Sex Hormones Genotypes and Phenotypes and Determinants of Sex Hormone Binding Globulin in relation to Type 2 Diabetes Risk

Type 2 diabetes (T2D) is a common and complex metabolic disease that is associated with serious complications and premature mortality. Several prospective studies and clinical experiments support the role of sex hormones in the development of T2D.This dissertation examines the roles of sex hormones and sex hormone-binding globulin (SHBG) in the development of T2D as well as the determinants of SHBG levels. Chapter 1 introduces general background information regarding sex hormones and SHBG in relation to the pathogenesis of T2D as well as determinants of plasma SHBG levels. Chapter 2 explores whether the levels of sex hormones and SHBG may play a role in the inverse relation between coffee intake and the risk of T2D in the Women's Health Study. Chapter 3 examines the potential determinants of circulating levels of SHBG in a pooled analysis of studies included in the Women's Health Initiative Randomized Trial and Observational Study. Chapter 4 investigates roles of sex hormone pathway genes in the development of T2D and examines consistency across African-American women, Hispanic women, and European-American based on data from the Women's Health Initiative SNP Health Association Resource (WHI-SHARe) and the WHI Genomics and Randomized Trials Network (WHI-GARNET). Our findings indicated that the observed inverse associations of caffeinated-coffee and caffeine intakes with the risk of T2D were substantially attenuated after taking into account of SHBG levels. Findings from a pooled analysis of studies included in the Women's Health Initiative suggested that age, usage of exogenous estrogen, BMI, and lifestyle factors may be associated with plasma levels of SHBG. In a genetic study examining associations between sex hormone pathway genes and T2D risk, possible associations between genes involved in sex hormones synthesis and metabolism, estrogen receptors, and androgen receptor and the risk of T2D were seen in African Americans, and possible relations between genes involved in the metabolism of androgen and progesterone receptor and the risk of T2D risk were seen in Hispanics. The directions of effect estimates were generally consistent across ethnicity.These findings support the notion that sex hormones and SHBG may play roles in the pathogenesis of T2D. Also, the findings suggest that age, usage of exogenous estrogen, physical activity, regular coffee intake, and adiposity may play roles in the regulation of SHBG metabolism. Further studies in replicative and experimental settings are warranted to confirm the findings