Robert A. Mooney

Interleukin (IL)-6 is a pleiotropic cytokine with involvement in such diverse physiological and pathological functions as innate immunity and acute phase response, hematopoiesis, liver regeneration, and repair (1, 26). Evidence also supports a role for IL-6 in glucose metabolism and insulin action, but the nature of this role is controversial. As discussed by Dr. Pedersen and Dr. Febbraio, my Point:Counterpoint colleagues whose research has made major contributions to this field, IL-6 can display beneficial effects in regulating glucose metabolism, particularly in skeletal muscle (8). The important question as I see it, however, is whether IL-6, in pathological conditions, contributes to glucose dysregulation. Although IL-6 may have a benign or beneficial role under certain experimental conditions, I will argue that in its relationship to obesity and insulin resistance, which affects as many as one-third of adults in the United States, the contribution of IL-6 is decidedly detrimental, particularly in the liver.

Recent evidence indicates that obesity, with its associated insulin resistance and Type 2 diabetes, is a chronic inflammatory state (29). Considerable effort is directed at determining the contribution of the cytokines, adipokines, and related factors to the altered glucose homeostasis and insulin resistance of this inflammatory state. Circulating IL-6 levels are two- to fourfold higher in obese, Type 2 diabetics than in nonobese controls (7, 17, 18). Kern et. al (12) reported that plasma IL-6 levels correlate better than TNF-α with obesity and insulin resistance. Similarly, Bastard et al. (3) reported that adipose tissue IL-6 levels but not TNF-α or leptin levels correlate with insulin resistance in obese subjects. IL-6 levels in serum and adipose tissue also decrease with weight loss (2). A recent study demonstrated that levels of CRP and IL-6 correlate with both insulin resistance and obesity and predict the development of Type 2 diabetes (19). Adipose tissue makes an important contribution to circulating IL-6 levels (16), and the liver is a well- characterized target of IL-6. Omental fat is more strongly linked to insulin resistance than non-visceral fat depots (6) and secretes as much as two- to threefold more IL-6 than subcutaneous fat (9). Importantly, venous drainage of omental fat uses the portal venous system, hence potentially having a preferential effect on the liver.

Is IL-6 an active participant in the insulin resistance and altered carbohydrate metabolism of obesity or is this guilt by association? Both in vivo and in vitro evidence is available to address this question. Kanemaki et al. (11) and others (20) reported that IL-6 inhibits insulin-dependent glycogen synthesis and promotes glucose release from isolated primary hepatocytes. Our group has shown that IL-6 impairs insulin receptor signaling in HepG2 cells and primary hepatocytes and confirms that insulin-dependent glycogen synthesis is inhibited by IL-6 (23). Rotter et al. (21) reported that gene transcription of IRS-1, GLUT4, and PPAR-γ decreased in response to chronic IL-6 in 3T3L1 adipocytes. Insulin-dependent glucose transport and IRS-1 tyrosine phosphorylation were also suppressed.

While in vitro investigations have shown direct inhibitory effects of IL-6 on insulin- responsive target cells, in vivo experiments also support such an effect of IL- 6. In rodents, IL-6 injections lead to increased plasma glucose and insulin levels after 90 min and a marked decrease in liver glycogen (25). Additionally, we reported that mice acutely exposed to IL-6 for 90 min have reduced insulin signal transduction in the liver (24). If the objective is to characterize the role of IL-6 in obesity, however, IL-6 levels should be maintained in a chronically elevated state to mimic obesity. To this end, we used implantable osmotic pumps that deliver IL-6 continuously to mice over 5–7 days. Under these conditions, IL-6 produced a hepatic insulin resistance as determined by impaired insulin receptor signal transduction. Interestingly, skeletal muscle response to insulin was unimpaired (15). Using a more acute IL-6 treatment, Kim et al. (13) infused IL-6 for 3 h during a hyperinsulinemic-euglycemic clamp study. Under these conditions, insulin resistance was observed in both the liver and skeletal muscle. Perhaps the latter reflects the higher dose used and the shorter time frame of the study.

To directly address the role of IL-6 in glucose dysregulation of obesity, an IL-6 neutralizing antibody was used to deplete IL-6 in genetically obese Lepob mice (14). Prior to antibody treatment, elevated STAT3 phosphorylation and increased expression of acute phase proteins haptoglobin and fibrinogen were observed in liver and adipose tissue of the obese mice compared with lean controls, consistent with an obesity-associated elevation of endogenous IL-6. Neutralization of IL-6 returned these markers toward levels seen in lean mice. Importantly, insulin receptor signaling increased in the liver but not in adipose tissue in response to IL-6 depletion. Of relevance to our current discussion, depletion of IL-6 increased insulin sensitivity in the obese mice as reflected in a marked improvement in insulin-dependent suppression of endogenous glucose production (14). Cai et al. (4) reported a similar increase in hepatic insulin sensitivity following treatment of a transgenic mouse model of insulin resistance with IL-6 neutralizing antibody. They argue further that the liver can be an important source of IL-6, with steatosis being a potent stimulus for increased production.

Is IL-6 a promoter of insulin sensitivity and glucose utilization as suggested in part by the expertly performed, acute, human studies by Drs. Pedersen, Febbraio, and colleagues, or is IL-6 the antagonist of insulin action as argued in the studies outlined here? What factors may account for the apparent contradictory effects of IL-6 on glucose homeostasis? Chronicity may be one factor. Most human investigations are by necessity limited to several hours. Obesity is a chronic condition, and the role of IL-6 in this condition may require chronic elevations. Chronic, but not acute, exposure to IL-6 causes inhibitory changes in insulin action in 3T3L1 adipocytes (21). Evidence from the liver regeneration field suggests that short-term (1–2 days) IL-6 exposure yields a protective effect, whereas long term (5–7 days) IL-6 exposure is injurious (10). Differences in response to IL-6 between the insulin responsive tissues are also a factor. While skeletal muscle appears to be the major target for the reported beneficial effects of IL-6, Weigert et al. (28) recently confirmed that, in the liver of mice, IL-6 activates two inhibitory mechanisms that are implicated in insulin resistance, marked induction of SOCS-3 and phosphorylation of IRS-1 on serine-307. Interestingly, IL-6 had no appreciable effect on these inhibitory mechanisms in skeletal muscle. Carey et al. (5) recently confirmed the small effect of IL-6 on SOCS-3 expression in muscle. This tissue-specific difference in induction of SOCS-3 may be quite relevant to this current discussion because we and others have linked SOCS-3 to inhibition of insulin receptor signal transduction in the liver (22, 24, 27). Finally, physiological context may play an important role in determining the response to an inflammatory cytokine such as IL-6. In 3T3L1 adipocytes, IL-6 alone had no acute effect and IL-1α had only a small inhibitory effect on insulin receptor signal transduction (28). Together, however, these two inflammatory cytokines very potently inhibited insulin receptor signaling. Thus, although considerable evidence supports a role for IL-6 in promoting insulin resistance and glucose dysregulation, optimum characterization of this role may require consideration of the synergy between IL-6 and other elements of the proinflammatory milieu.


The author recognizes support from the National Institute of Diabetes and Digestive and Kidney Diseases (Grants DK-38138 and DK-60732) and the American Diabetes Association (7–04-RA-78).