Glucose, Age,. Obesity,. Inflammation,. Hemoglobin, and. Iron in Apparently. Healthy Japanese. Men and Women. It has been reported that fasting plasma.
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OBSERVATIONS Bilirubin Is Negatively Associated With A1C Independently of Fasting Plasma Glucose, Age, Obesity, Inflammation, Hemoglobin, and Iron in Apparently Healthy Japanese Men and Women
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t has been reported that fasting plasma glucose (FPG) is not significantly associated with risks of cardiovascular disease (CVD) and death from any cause adjusting for A1C, but A1C was significantly associated with risks of CVD and death from any cause adjusting for FPG in nondiabetic adults (1). A1C levels appear to increase with age, and any condition that changes red cell turnover, such as hemolytic anemia, chronic malaria, major blood loss, or blood transfusions, will influence A1C levels (2). Other than age and iron deficiency, some cardiovascular risk factors related with inflammation and oxidant stress may have independent associations with A1C. Although oxidation of LDL cholesterol is critical for atherosclerotic vascular changes, bilirubin suppresses the oxidation of lipid more than ␣-tocopherol (3) and increased serum levels of bilirubin are associated with reduced risk for CVD in some epidemiological studies (4,5). Thus, I hypothesized that the association of A1C with CVD beyond FPG in nondiabetic adults may at
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least partly be mediated by the association between A1C and bilirubin in nondiabetic subjects and examined the crosssectional association between A1C and serum total bilirubin (TB) adjusting for FPG, age, obesity, inflammatory parameters, hemoglobin, and iron in apparently healthy Japanese men and women. Multivariate linear regressions using A1C as a dependent variable and FPG, age, BMI, TB, hemoglobin, iron, white blood cell count (WBC), and high-sensitivity C-reactive protein (hs-CRP) and logistic regressions using the highest quartile (ⱖ5.6 National Glycohemoglobin Standardization Program [NGSP] unit%) and the highest decile (ⱖ5.8 NGSP%) of A1C as a dependent variable and FPG, age, BMI, TB, hemoglobin, iron, WBC, hs-CRP, and smoking status as independent variables were performed in apparently healthy Japanese 1,803 men and 1,150 women who had no history of CVD and were with no antihypertensive, antidiabetic, or antihyperlipidemic medication. FPG (P ⬍ 0.0001), age (P ⬍ 0.0001), TB (P ⫽ 0.0003), BMI (P ⫽ 0.02), hemoglobin (P ⬍ 0.0001), and WBC (P ⫽ 0.001) in men and FPG (P ⬍ 0.0001), age (P ⬍ 0.0001), TB (P ⫽ 0.002), and iron (P ⫽ 0.004) in women were significantly associated with A1C in multivariate linear regressions. FPG (P ⬍ 0.0001), age (P ⬍ 0.0001), TB (P ⬍ 0.01), BMI (P ⬍ 0.05), hemoglobin (P ⬍ 0.05), and WBC (P ⬍ 0.05) in men and FPG (P ⬍ 0.0001), age (P ⬍ 0.0001) and TB (P ⬍ 0.01) in women were significantly associated with both the highest quartile and the highest decile of A1C in multivariate logistic regressions. Thus, bilirubin was significantly negatively associated with A1C independently of FPG, age, obesity, inflammation, hemoglobin, and iron in apparently healthy Japanese men and women. Therefore, the association of A1C with CVD beyond FPG in nondiabetic
adults may at least partly be mediated by the association between A1C and bilirubin in nondiabetic subjects. EIJI ODA, MD From the Medical Check-up Center, Tachikawa Medical Center, Nagaoka, Niigata, Japan. Corresponding author: Eiji Oda, ijie@venus. sannet.ne.jp. DOI: 10.2337/dc10-1246 © 2010 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http:// creativecommons.org/licenses/by-nc-nd/3.0/ for details.
Acknowledgments — No potential conflicts of interest relevant to this article were reported. ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
References 1. Selvin E, Steffes MW, Zhu H, Matsushita K, Wagenknecht L, Pankow J, Coresh J, Brancati FL. Glycated hemoglobin, diabetes, and cardiovascular risk in nondiabetic adults. N Engl J Med 2010;362:800 – 811 2. International Expert Committee. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. Diabetes Care 2009;32:1327– 1334 3. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science 1987;235:1043–1046 4. Troughton JA, Woodside JV, Young IS, Arveiler D, Amouyel P, Ferrie`res J, Ducimetie`re P, Patterson CC, Kee F, Yarnell JW, Evans A, PRIME Study Group. Bilirubin and coronary heart disease risk in the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Eur J Cardiovasc Prev Rehabil 2007;14:79 – 84 5. Kimm H, Yun JE, Jo J, Jee SH. Low serum bilirubin level as an independent predictor of stroke incidence: a prospective study in Korean men and women. Stroke 2009;40:3422–3427
DIABETES CARE, VOLUME 33, NUMBER 10, OCTOBER 2010
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