Adiposity and insulin resistance are fundamental features in the pathogenesis of type 2 diabetes mellitus (DM). Emerging data suggest that sex-steroid hormones and adipocyte-derived hormones and cytokines (""""""""adipokines"""""""") may be associated with type 2 DM risk and that some of these novel markers may exhibit a sexual dimorphism with respect to this risk. In two large prospective cohorts of men and women with archived blood specimens, we propose to investigate the roles of endogenous steroid hormones and adipokines in the development of type 2 DM. A total of 1,200 incident eases of type 2 DM will be identified and confirmed among 12,304 women in the Women's Health Study (WHS) and 11,130 men in the Physicians' Health Study II (PHS II). We will assay five steroid hormones (i.e., total and bioavailable testosterone, estradiol-17beta [E2], dehydroepiandrosterone sulfate [DHEAS], and sex hormone binding globulin [SHBG]), and three adipokines (tumor necrosis factor-alpha [TNF], adiponectin, and resistin). These biochemical markers can be reliably measured using frozen plasma samples. Applying state-of-the-art genotyping technology and statistical methods, we will define functional variants and determine the structure of haplotypes in nine relevant candidate genes and evaluate their roles as predictors for risk of type 2 DM. These genes will include hormone-metabolizing genes (aromatase [CYP19], androgen receptor, estrogen receptor alpha [ESR1], and SHBG), as well as those related to adiposity and insulin resistance (i.e., peroxisome proliferator-activated receptor-gamma [PPARgamma] and genes that respond to PPAR3' signaling, including TNFalpha, adiponectin, resistin, and the adipocyte-fatty acid binding protein [aP2]). Elucidation of interrelationships between these novel biochemical and genetic markers and the development of type 2 DM may help identify high risk individuals and suggest new treatment and/or prevention strategies, some of which may be sex-specific. Several unique features of these established cohort studies, including their identical prospective design and data collection procedures, high follow-up rates, availability of stored blood specimens, and cost efficiency, make these populations exceptional resources for the etiologic investigation of type 2 DM in women and men.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK066401-02
Application #
6898886
Study Section
Epidemiology of Chronic Diseases Study Section (ECD)
Program Officer
Mckeon, Catherine T
Project Start
2004-07-01
Project End
2005-09-29
Budget Start
2005-06-01
Budget End
2005-09-29
Support Year
2
Fiscal Year
2005
Total Cost
$153,430
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Yang, Aimin; Liu, Simin; Cheng, Ning et al. (2016) Reproductive factors and risk of type 2 diabetes in an occupational cohort of Chinese women. J Diabetes Complications 30:1217-22
Rautiainen, Susanne; Wang, Lu; Lee, I-Min et al. (2015) Higher Intake of Fruit, but Not Vegetables or Fiber, at Baseline Is Associated with Lower Risk of Becoming Overweight or Obese in Middle-Aged and Older Women of Normal BMI at Baseline. J Nutr 145:960-8
Rohwer, Rachelle D; Liu, Simin; You, Nai-Chieh et al. (2015) Interrelationship Between Alcohol Intake and Endogenous Sex-Steroid Hormones on Diabetes Risk in Postmenopausal Women. J Am Coll Nutr 34:273-80
Song, Yan; Huang, Yen-Tsung; Song, Yiqing et al. (2015) Birthweight, mediating biomarkers and the development of type 2 diabetes later in life: a prospective study of multi-ethnic women. Diabetologia 58:1220-30
Goto, Atsushi; Chen, Brian H; Song, Yiqing et al. (2014) Age, body mass, usage of exogenous estrogen, and lifestyle factors in relation to circulating sex hormone-binding globulin concentrations in postmenopausal women. Clin Chem 60:174-85
Livesey, Geoffrey; Taylor, Richard; Livesey, Helen et al. (2013) Is there a dose-response relation of dietary glycemic load to risk of type 2 diabetes? Meta-analysis of prospective cohort studies. Am J Clin Nutr 97:584-96
Chan, Kei Hang K; Niu, Tianhua; Ma, Yunsheng et al. (2013) Common genetic variants in peroxisome proliferator-activated receptor-? (PPARG) and type 2 diabetes risk among Women's Health Initiative postmenopausal women. J Clin Endocrinol Metab 98:E600-4
Chen, Brian H; Brennan, Kathleen; Goto, Atsushi et al. (2012) Sex hormone-binding globulin and risk of clinical diabetes in American black, Hispanic, and Asian/Pacific Islander postmenopausal women. Clin Chem 58:1457-66
Britton, Kathryn A; Lee, I-Min; Wang, Lu et al. (2012) Physical activity and the risk of becoming overweight or obese in middle-aged and older women. Obesity (Silver Spring) 20:1096-103
Song, Yiqing; Liu, Simin (2012) Magnesium for cardiovascular health: time for intervention. Am J Clin Nutr 95:269-70

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