Specific AimsFor decades, African Americans (AA) have been disproportionately affected by obesity, diabetes,hypertension, and cardiovascular disease, which contributes to major health disparities. Despiteincreased attention, research, and behavioral/pharmacological advancements, the wide disparity inthe health of AA remains a major challenge to public health in the United States. Although a largenumber of factors interact in complex ways to contribute to these health disparities, geneticpredisposition, high levels of stress over a lifetime, (racial discrimination and socioeconomic position)and perhaps other negative environmental experiences are undoubtedly important for AA.Additionally, the increased incidence of low birth weight among AA may be factor, since being bornsmall for gestational age is known to predispose individuals to a variety of illnesses in their adult life,including metabolic syndrome. Any and all of these factors may contribute to dysregulation ofhypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) function, andthereby predispose to the previously mentioned cardiovascular and metabolic disturbances.In an ongoing study we have shown that AA men and women, compared to CA men and women,have lower circulating levels of the adrenal steroids, cortisol and dehyroepiandrosterone (DHEA), atbaseline and in response to metabolic and physical stressors. AA subjects also exhibit increasedsensitivity to exogenous glucocorticoids, with markedly enhanced insulin responses to a standardizedmeal, which may predispose them to insulin resistance. Of note, these subjects were screened anddid not have any overt disease, but, in spite of this, exhibited altered functioning and detectable HPAaxis abnormalities. We believe these data support the concept that aberrations in HPA axisfunctioning may be common in AA, and contribute to the health disparities between AA and CA.Our long-term goal is to identify psychosocial, behavioral, and physiologic factors that can bemodified to reduce the burden imposed by health disparities of ethnic groups. The objective of thisproposal is to evaluate how the status and functioning of the HPA axis interacts with other physiologic,psychologic, and sociologic factors in AA of varying degrees of health. We are hypothesizing thatdifferences in HPA axis regulation in AA as a function of physiological and psychological stressors,psychosocial exposures and socioeconomic status, may partially account for the health disparitiesamong this group. The rationale for this proposal is that sufficient data exist to implicate HPA axisdysfunction as a potential mediator of multiple health disparities in AA and possibly, other ethnicgroups. Specifically we intend to:a1. Quantify the relation between HPA axis functioning and measures of health status,lifestyle behaviors, life events, and psychosocial profiles in AA men and women.HPA axis functioning will be measured using salivary cortisol and DHEA concentrations beforeand in response to a socially provocative film. Salivary cortisol and DHEA will also be measured inthe a.m. and p.m. to determine the intactness of the circadian rhythm. Changes in these biologicmeasures will be evaluated with respect to: birth weight, an index of health status (lipid profiles,resting blood pressure and heart rate, body fat, waist circumference), lifestyle behaviors (sleephygiene, physical activity, dietary patterns, drinking, and smoking), socioeconomic status (SES:education and income), psychosocial factors (perceived racism, coping style, acculturation, healthlocus of control, and cognitive hardiness), and life events (Beck Depression Inventory, perceivedstress, stressful life events, daily hassles scale).a2. Quantify the contribution of lifestyle behaviors, life events and psychosocial profiles toinsulin resistance in AA men and women.Fasting blood glucose and insulin will be measured and insulin resistance/sensitivity calculated.We will analyze insulin resistance/sensitivity against the indexes described above to estimate theproportion of variance in IR that can be explained by lifestyle behaviors, psychosocial factors, SES,and life events.a3. Determine how exogenous dehyroepiandrosterone (DHEA) supplementation affectsinsulin resistance, glucocorticoid sensitivity, and HPA axis reactivity in AA men andwomen.Serum insulin and glucose responses to a meal and baseline serum adiponectin, cortisol andDHEA concentrations will be examined in men and women under conditions of placebo and 0.5 mg ofdexamethasone (DEX). ACTH, cortisol and DHEA will be examined in response to exercise. Thesemeasures will be evaluated before and after taking DHEA (100 mg/day) or Placebo for 4-wks.a4. Quantify the effects of exogenous DHEA supplementation on inflammatory markers andthe relation between stress reactivity and inflammatory profiles.Baseline concentrations of CRP, IL6, IL1P, IL10, IL12, and TNF in serum will be examined underconditions of placebo and 0.5 mg of dexamethasone (DEX) and in response to exercise. Serum levelswill be re-evaluated again after taking DHEA (100 mg/day) or Placebo for 4-wks.To accomplish these aims, two studies will be conducted. The first study will include up to 600AA men and women who will provide a blood sample for fasting levels of blood glucose, insulin, andDHEAS and complete multiple questionnaires (as noted above). In addition, salivary samples will beobtained for measuring cortisol and DHEA over a 24 hours period. After the baseline sample,participants will view 30 min of a socially provocative movie, after which another salivary sample willbe obtained for measuring cortisol and DHEA. Heart rate and blood pressure will be determined,along with height, weight, body fat, and waist circumference.For the second study, we will recruit a subset of participants from study one. AA men (n=40) andAA women (n=40) will undergo baseline testing to quantify glucocorticoid sensitivity (0.5 mg DEX) andestablish insulin, glucose, and HPA reactivity to exercise and a meal. Participants will then take 100mg of DHEA (or placebo) for 4 wks and then undergo the same tests. Inflammatory profiles (CRP, IL6,IL1p, IL10, IL12, and TNFa) will be quantified at baseline and after supplementation with DHEA orPlacebo for 4-wks.
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