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Editorial |
Walter and Eliza Hall Institute of Medical Research 3050 Victoria, Australia
Address all correspondence and requests for reprints to: Dr. Leonard C. Harrison, Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3050 Victoria, Australia. E-mail: harrison{at}wehi.edu.au.
It has long been recognized that sepsis, a potent activator of the innate immune system, is associated with insulin resistance in critical illness and increases insulin requirements in people with type 2 diabetes (T2D). More recently, circulating markers of innate immune activation such as C-reactive protein, IL-6, TNF-
, and monocyte chemoattractant protein-1 have been associated with obesity-T2D and vascular disease (1) and have been shown to predict the risk of T2D in at-risk populations (1, 2). These findings support the view that even low-grade activation of the innate immune system leads to insulin resistance.
Defining the mechanism(s) by which innate immune system activation might cause insulin resistance would present opportunities to design antiinflammatory treatments for sepsis-induced insulin resistance and perhaps other insulin-resistant states such as T2D and vascular disease. One proposed mechanism, based on the observation that obesity-associated inflammation in mice arises from macrophages in adipose tissue (3, 4), invokes disruption of adipocyte metabolism by the direct action of macrophage-derived inflammatory factors such as IL-6 and TNF-, with altered adipokine secretion leading to insulin resistance in other tissues such as liver.
In this issue of JCEM, Anderson et al. (5) report the effects of an iv bolus of endotoxin on inflammatory cytokines and adipokines over 24 h in 20 healthy men and women. Insulin resistance, measured as homeostasis model assessment of insulin resistance, increased by around 40% 24 h after endotoxin administration. Plasma concentrations of TNF- and IL-6 peaked 2 h after endotoxin and returned to baseline by 8 h. IL-6 expression in adipose tissue, measured by quantitative RT-PCR, mirrored the plasma profile, but adipose tissue TNF- mRNA increased by 4 h and remained elevated at 24 h. Plasma concentrations of adiponectin and the proportion of high-molecular-weight adiponectin (the form most important for its insulin-sensitizing effects) did not change after endotoxin. Plasma concentrations of leptin rose marginally after endotoxin, whereas plasma concentrations of resistin increased gradually to peak at 12 h and remained significantly (2-fold) elevated at 24 h.
This study indicates that adiponectin is unlikely to mediate endotoxin-induced insulin resistance, in contrast with studies that show that chronic insulin resistance in obesity and T2D is associated with decreased plasma concentrations of total adiponectin and of the ratio of its high- to low-molecular-weight forms (6). However, a role for resistin is suggested by the sustained elevation of plasma resistin observed in this and one previous study (7).
Resistin is a 12.5-kDa cysteine-rich protein that circulates in blood as either a high- or a low-molecular-weight form (8). Mouse studies show white adipose tissue to be the major source of resistin and also demonstrate a role for low-molecular-weight resistin in mediating liver insulin resistance (9, 10). In humans, the role of resistin is less certain. Both human leukocytes and adipocytes express resistin, and it is unclear which is the more important tissue source. In the present study, the finding of minimal induction of resistin mRNA in adipose tissue, despite a dramatic elevation of resistin protein in plasma, suggests that circulating leukocytes are the main source of resistin after endotoxin treatment. This is consistent with the observation that endotoxin induces resistin secretion from cultured human macrophages (7).
Although the study of Anderson et al. suggests a role for resistin in endotoxin-induced insulin resistance in humans, it is clear that further work is needed to demonstrate causality. One important issue is whether the relative amounts of high- and low-molecular-weight resistin differ after endotoxin treatment and whether this occurs in other insulin-resistant states in humans. Further human studies into the effects of resistin treatment or resistin inhibition on insulin resistance and tissue glucose flux will also be critical to clarify the physiological importance of this adipokine.
Footnotes
Abbreviation: T2D, Type 2 diabetes.
Received April 11, 2007.
Accepted April 11, 2007.
References
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