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.
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.
Spranger
Joachim
J
Department of Endocrinology, Diabetes and Nutrition, Benjamin Franklin Medical Center, Free University Berlin, Berlin, Germany. joachim.spranger@medizin.fu-berlin.de
Kroke
Anja
A
Möhlig
Matthias
M
Hoffmann
Kurt
K
Bergmann
Manuela M
MM
Ristow
Michael
M
Boeing
Heiner
H
Pfeiffer
Andreas F H
AF
D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D001824:Body Constitution; D015992:Body Mass Index; D002097:C-Reactive Protein / Q000032:analysis; D016022:Case-Control Studies; D016207:Cytokines / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000209:etiology; D005060:Europe / Q000453:epidemiology; D015444:Exercise; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D007249:Inflammation / Q000150:complications; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D009747:Nutritional Physiological Phenomena; D011446:Prospective Studies; D012307:Risk Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D001786:Blood Glucose; D002097:C-Reactive Protein; D016207:Cytokines; D006442:Glycated Hemoglobin; D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha