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Inflammatory Cytokines and the Risk to Develop Type 2 Diabetes Results of the Prospective Population-Based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study

Department of Endocrinology, Diabetes and Nutrition, Benjamin Franklin Medical Center, Free University Berlin, Berlin, Germany.
Diabetes (Impact Factor: 8.47). 03/2003; 52(3):812-7. DOI: 10.2337/diabetes.52.3.812
Source: PubMed

ABSTRACT A subclinical inflammatory reaction has been shown to precede the onset of type 2 (non-insulin-dependent) diabetes. We therefore examined prospectively the effects of the central inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha (TNF-alpha) on the development of type 2 diabetes. We designed a nested case-control study within the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study including 27,548 individuals. Case subjects were defined to be those who were free of type 2 diabetes at baseline and subsequently developed type 2 diabetes during a 2.3-year follow-up period. A total of 192 cases of incident type 2 diabetes were identified and matched with 384 non-disease-developing control subjects. IL-6 and TNF-alpha levels were found to be elevated in participants with incident type 2 diabetes, whereas IL-1beta plasma levels did not differ between the groups. Analysis of single cytokines revealed IL-6 as an independent predictor of type 2 diabetes after adjustment for age, sex, BMI, waist-to-hip ratio (WHR), sports, smoking status, educational attainment, alcohol consumption, and HbA(1c) (4th vs. the 1st quartile: odds ratio [OR] 2.6, 95% CI 1.2-5.5). The association between TNF-alpha and future type 2 diabetes was no longer significant after adjustment for BMI or WHR. Interestingly, combined analysis of the cytokines revealed a significant interaction between IL-1beta and IL-6. In the fully adjusted model, participants with detectable levels of IL-1beta and elevated levels of IL-6 had an independently increased risk to develop type 2 diabetes (3.3, 1.7-6.8), whereas individuals with increased concentrations of IL-6 but undetectable levels of IL-1beta had no significantly increased risk, both compared with the low-level reference group. These results were confirmed in an analysis including only individuals with HbA(1c) <5.8% at baseline. Our data suggest that the pattern of circulating inflammatory cytokines modifies the risk for type 2 diabetes. In particular, a combined elevation of IL-1beta and IL-6, rather than the isolated elevation of IL-6 alone, independently increases the risk of type 2 diabetes. These data strongly support the hypothesis that a subclinical inflammatory reaction has a role in the pathogenesis of type 2 diabetes.

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    • "Another study also showed that IL-6 levels were robustly increased in fat cells from insulin-resistant individuals (Rotter et al. 2003). Results from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study showed that a combined elevation of IL-1 β and IL-6, rather than the isolated elevation of IL-6 alone, independently enhanced the risk of type 2 diabetes (Spranger et al. 2003). Very recently, circulating IL-6 levels, but not soluble IL-6 (sIL-6), were shown to significantly correlate with body mass index (BMI) and the homeostasis model assessment index for insulin resistance (HOMA-IR) also in obese children and adolescents (De Filippo et al. 2015). "
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    • "It is now well established that adipose tissue is not only involved in energy storage but possesses also endocrine functions by regulating the production of various hormones and cytokines (Ouchi et al., 2011). Indeed, adipose tissue produces: (a) proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) (Hotamisligil et al., 1993), interleukin (IL)-6 (Muller et al., 2002; Pickup et al., 1997) and IL-1β (Spranger et al., 2003), (b) chemokines such as monocyte chemotactic protein-1 (MCP-1) (Kamei et al., 2006; Kanda et al., 2006) and C-X-C motif chemokine 5 (CXCL5) (Chavey et al., 2009), and (c) hormones such as leptin and adiponectin (Wozniak et al., 2009). These molecules, in particular the proinflammatory cytokines TNF-α and IL-6, were shown to be overexpressed in adipose tissue of both mice and humans with obesity and insulin resistance (Bullo et al., 2003; Hotamisligil and Spiegelman, 1994; Kern et al., 1995), suggesting a link between obesity, inflammation and insulin resistance . "
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