AS238 - Biochemical predictors of type 2 diabetes mellitus in women

Investigator Names and Contact Information

Simin Liu, MD, ScD

Introduction/Intent

Despite much progress in biomedical science, type 2 diabetes (T2D) continues to be a leading cause of death and disability for millions of Americans. The fundamental basis of type 2 diabetes (T2D) pathogenesis involves impaired insulin action and secretion. Clinically, obesity and android fat distribution are the most prominent features of patients with impaired insulin action and T2D. However, mechanisms linking obesity, especially android-type, to the increased risk of T2D are not well understood. After carefully reviewing the scientific literature published in the past 40 years, it seems that one key difference was in which sex-steroid hormones affected T2D risk differently in men and women⁶. A majority of these studies were cross-sectional indicating that men with T2D had significantly lower testosterone levels compared with nondiabetic men; in contrast, women with T2D had higher testosterone levels compared with nondiabetic women. Our research group has devoted much effort in the quest for insight into the epidemiologic architecture concerning the role of hormone in T2D etiology. In our own molecular epidemiology work, we have consistently observed that sex-hormone binding globulin (SHBG) appeared to best capture the cumulative effect of both genetic and environmental factors on diabetes risk, an observation also repeated by others from Canada. This protein may have implications for clinical stratification and treatment of T2D⁷. Given the potential significance of the gender-specific pathophysiology of T2D, it is surprising that few prospective studies have directly examined the role of sex-steroid hormones in predicting T2D risk, especially in women and minorities. Therefore, we examined this hypothesis in a case-control study of nested in the Women’s Health Study (WHS), and observed sex-steroid hormones play powerful predictive roles in the development of T2D among these Caucasian female health professionals¹. Directly following on these findings, we propose, in this application, to validate and confirm our previous work on sex-steroid hormones, as well as adipokines, in predicting T2D risk in a large, well-characterized prospective cohort of multi-ethnic women who enrolled in the Women’s Health Initiative Observational Study (WHI-OS). Second, we will examine the interrelationship between sex-steroid hormones and adipokines on T2D risk, which remains largely unexplored, and because the joint effects of these factors on T2D risk are also poorly understood. Some of these hypotheses have never been examined prospectively, and therefore will have tremendous value in defining the potential causal role of sex-steroids in T2D etiology. Using these unparalleled resources from the WHI, we have established an excellent track record of documenting important dietary, biochemical, hormonal, and genetic risk factors for T2D. The large prospective resources from WHI offer us a unique opportunity to investigate promising biomarkers as predictors of T2D. Thus, the current proposal represents an exceptionally cost-effective means to continue advancing our understanding of the pathophysiology and clinical risk prediction of this disease. Ultimately, we will use the above information as well as all routine clinical measures and available biomarkers, to build prediction models of T2D for each ethnic group. The specific aims are:

Primary 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-17B (E2) and SHBG, are prospectively associated with increased T2D risk.
2. To assess the relationships between some less-well investigated adipokines and T2D risk; to examine whether such associations differ by obesity. The markers to be examined include leptin, soluble leptin receptor, resistin and adiponectin.
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.

Secondary Aim

4. To further examine whether each adipokine marker mediates or modifies the relationship between sex-steroid hormones and T2D risk.

Results/Findings

Some of the publications related to this ancillary study are:

Ms1452 - Chen BH, Brennan K, Goto A, Song Y, Aziz N, You NC, Wellons MF, Manson JE, White DL, Butch AW, Liu S. Sex hormone-binding globulin and risk of clinical diabetes in American Black, Hispanic, and Asian/Pacific Islander postmenopausal women. Clin Chem. 2012 Oct;58(10):1457-66. Epub 2012 Aug 20

For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Papers section of this website.

References

1. Ding EL, Song Y, Manson JE, Rifai N, Buring JE, Liu S. Plasma sex steroid hormones and risk of developing type 2 diabetes in women: a prospective study. Diabetologia 2007; 50:2076-2084.
2. Ding EL, Song Y, Malik VS, Liu S. Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 2006; 295:1288-99.
3. Selva DM, Hogeveen KN, Innis SM, Hammond GL. Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone-binding globulin gene. J Clin Invest 2007; 117:3979-87.