This proposal focuses on the prospective Women s Health Initiative Observational Study (WHI-OS) in which a total of 93,676 women aged 50-79 are followed for an average of 10 years to study the causes and treatments of health outcomes. Using these unparalleled resources, we have established an excellent track record of documenting important dietary, biochemical, hormonal, and genetic risk factors for T2D in the previous funding cycle. In this application, we propose to investigate the roles of endogenous sex-steroid hormones, novel adipokines, and their interactions in the development of T2D in a nested case-control study from WHI-OS of 2,150 incident T2D cases and 3,200 comparable controls (1:1 matching in white, and 1:2 matching in minorities). In particular, we will examine the following primary specific aims: 1) To examine the relationships between sex-steroid hormone levels and the risk of T2D in a large and ethnically diverse cohort of postmenopausal women. We hypothesize that markers for hyperandrogenism, including high plasma levels of bioavailable testosterone and dehydroepiandrosterone sulfate (DHEAS) and low levels of estradiol-17β (E2) and SHBG, are prospectively associated with increased T2D risk; 2) To assess the relationships between novel adipokines and T2D risk; to examine whether such associations differ by adiposity or obesity; 3)To build a parsimonious prediction model, including all clinical measures and all available and proposed biomarkers, to evaluate the comparative usefulness of these biomarkers versus established diabetes risk factors as independent predictors for T2D in each ethnic group; to develop simple and effective T2D risk scores that improve the identification of women at risk of developing T2D. Further, we will examine whether each adipokine marker mediates or modifies the relationship between sex-steroid hormones and T2D risk as a secondary aim. Because the significant accomplishment in the previous finding cycle, we now have established a large case-control study with extensive and well-characterized environmental and biochemical phenotypes. Thus, the current proposal represents an exceptionally cost-effective means to continue advancing our understanding of T2D pathophysiology, especially among minority Americans, including Hispanic/Latinos, Blacks/Africans, and Asians/Pacific Islanders, who bear a disproportionately high burden of this disease yet have been poorly studied. Knowledge gained from this proposed study may suggest new diagnostic and intervention strategies to lower T2D incidence in populations.
Statement Type 2 diabetes mellitus (T2D) is considered ?the epidemic of the 21st century?, affecting approximately 20 million individuals in the US alone, or almost 10% of the US population. Although insulin resistance and progressive pancreatic beta-cell dysfunction have been identified as the two fundamental steps in the pathogenesis of T2D, specific cellular defects affecting insulin sensitivity and/or β-cell function remain largely undefined, especially among minority women. In a large prospective case-control study of 5,350 ethnically diverse postmenopausal women, we will evaluate the roles of biomarkers in sex-steroid pathway (i.e., testosterone, dehydroepiandrosterone sulfate [DHEAS], sex hormone binding globulin [SHBG], and estradiol- 17β[E2]), and novel adipokines (i.e., adiponectin, resistin, leptin, and leptin receptor) in the development of T2D. We believe that the findings from this series of comprehensive yet focused analyses will shed new light on the etiology of T2D, especially among minority Americans who bear a disproportionately high burden of this disease yet have been poorly studied. Knowledge gained from this proposed study may suggest new intervention strategies to lower the incidence of T2D in the general population.
