A prospective study of inflammatory cytokines and diabetes mellitus in a multiethnic cohort of postmenopausal women.

Department of Epidemiology, University of California, Los Angeles, CA 90095-1772, USA.
Archives of Internal Medicine (Impact Factor: 13.25). 01/2007; 167(15):1676-85. DOI: 10.1001/archinte.167.15.1676
Source: PubMed

ABSTRACT Inflammatory cytokines, including tumor necrosis factor alpha, IL-6 (interleukin 6), and high-sensitivity C-reactive protein (hsCRP), have been related to both insulin resistance and type 2 diabetes mellitus. However, prospective studies that comprehensively assess their roles in the development of type 2 diabetes are few, especially in minority populations.
Among 82,069 postmenopausal women aged 50 to 79 years without cardiovascular disease or diabetes mellitus who participated in the Women's Health Initiative Observational Study, we prospectively examined the relationships of plasma levels of tumor necrosis factor alpha receptor 2, IL-6, and hsCRP to diabetes risk. During a median follow-up period of 5.9 years, 1584 women who had clinical diabetes were matched by age, ethnicity, clinical center, time of blood draw, and duration of follow-up to 2198 study participants who were free of the disease.
After adjustment for matching factors and known diabetes risk factors, all 3 markers were significantly associated with increased diabetes risk; the estimated relative risks comparing the highest with the lowest quartiles were 1.47 (95% confidence interval [CI], 1.10-1.97) for tumor necrosis factor alpha receptor 2, 3.08 (95% CI, 2.25-4.23) for IL-6, and 3.46 (95% CI, 2.50-4.80) for hsCRP (P for trend, <.01 for all biomarkers). When mutually adjusted, IL-6 and hsCRP remained significant in each ethnic group. While no statistically significant interactions were observed between ethnicity and these biomarkers on diabetes risk, there were consistent trends for the associations of hsCRP and IL-6 with increased diabetes risk in all ethnic groups.
These prospective data showed that elevated levels of IL-6 and hsCRP were consistently and significantly associated with an increased risk of clinical diabetes in postmenopausal women.

1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: Systemic low-grade inflammation, as measured by high-sensitive C-reactive protein (hsCRP), may contribute to the risk of type 2 diabetes in patients with manifest arterial disease. Cohort study in 4072 patients with manifest arterial disease without diabetes. The relation between quartiles of hsCRP and type 2 diabetes was assessed with Cox regression analyses, taking age, smoking and blood pressure-lowering medication and lipid-lowering medication into account. Insulin resistance was estimated with homeostasis model of insulin resistance (HOMA-IR). In exploratory models, adjustments were performed for body mass index (BMI) and visceral and subcutaneous adipose tissue thickness. During a median follow-up of 5·0 (IQR 2·5-8·2) years, 288 subjects developed diabetes. High hsCRP was independently associated with incident diabetes (Q4 vs. Q1 males: HR 1·62; 95% CI 1·06-2·48; females: HR 3·12; 95% CI 1·57-6·21). HOMA-IR at baseline is related to hsCRP plasma levels (Q4 vs. Q1: males: β 0·27; 95% CI 0·19-0·36; females: β 0·35; 95% CI 0·22-0·48). The risk of diabetes associated with hsCRP was abolished in males (Q4 vs. 1 HR 1·23; 95% CI 0·80-1·88) and attenuated in females (Q4 vs. 1 HR 2·32; 95% CI 1·14-4·75) after adding BMI to the model, but not modified by statin use (P for interaction: 0·61). Patients with manifest arterial disease with high hsCRP plasma levels are at increased risk to develop type 2 diabetes and are more insulin resistant as compared to those with low hsCRP levels. This increase in risk is more pronounced in females than in males and is not modified by statin use.
    European Journal of Clinical Investigation 07/2013; DOI:10.1111/eci.12142 · 2.83 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background-Although cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D) share many common risk factors, potential molecular mechanisms that may also be shared for these 2 disorders remain unknown. Methods and Results-Using an integrative pathway and network analysis, we performed genome-wide association studies in 8155 blacks, 3494 Hispanic American, and 3697 Caucasian American women who participated in the national Women's Health Initiative single-nucleotide polymorphism (SNP) Health Association Resource and the Genomics and Randomized Trials Network. Eight top pathways and gene networks related to cardiomyopathy, calcium signaling, axon guidance, cell adhesion, and extracellular matrix seemed to be commonly shared between CVD and T2D across all 3 ethnic groups. We also identified ethnicity-specific pathways, such as cell cycle (specific for Hispanic American and Caucasian American) and tight junction (CVD and combined CVD and T2D in Hispanic American). In network analysis of gene-gene or protein-protein interactions, we identified key drivers that included COL1A1, COL3A1, and ELN in the shared pathways for both CVD and T2D. These key driver genes were cross-validated in multiple mouse models of diabetes mellitus and atherosclerosis. Conclusions-Our integrative analysis of American women of 3 ethnicities identified multiple shared biological pathways and key regulatory genes for the development of CVD and T2D. These prospective findings also support the notion that ethnicity-specific susceptibility genes and process are involved in the pathogenesis of CVD and T2D.
    Circulation Cardiovascular Genetics 11/2014; 7(6). DOI:10.1161/CIRCGENETICS.114.000676 · 6.73 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The prevalence of cardiovascular disease (CVD) is increasing around the globe and is the leading cause of death around the world. Though once thought of as an adult problem, it is now recognised that the early manifestations of disease may occur during childhood. Numerous risk factors have been linked to CVD with much of the research focusing on understanding the prevalence and relationship of traditional risk factors such as dyslipidemia, smoking, diabetes mellitus, hypertension, obesity, psychosocial stress, poor diet, physical inactivity and alcohol consumption to the early etiology of disease. While this line of investigation has greatly enhanced our understanding of the relationship between these risk factors and disease, they do not fully explain all cardiovascular events. To enhance our understanding and help with the management of CVD, investigations that involve the measurement of traditional as well as novel risk factors may be necessary. Public health strategies that aim to reduce the prevalence of obesity and overweight encourage youth to increase their physical activity levels as a means of protecting against poor cardiometabolic profiles. Interventions that increase physical activity levels and improve cardiorespiratory fitness cause a reduction in certain CVD risk factors but the lack of agreement between findings makes it impossible to give precise recommendations that will ensure CVD risk reduction. Yet it is important that research continues in order to establish the most appropriate means of improving the health and well-being of those at most risk of future CVD.
    02/2012; 1(1):59-66. DOI:10.4081/jphr.2012.e11



Similar Publications