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      Inflammation and the Incidence of Type 2 Diabetes : The Multi-Ethnic Study of Atherosclerosis (MESA)

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          Abstract

          OBJECTIVE

          Many studies have documented associations between inflammation and type 2 diabetes incidence. We assessed potential variability in this association in the major U.S. racial/ethnic groups.

          RESEARCH DESIGN AND METHODS

          Incident type 2 diabetes was assessed among men and women aged 45–84 years without prior clinical cardiovascular disease or diabetes in the prospective Multi-Ethnic Study of Atherosclerosis. Interleukin (IL)-6, fibrinogen, and C-reactive protein (CRP) were measured at baseline (2000–2002); fasting glucose and diabetes medication use was assessed at baseline and three subsequent in-person exams through 2007. Type 2 diabetes was defined as use of diabetes drugs or glucose ≥126 mg/dl. Covariates included baseline demographics, clinic, smoking, alcohol, exercise, hypertension medication, systolic blood pressure, insulin resistance, and BMI. Cox proportional hazards regression was used to calculate hazard ratios (HRs) by quartiles of CRP, IL-6, and fibrinogen.

          RESULTS

          Among 5,571 participants (mean age 61.6 years, 53% female, 42.1% white, 11.5% Chinese, 25.7% black, and 20.7% Hispanic), 410 developed incident diabetes during a median follow-up time of 4.7 years (incidence 16.8 per 1,000 person-years). CRP, IL-6, and fibrinogen levels were associated with incident diabetes in the entire sample. After adjustment, the associations were attenuated; however, quartile 4 (versus quartile 1) of IL-6 (HR 1.5 [95% CI 1.1–2.2]) and CRP (1.7 [1.3–2.4]) remained associated with incident diabetes. In stratified analyses, similar associations were observed among white, black, and Hispanic participants.

          CONCLUSIONS

          Higher levels of inflammation predict short-term incidence of type 2 diabetes in a multiethnic American sample.

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          Most cited references18

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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.

          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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            Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population: National Health And Nutrition Examination Survey 1999-2002.

            The purpose of this study was to examine the prevalences of diagnosed and undiagnosed diabetes, and impaired fasting glucose (IFG) in U.S. adults during 1999-2002, and compare prevalences to those in 1988-1994. The National Health and Nutrition Examination Survey (NHANES) contains a probability sample of adults aged > or =20 years. In the NHANES 1999-2002, 4,761 adults were classified on glycemic status using standard criteria, based on an interview for diagnosed diabetes and fasting plasma glucose measured in a subsample. The crude prevalence of total diabetes in 1999-2002 was 9.3% (19.3 million, 2002 U.S. population), consisting of 6.5% diagnosed and 2.8% undiagnosed. An additional 26.0% had IFG, totaling 35.3% (73.3 million) with either diabetes or IFG. The prevalence of total diabetes rose with age, reaching 21.6% for those aged > or =65 years. The prevalence of diagnosed diabetes was twice as high in non-Hispanic blacks and Mexican Americans compared with non-Hispanic whites (both P < 0.00001), whereas the prevalence of undiagnosed diabetes was similar by race/ethnicity, adjusted for age and sex. The prevalence of diagnosed diabetes was similar by sex, but prevalences of undiagnosed diabetes and IFG were significantly higher in men. The crude prevalence of diagnosed diabetes rose significantly from 5.1% in 1988-1994 to 6.5% in 1999-2002, but the crude prevalences were stable for undiagnosed diabetes (from 2.7 to 2.8%) and IFG (from 24.7 to 26.0%). Results were similar after adjustment for age and sex. Although the prevalence of diagnosed diabetes has increased significantly over the last decade, the prevalences of undiagnosed diabetes and IFG have remained relatively stable. Minority groups remain disproportionately affected.
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              Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study.

              Elevated serum levels of acute-phase proteins, indicating chronic subclinical inflammation, have been associated with cardiovascular disease as well as the insulin resistance syndrome. Chronic inflammation may also be a risk factor for developing type 2 diabetes. We studied the concentrations of C-reactive protein (CRP), fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) in 1,047 nondiabetic subjects in relation to incident diabetes within 5 years in the Insulin Resistance Atherosclerosis Study. Subjects with diabetes at follow-up (n = 144) had higher baseline levels of fibrinogen (mean +/- SD; 287.8 +/- 58.8 vs. 275.1 +/- 56.0 mg/dl; P = 0.013) as well as of CRP (median [interquartile range]; 2.40 [1.29, 5.87] vs. 1.67 mg/l [0.75, 3.41]; P = 0.0001) and PAI-1 (24 [15, 37.5] vs. 16 ng/ml [9, 27]; P = 0.0001) than nonconverters. The odds ratio (OR) of converting to diabetes was significantly increased with increasing baseline concentrations of the inflammatory markers. In contrast to PAI-1, the association of CRP and fibrinogen with incident diabetes was significantly attenuated after adjustment for body fat (BMI or waist circumference) or insulin sensitivity (S(I)), as assessed by a frequently sampled intravenous glucose tolerance test. In a logistic regression model that included age, sex, ethnicity, clinical center, smoking, BMI, S(I), physical activity, and family history of diabetes, PAI-1 still remained significantly related to incident type 2 diabetes (OR [95% CI] for 1 SD increase: 1.61 [1.20-2.16]; P = 0.002). Chronic inflammation emerges as a new risk factor for the development of type 2 diabetes; PAI-1 predicts type 2 diabetes independent of insulin resistance and other known risk factors for diabetes.
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                Author and article information

                Journal
                Diabetes Care
                diacare
                dcare
                Diabetes Care
                Diabetes Care
                American Diabetes Association
                0149-5992
                1935-5548
                April 2010
                22 January 2010
                : 33
                : 4
                : 804-810
                Affiliations
                [1] 1Division of Public Health Sciences, Wake Forest University Health Sciences, Winston-Salem, North Carolina;
                [2] 2Department of Epidemiology and Prevention, Wake Forest University Health Sciences, Winston-Salem, North Carolina;
                [3] 3Department of Preventive Medicine, Northwestern University, Chicago, Illinois;
                [4] 4Department of Medicine, Johns Hopkins University, Baltimore, Maryland;
                [5] 5Departments of Medicine and Epidemiology, Columbia University Medical Center, New York, New York;
                [6] 6Department of Pathology, University of Vermont College of Medicine, Burlington, Vermont;
                [7] 7Department of Medicine, Cedars Sinai Medical Center, Los Angeles, California.
                Author notes
                Corresponding author: A.G. Bertoni, abertoni@ 123456wfubmc.edu .
                Article
                1679
                10.2337/dc09-1679
                2845031
                20097779
                fee6b5e5-fbd0-4745-80c4-0ff4be30cb57
                © 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.

                History
                : 8 September 2009
                : 16 January 2010
                Categories
                Original Research
                Epidemiology/Health Services Research

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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