi:10.1152/japplphysiol.01208b.2006
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POINT-COUNTERPOINT

REBUTTAL FROM DRS. PEDERSEN AND FEBBRAIO

We thank Dr. Mooney for presenting his argument in a concise and scholarly fashion and acknowledge the contribution that his work has made to the field (6). We do not question the validity of the work that indicates that IL-6 may induce insulin resistance in some experimental models, but we feel that two critical issues have been neglected by Dr. Mooney. First, Dr. Mooney highlights that IL-6 is "associated" with insulin resistance in humans. However, association does not equate to causality. Dr. Mooney cites studies (1, 3) that show that IL-6 is associated with insulin resistance in humans, but we would also like to point out that, in our hands, IL-6 is strongly associated with obesity but not insulin resistance using the "gold standard" of measuring insulin sensitivity, the hyperinsulinemic euglycemic clamp (2). This suggests that IL-6 may be a consequence rather than a cause of insulin resistance and it is indeed dangerous to confuse the two. Second, notwithstanding the important issue of "chronicity," all of the work that demonstrates a negative effect of chronic IL-6 in vivo, including the elegant work by Dr. Mooney, who has implanted mini osmotic pumps (5) or used IL-6 antibodies (4), has been performed in rodents. In humans, the effect seems opposite. As cited by us in our original Point article (8), blocking IL-6 in patients with rheumatoid arthritis causes hyperglycemia. Moreover, when a neutralizing anti-IL-6 receptor antibody is given to patients with multicentric Castleman disease for up to 60 wk, patients increase their body weight by 10% and become markedly hypertriglyceridemic (7), in perfect concordance with the work of Jansson and coworkers (10), who have examined the metabolic status of the IL-6 knockout mouse. These critical observations in humans (7) argue against the notion that IL-6 antibody treatment would be a favorable outcome for metabolic disease. Finally, as discussed in our original Point article (8), TNF-{alpha} and not IL-6 may indeed be the "sheep in wolf's clothing." In a recent study (9), plasma-IL-6 concentrations were markedly lowered by anti-TNF-{alpha} therapy. This finding that plasma TNF-{alpha} was not elevated despite high levels of IL-6 and that plasma-IL-6 levels decreased in response to anti-TNF-{alpha} therapy supports the notion that TNF-{alpha} may stimulate IL-6 production and consequently IL-1ra and CRP. In line with this, chronically elevated levels of IL-6 are likely to reflect local ongoing TNF-{alpha} production, the real cause of cytokine-induced insulin resistance in humans.

REFERENCES

  1. Bastard JP, Maachi M, Van Nhieu JT, Jardel C, Bruckert E, Grimaldi A, Robert JJ, Capeau J, Hainque B. Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. J Clin Endocrinol Metab 87: 2084–2089, 2002.[Abstract/Free Full Text]
  2. Carey AL, Bruce CR, Sacchetti M, Anderson MJ, Olson DB, Saltin B, Hawley JA, Febbraio MA. IL-6 and TNF{alpha} are not elevated in patients with type two diabetes: evidence that plasma IL-6 is related to fat mass and not insulin responsiveness. Diabetologia 47: 1029–1037, 2004.[ISI][Medline]
  3. Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 280: E745–E751, 2001.[Abstract/Free Full Text]
  4. Klover PJ, Clementi AH, Mooney RA. Interleukin-6 depletion selectively improves hepatic insulin action in obesity. Endocrinology 146: 3417–3427, 2005.[Abstract/Free Full Text]
  5. Klover PJ, Zimmers TA, Koniaris LG, Mooney RA. Chronic exposure to interleukin-6 causes hepatic insulin resistance in mice. Diabetes 52: 2784–2789, 2003.[Abstract/Free Full Text]
  6. Mooney RA. Counterpoint: Interleukin-6 does not have a beneficial role in insulin sensitivity and glucose homeostasis. J Appl Physiol. In press.
  7. Nishimoto N, Kanakura Y, Aozasa K, Johkoh T, Nakamura M, Nakano S, Nakano N, Ikeda Y, Sasaki T, Nishioka K, Hara M, Taguchi H, Kimura Y, Kato Y, Asaoku H, Kumagai S, Kodama F, Nakahara H, Hagihara K, Yoshizaki K, Kishimoto T. Humanized anti-interleukin-6 receptor antibody treatment of multicentric Castleman disease. Blood 106: 2627–2632.
  8. Pedersen BK, Febbraio MA. Point: Interleukin-6 does have a beneficial role in insulin sensitivity and glucose homeostasis. J Appl Physiol. In press.
  9. Rosenvinge A, Krogh-Madsen R, Baslund B, Pedersen BK. Insulin resistance in patients with rheumatoid arthritis—effect of anti-TNF-{alpha} therapy. Scand J Rheumatol. In press.
  10. Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, Jansson JO. Interleukin-6-deficient mice develop mature-onset obesity. Nat Med 8: 75–79, 2002.[CrossRef][ISI][Medline]




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