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the potential role of inflammation in insulin resistance and obesity.
Low-Grade Inflammation, Obesity, and Insulin Resistance in Adolescents Christian Herder, Sophie Schneitler, Wolfgang Rathmann, Burkhard Haastert, Heiko Schneitler, Horst Winkler, Renate Bredahl, Erik Hahnloser, and Stephan Martin Institute for Clinical Diabetes Research (C.H., S.S., S.M.) and Institute of Biometrics and Epidemiology (W.R., B.H.), German Diabetes Center, Leibniz Institute at Heinrich Heine University, 40225 Dusseldorf, Germany; and Gesundheitsamt ̈ (Public Health Office) (H.S., H.W., R.B., E.H.), 40227 Dusseldorf, Germany
IN ADULTS, NUMEROUS STUDIES have shown that a differential, subclinical, chronic activation of the immune system precedes the manifestation of type 2 diabetes mellitus (T2DM). Elevated systemic concentrations of specific acute phase proteins, cytokines, and chemokines as well as reduced levels of the adipokine adiponectin predict the development of T2DM (1, 2). This association between low-grade inflammation and T2DM remains significant after adjustment for traditional risk factors so that it is reasonable to assume that low-grade inflammation is relevant in the pathogenesis of T2DM. However, some of the association between elevated levels of immune mediators and T2DM is also explained by obesity because adipose tissue has been shown to secrete many of the cytokines and chemokines that are considered T2DM risk factors (3–7). The analysis of the role of low-grade inflammation in the development of insulin resistance and T2DM in children and adolescents is relevant because, in contrast to adults, it can be assumed that associations between low-grade inflammation, insulin resistance, and T2DM are not confounded by chronic inflammatory conditions such as cardiovascular disease, arthritis, or bronchitis that are frequent comorbidities in T2DM patients or in old age. However, to the best of our knowledge, data from prospective studies that investigate low-grade inflammation as a risk factor for T2DM in youth are not available. There is some evidence from case-control and cross-sectional surveys that low-grade inflammation is associated with T2DM risk and insulin resistance in children and adolescents.
Most data come from studies that describe the positive association between C- reactive protein (CRP) and obesity as a major risk factor for T2DM (8 –21). Only a few studies also investigated the relationship between CRP and glucose metabolism and found that higher levels of CRP were associated with elevated fasting insulin levels and/or insulin resistance (14, 19, 20). These observations were extended in one study that showed that the positive association between CRP and insulin is markedly attenuated after adjusting for BMI (14). This finding indicates that in youth as well as adults, the association between inflammation and T2DM risk cannot be explained by obesity alone and may support the development of T2DM at all ages. Although CRP is widely considered a general marker of immune activation, cross-sectional studies show that CRP is only moderately or weakly correlated with many cytokines, chemokines, and adiponectin (22–24) and that the significant association between elevated levels of these mediators of innate immunity and incident T2DM is independent of CRP levels (25,26). Thus, it can be expected that these markers represent different components of the immune system and that they provide different information than CRP measurement. It is therefore interesting that several other reports suggested that also circulating concentrations of IL-6 (18, 21, 27), TNF␣ (16, 28), soluble TNF␣ receptors (18, 28, 29), and E-selectin (21) are elevated in obesity and that IL-6 (27) and soluble TNF␣ receptor 2 may be associated with insulin resistance in children and adolescents (29). In addition, there are data from multiple adolescent populations on the inverse association between adiponectin and obesity and insulin resistance (30 –32). Adiponectin may be largely independent of systemic levels of many cytokines and chemokines (23) but has been shown to have strong anti-inflammatory effects on the molecular and cellular level (33, 34) so that it may also be considered as immune marker. Taken together, there is growing evidence that obesity is associated with low-grade inflammation in youth, but data on the association with insulin resistance are limited to CRP and soluble TNF␣ receptor 2. The objectives of this study were thus as follows: 1) to investigate the association between low-grade inflammation and measures of both obesity and glucose me- tabolism by analyzing immune mediators that are expressed in adipocytes and may represent novel risk factors for the development of T2DM in adults, and 2) to examine whether the association between low-grade inflammation and insulin resistance is independent of obesity as assessed by body mass index (BMI) and waist circumference (WC).
To make a long story short, here is the conclusion:
Conclusions
In conclusion, high BMI and high WC are associated with a specific pattern of low-grade immune activation in adolescents. The same proinflammatory pattern is also seen in insulin- resistant boys and girls. Obesity appears to mediate some of this association. However, prospective studies will be necessary to evaluate the relevance of subclinical inflammation for T2DM risk in youth and allow comparisons of the role of this mech- anism among children, adolescents, and adults.
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