Sex hormone-binding globulin and risk of clinical diabetes in American black, Hispanic, and Asian/Pacific Islander postmenopausal women.

BACKGROUND Recent prospective studies have shown a strong inverse association between sex hormone-binding globulin (SHBG) concentrations and risk of clinical diabetes in white individuals. However, it remains unclear whether this relationship extends to other racial/ethnic populations. METHODS We evaluated the association between baseline concentrations of SHBG and clinical diabetes risk in the Women's Health Initiative Observational Study. Over a median follow-up of 5.9 years, we identified 642 postmenopausal women who developed clinical diabetes (380 blacks, 157 Hispanics, 105 Asians) and 1286 matched controls (777 blacks, 307 Hispanics, 202 Asians). RESULTS Higher concentrations of SHBG at baseline were associated with a significantly lower risk of clinical diabetes [relative risk (RR), 0.15; 95% CI, 0.09-0.26 for highest vs lowest quartile of SHBG, adjusted for BMI and known diabetes risk factors]. The associations remained consistent within ethnic groups [RR, 0.19 (95% CI, 0.10-0.38) for blacks; RR, 0.17 (95% CI, 0.05-0.57) for Hispanics; and 0.13 (95% CI, 0.03-0.48) for Asians]. Adjustment for potential confounders, such as total testosterone (RR, 0.11; 95% CI, 0.07-0.19) or HOMA-IR (RR, 0.26; 95% CI, 0.14-0.48) did not alter the RR substantially. In addition, SHBG concentrations were significantly associated with risk of clinical diabetes across categories of hormone therapy use (never users: RR(per SD) = 0.42, 95% CI, 0.34-0.51; past users: RR(per SD) = 0.53;, 95% CI, 0.37-0.77; current users: RR(per SD) = 0.57; 95% CI, 0.46-0.69; P-interaction = 0.10). CONCLUSIONS In this prospective study of postmenopausal women, we observed a robust, inverse relationship between serum concentrations of SHBG and risk of clinical diabetes in American blacks, Hispanics, and Asians/Pacific Islanders. These associations appeared to be independent of sex hormone concentrations, adiposity, or insulin resistance.

[1]  M. Yamakido,et al.  Association of sex hormone-binding globulin and insulin resistance among Japanese-American subjects. , 2000, Diabetes research and clinical practice.

[2]  A. Araujo,et al.  The effect of diurnal variation on clinical measurement of serum testosterone and other sex hormone levels in men. , 2009, The Journal of clinical endocrinology and metabolism.

[3]  S. Gapstur,et al.  The association of endogenous sex hormones, adiposity, and insulin resistance with incident diabetes in postmenopausal women. , 2009, The Journal of clinical endocrinology and metabolism.

[4]  Jennifer G. Robinson,et al.  Validity of diabetes self-reports in the Women's Health Initiative: comparison with medication inventories and fasting glucose measurements , 2008, Clinical trials.

[5]  M. S. Khan,et al.  Solubilization and partial characterization of the sex hormone-binding globulin receptor from human prostate. , 1989, The Journal of biological chemistry.

[6]  M. S. Khan,et al.  The control of the interaction of sex hormone-binding globulin with its receptor by steroid hormones. , 1990, The Journal of biological chemistry.

[7]  E. Ding,et al.  Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. , 2006, JAMA.

[8]  A. Stubbs,et al.  Estrogen and androgen regulation of sex hormone binding globulin secretion by a human liver cell line , 1990, The Journal of Steroid Biochemistry and Molecular Biology.

[9]  H. Schulz,et al.  Role of Endocytosis in Cellular Uptake of Sex Steroids , 2005, Cell.

[10]  R. Turner,et al.  Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man , 1985, Diabetologia.

[11]  G Lindstedt,et al.  Low Sex-Hormone-Binding Globulin Concentration as Independent Risk Factor for Development of NIDDM: 12-Yr Follow-Up of Population Study of Women in Gothenburg, Sweden , 1991, Diabetes.

[12]  JoAnn E. Manson,et al.  Design of the Women's Health Initiative clinical trial and observational study. The Women's Health Initiative Study Group. , 1998, Controlled clinical trials.

[13]  S. Krupenko,et al.  Interaction of sex hormone-binding globulin with plasma membranes from the rat epididymis and other tissues , 1994, The Journal of Steroid Biochemistry and Molecular Biology.

[14]  M. S. Khan,et al.  Biologically active steroids activate receptor-bound human sex hormone-binding globulin to cause LNCaP cells to accumulate adenosine 3',5'-monophosphate. , 1990, The Journal of clinical endocrinology and metabolism.

[15]  J. Manson,et al.  A prospective study of inflammatory cytokines and diabetes mellitus in a multiethnic cohort of postmenopausal women. , 2007, Archives of internal medicine.

[16]  G. Hammond,et al.  Sex hormone-binding globulin: gene organization and structure/function analyses. , 1996, Hormone research.

[17]  D. Schoenfeld,et al.  Measurement of free testosterone in normal women and women with androgen deficiency: comparison of methods. , 2004, The Journal of clinical endocrinology and metabolism.

[18]  Scott Davis,et al.  Implementation of the Women's Health Initiative study design. , 2003, Annals of epidemiology.

[19]  S. Kahn,et al.  Interactions of sex hormone-binding globulin with target cells , 2010, Molecular and Cellular Endocrinology.

[20]  C. Porto,et al.  Receptors for androgen-binding proteins: Internalization and intracellular signalling , 1995, The Journal of Steroid Biochemistry and Molecular Biology.

[21]  F. Berrino,et al.  Free estradiol and breast cancer risk in postmenopausal women: comparison of measured and calculated values. , 2003, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[22]  C. Frampton,et al.  Plasma variation of corticosteroid-binding globulin and sex hormone-binding globulin. , 2006, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[23]  B. O’Malley,et al.  An alternative ligand-independent pathway for activation of steroid receptors. , 1995, Recent progress in hormone research.

[24]  E. Riboli,et al.  Validity of free testosterone and free estradiol determinations in serum samples from postmenopausal women by theoretical calculations. , 2002, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[25]  M. Jarvelin,et al.  Genetic evidence that raised sex hormone binding globulin (SHBG) levels reduce the risk of type 2 diabetes , 2009, Human molecular genetics.

[26]  T. Bäckström,et al.  Calculation of free and bound fractions of testosterone and estradiol-17 beta to human plasma proteins at body temperature. , 1982, Journal of steroid biochemistry.

[27]  R. Frairia,et al.  Sex steroid binding protein (SBP) receptors in estrogen sensitive tissues , 1991, The Journal of Steroid Biochemistry and Molecular Biology.

[28]  W. Rosner,et al.  Testosterone-binding globulins in human plasma: studies on sex distribution and specificity. , 1968, The Journal of clinical investigation.

[29]  C. Cheng,et al.  The cDNA‐deduced primary structure of human sex hormone‐binding globulin and location of its steroid‐binding domain , 1987, FEBS letters.

[30]  S. Haffner,et al.  Decreased sex hormone-binding globulin predicts noninsulin-dependent diabetes mellitus in women but not in men. , 1993, The Journal of clinical endocrinology and metabolism.

[31]  J. Manson,et al.  Insulin Sensitivity and Insulin Secretion Determined by Homeostasis Model Assessment and Risk of Diabetes in a Multiethnic Cohort of Women , 2007, Diabetes Care.

[32]  J. Carter.  Sex hormone-binding globulin and risk of type 2 diabetes in women and men , 2010 .

[33]  A. Vermeulen,et al.  A critical evaluation of simple methods for the estimation of free testosterone in serum. , 1999, The Journal of clinical endocrinology and metabolism.