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

Department of Epidemiology, University of California, Los Angeles, CA 90095-1772, USA.
Archives of Internal Medicine (Impact Factor: 17.33). 08/2007; 167(15):1676-85. DOI: 10.1001/archinte.167.15.1676
Source: PubMed


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.

  • Source
    • ") and global deletion of the Il-6 gene promotes insulin resistance in mice (Matthews et al., 2010). On the other hand, increased IL-6 expression in the liver, induced by chronic inflammation, can promote hepatic insulin resistance and HCC (Fernandez-Real et al., 2001; Johnson et al., 2012; Klover et al., 2003, 2005; Liu et al., 2007; Pang et al., 2011). Consistent with this, inhibition of elevated IL-6 signaling increases insulin sensitivity in mice and humans with diabetes and/or rheumatoid disease (Klover et al., 2003, 2005; Ogata et al., 2011; Schultz et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Type 2 diabetes (T2D) and male gender are associated with hepatocellular carcinoma (HCC) development. We demonstrate that heterozygous deletion of the Ncoa5 gene causes spontaneous development of HCC exclusively in male mice. Tumor development is preceded by increased interleukin-6 (IL-6) expression, early-onset glucose intolerance, and progressive steatosis and dysplasia in livers. Blockading IL-6 overexpression averts glucose intolerance and partially deters HCC development. Moreover, reduced NCOA5 expression is associated with a fraction of human HCCs and HCCs with comorbid T2D. These findings suggest that NCOA5 is a haploinsufficient tumor suppressor and that NCOA5 deficiency increases susceptibility to both glucose intolerance and HCC, partially by increasing IL-6 expression. Thus, our findings open additional avenues for developing therapeutic approaches to combat these diseases.
    Full-text · Article · Dec 2013 · Cancer cell
  • Source
    • "Recent research has established that obesity is a chronic lowgrade inflammatory condition (Herder et al., 2007; Liu et al., 2007; Amati et al., 2010; Balistreri et al., 2010; Park et al., 2010; Thompson et al., 2011). Following bariatric surgery, patients usually experience approximately 30% weight loss as well as decreased overall inflammatory responses (Compher and Badellino, 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Over a third of the US population is obese and at high risk for developing type 2 diabetes, insulin resistance, and other metabolic disorders. Obesity is considered a chronic low-grade inflammatory condition that is primarily attributed to expansion and inflammation of adipose tissues. Indeed, adipocytes produce and secrete numerous proinflammatory and anti-inflammatory cytokines known as adipokines. When the balance of these adipokines is shifted toward higher production of proinflammatory factors, local inflammation within adipose tissues and subsequently systemic inflammation occur. These adipokines including leptin, visfatin, resistin, apelin, vaspin, and retinol binding protein-4 can regulate inflammatory responses and contribute to the pathogenesis of diabetes. These effects are mediated by key inflammatory signaling molecules including activated serine kinases such as c-Jun N-terminal kinase and serine kinases inhibitor κB kinase and insulin signaling molecules including insulin receptor substrates, protein kinase B (PKB, also known as Akt), and nuclear factor kappa B. Bariatric surgery can decrease body weight and improve insulin resistance in morbidly obese subjects. However, despite reports suggesting reduced inflammation and weight-independent effects of bariatric surgery on glucose metabolism, mechanisms behind such improvements are not yet well understood. This review article focuses on some of these novel adipokines and discusses their changes after bariatric surgery and their relationship to insulin resistance, fat mass, inflammation, and glucose homeostasis.
    Full-text · Article · Jun 2013 · Frontiers in Endocrinology
  • Source
    • "In contrast, smoking, in particular heavy smoking, is clearly associated with an increased risk of type 2 diabetes (5). The increased risk has been attributed to impaired insulin sensitivity (6), increased systematic inflammation (7), greater accumulation of abdominal adipose tissue (8), and/or adverse effects on pancreatic tissue and β-cell function (9). Overweight may modify the influence of smoking on type 2 diabetes; in one Japanese study, the association between smoking and type 2 diabetes was limited to overweight individuals (10), and findings from a Finnish study suggest that smoking is more detrimental in individuals with high BMI (11). "
    [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE To investigate the association between smoking habits and risk of autoimmune diabetes in adults and of type 2 diabetes.RESEARCH DESIGN AND METHODS We used data from the three surveys of the Nord Trøndelag Health Study, spanning 1984-2008 and including a cohort of 90,819 Norwegian men (48%) and women (52%) aged ≥20 years. Incident cases of diabetes were identified by questionnaire and classified as type 2 diabetes (n = 1,860) and autoimmune diabetes (n = 140) based on antibodies to glutamic decarboxylase (GADA) and age at onset of diabetes. Hazard ratios (HR) adjusted for confounders were estimated by Cox proportion hazards regression models.RESULTSThe risk of autoimmune diabetes was reduced by 48% (HR 0.52 [95% CI 0.30-0.89]) in current smokers and 58% in heavy smokers (0.42 [0.18-0.98]). The reduced risk was positively associated with number of pack-years. Heavy smoking was associated with lower levels of GADA (P = 0.001) and higher levels of C-peptide (964 vs. 886 pmol/L; P = 0.03). In contrast, smoking was associated with an increased risk of type 2 diabetes, restricted to overweight men (1.33 [1.10-1.61]). Attributable proportion due to an interaction between overweight and heavy smoking was estimated to 0.40 (95% CI 0.23-0.57).CONCLUSIONS In this epidemiological study, smoking is associated with a reduced risk of autoimmune diabetes, possibly linked to an inhibitory effect on the autoimmune process. An increased risk of type 2 diabetes was restricted to overweight men.
    Full-text · Article · Nov 2012 · Diabetes care
Show more