Person:

Adler, Gail

Serum- and glucocorticoid-inducible kinase 1 (SGK1) plays a central role in epithelial sodium channel (ENaC)-dependent Na+ transport in the distal nephron. We hypothesized that SGK1 gene variants may contribute to the effect of dietary salt intake on BP in humans with hypertension, and consequentially influence renin-angiotensin-aldosterone (RAA) system activity. Our study population included 421 hypertensive Caucasian participants of the HyperPath group who had completed a dietary salt protocol with measurement of BP and RAA system activity. Three SGK1 tagging single nucleotide polymorphisms (SNPs) from the HapMap CEU population captured the genetic variation in the SGK1 region. Assuming an additive genetic model, two SNPs (rs2758151 and rs9402571) were associated with BP and plasma renin activity (PRA) effects of dietary salt intake. Major alleles were associated with higher systolic BP on high salt and decreased PRA on low salt. In contrast, low salt neutralized genotype differences. Similar, non-significant trends were observed in a normotensive population (N=152). Genotype was also associated with two salt-sensitive subtypes of hypertension. SGK1 genetic variants are associated with salt sensitivity of BP and PRA in human hypertension. Genotype status at these SGK1 variants may identify individuals prone to salt-sensitive hypertension.

We present a novel approach for analyzing biological time-series data using a context-free language (CFL) representation that allows the extraction and quantification of important features from the time-series. This representation results in Hierarchically AdaPtive (HAP) analysis, a suite of multiple complementary techniques that enable rapid analysis of data and does not require the user to set parameters. HAP analysis generates hierarchically organized parameter distributions that allow multi-scale components of the time-series to be quantified and includes a data analysis pipeline that applies recursive analyses to generate hierarchically organized results that extend traditional outcome measures such as pharmacokinetics and inter-pulse interval. Pulsicons, a novel text-based time-series representation also derived from the CFL approach, are introduced as an objective qualitative comparison nomenclature. We apply HAP to the analysis of 24 hours of frequently sampled pulsatile cortisol hormone data, which has known analysis challenges, from 14 healthy women. HAP analysis generated results in seconds and produced dozens of figures for each participant. The results quantify the observed qualitative features of cortisol data as a series of pulse clusters, each consisting of one or more embedded pulses, and identify two ultradian phenotypes in this dataset. HAP analysis is designed to be robust to individual differences and to missing data and may be applied to other pulsatile hormones. Future work can extend HAP analysis to other time-series data types, including oscillatory and other periodic physiological signals.

The pulsatile release of cortisol from the adrenal glands is controlled by a hierarchical system that involves corticotropin releasing hormone (CRH) from the hypothalamus, adrenocorticotropin hormone (ACTH) from the pituitary, and cortisol from the adrenal glands. Determining the number, timing, and amplitude of the cortisol secretory events and recovering the infusion and clearance rates from serial measurements of serum cortisol levels is a challenging problem. Despite many years of work on this problem, a complete satisfactory solution has been elusive. We formulate this question as a non-convex optimization problem, and solve it using a coordinate descent algorithm that has a principled combination of (i) compressed sensing for recovering the amplitude and timing of the secretory events, and (ii) generalized cross validation for choosing the regularization parameter. Using only the observed serum cortisol levels, we model cortisol secretion from the adrenal glands using a second-order linear differential equation with pulsatile inputs that represent cortisol pulses released in response to pulses of ACTH. Using our algorithm and the assumption that the number of pulses is between 15 to 22 pulses over 24 hours, we successfully deconvolve both simulated datasets and actual 24-hr serum cortisol datasets sampled every 10 minutes from 10 healthy women. Assuming a one-minute resolution for the secretory events, we obtain physiologically plausible timings and amplitudes of each cortisol secretory event with R2 above 0.92. Identification of the amplitude and timing of pulsatile hormone release allows (i) quantifying of normal and abnormal secretion patterns towards the goal of understanding pathological neuroendocrine states, and (ii) potentially designing optimal approaches for treating hormonal disorders.

Background: Substantial empirical evidence has demonstrated that individuals who are socially isolated or have few positive social connections seem to age at a faster rate and have more chronic diseases. Oxytocin is a neurohypophyseal hormone hypothesized to coordinate both the causes and effects of positive social interactions, and may be involved in positive physiological adaptations such as buffering the deleterious effects of stress and promoting resilience. The proposed research will examine whether and how oxytocin influences responses to stress in humans and will consider effects in relation to those of social support. Methods/Design: Experimental research will be used to determine whether exogenously administered oxytocin (intranasal) influences psychological and physiological outcomes under conditions of stress across gender and age in adulthood. Hypotheses to be tested are: 1) Oxytocin ameliorates the deleterious neuroendocrine, cardiovascular, and subjective effects of stress; 2) Oxytocin and social support have similar and additive stress-buffering effects; 3) Oxytocin effects are stronger in women versus men; and 4) Oxytocin effects are similar across a range of adult ages. Hypotheses will be tested with a placebo-controlled, double-blind study using a sample of healthy men and women recruited from the community. Participants are randomly assigned to receive either oxytocin or placebo. They undergo a social stress manipulation with and without social support (randomly assigned), and outcome measures are obtained at multiple times during the procedure. Discussion: Understanding the determinants of healthy aging is a major public health priority and identifying effective measures to prevent or delay the onset of chronic diseases is an important goal. Experimental research on oxytocin, social relationships, and health in adulthood will contribute to the scientific knowledge base for maximizing active life and health expectancy. At conclusion of the study we will have solid evidence concerning the effects of oxytocin on stress response and whether it has similar effects across age and gender groups. A neurobiological understanding of resilience can inform efforts for both prevention and intervention of diseases or problems common in later life. Trial registration Clinical trial identification number is NCT01011465.

OBJECTIVE—Glycemic control decreases the incidence and progression of diabetic complications but increases the incidence of hypoglycemia. Hypoglycemia can impair hormonal and autonomic responses to subsequent hypoglycemia. Intensive glycemic control may increase mortality in individuals with type 2 diabetes at high risk for cardiovascular complications. We tested the hypothesis that prior exposure to hypoglycemia leads to impaired cardiovascular autonomic function. RESEARCH DESIGN AND METHODS—Twenty healthy subjects (age 28 ± 2 years; 10 men) participated in two 3-day inpatient visits, separated by 1–3 months. Autonomic testing was performed on days 1 and 3 to measure sympathetic, parasympathetic, and baroreflex function. A 2-h hyperinsulinemic [hypoglycemic (2.8 mmol/l) or euglycemic (5.0 mmol/l)] clamp was performed in the morning and in the afternoon of day 2. RESULTS—Comparison of the day 3 autonomic measurements demonstrated that antecedent hypoglycemia leads to 1) reduced baroreflex sensitivity (16.7 ± 1.8 vs. 13.8 ± 1.4 ms/mmHg, P = 0.03); 2) decreased muscle sympathetic nerve activity response to transient nitroprusside-induced hypotension (53.3 ± 3.7 vs. 40.1 ± 2.7 bursts/min, P < 0.01); and 3) reduced (P < 0.001) plasma norepinephrine response to lower body negative pressure (3.0 ± 0.3 vs. 2.0 ± 0.2 nmol/l at −40 mmHg). CONCLUSIONS— Baroreflex sensitivity and the sympathetic response to hypotensive stress are attenuated after antecedent hypoglycemia. Because impaired autonomic function, including decreased cardiac vagal baroreflex sensitivity, may contribute directly to mortality in diabetes and cardiovascular disease, our findings raise new concerns regarding the consequences of hypoglycemia.

Background: Overactivation of the aldosterone and mineralocorticoid receptor (MR) pathway is associated with hyperglycemia and dyslipidemia. Caveolin 1 (cav‐1) is involved in glucose/lipid homeostasis and may modulate MR signaling. We investigated the interplay between cav‐1 and aldosterone signaling in modulating insulin resistance and dyslipidemia in cav‐1–null mice and humans with a prevalent variant in the CAV1 gene. Methods and Results: In mouse studies, cav‐1 knockout mice exhibited higher levels of homeostatic model assessment of insulin resistance, cholesterol, and resistin and lower ratios of high‐ to low‐density lipoprotein (all P<0.001 versus wild type). Moreover, cav‐1 knockout mice displayed hypertriglyceridemia and higher mRNA levels for resistin, retinol binding protein 4, NADPH oxidase 4, and aldose reductase in liver and/or fat tissues. MR blockade with eplerenone significantly decreased glycemia (P<0.01), total cholesterol (P<0.05), resistin (P<0.05), and described enzymes, with no effect on insulin or triglycerides. In the human study, we analyzed the CAV1 gene polymorphism rs926198 in 556 white participants; 58% were minor allele carriers and displayed higher odds of insulin resistance (odds ratio 2.26 [95% CI 1.40–3.64]) and low high‐density lipoprotein (odds ratio 1.54 [95% CI 1.01–3.37]). Aldosterone levels correlated with higher homeostatic model assessment of insulin resistance and resistin and lower high‐density lipoprotein only in minor allele carriers. CAV1 gene expression quantitative trait loci data revealed lower cav‐1 expression in adipose tissues by the rs926198 minor allele. Conclusions: Our findings in mice and humans suggested that decreased cav‐1 expression may activate the effect of aldosterone/MR signaling on several pathways of glycemia, dyslipidemia, and resistin. In contrast, hyperinsulinemia and hypertriglyceridemia are likely mediated by MR‐independent mechanisms. Future human studies will elucidate the clinical relevance of MR blockade in patients with genotype‐mediated cav‐1 deficiency.

Objective: The hippocampus is crucial for paired-associate learning. Obesity is associated with increased MR activity in peripheral and possibly central tissues, decreased hippocampal size in humans and impaired hippocampal learning in rodents. The MR is expressed in hippocampal neurons and MR blockade improves hippocampal learning in obese animals. We sought to determine whether MR blockade would modulate paired-associate learning in obese men and women. Design and Methods Men and women ages 20-61 years with BMIs between 30-45 kg/m2 were randomly assigned to placebo (n=11; 7 women) or 50 mg spironolactone daily (n=12; 7 women) for six weeks. At baseline and post treatment, subjects underwent a clinical and hormonal evaluation. They also underwent a computerized task that assesses paired-associate learning and has been shown by functional magnetic resonance imaging to activate the hippocampus. Results: In an ANCOVA model that adjusted for baseline paired-associate learning, age, and race, spironolactone treatment was associated with a significant (p=0.043) improvement in hippocampal memory as compared to placebo treatment. Conclusions: Our findings demonstrate, for the first time, that blocking MR with chronic, low-dose spironolactone treatment improves paired-associate learning in obese individuals, suggesting that MR activation contributes to hippocampal memory modulation in humans.

Background: Prior studies suggest that vitamin D therapy may decrease cardiovascular disease risk in type 2 diabetes (T2DM) by lowering renin-angiotensin system (RAS) activity. However, randomized human intervention studies to evaluate the effect of vitamin D receptor (VDR) agonists on RAS activity are lacking. Objective: The objective of this article is to investigate the effect of direct VDR activation with calcitriol on circulating RAS activity and vascular hemodynamics in T2DM. Methods: A randomized, double-blinded, and placebo-controlled study wherein 18 participants with well-controlled T2DM without chronic kidney disease (CKD) were administered calcitriol or placebo for three weeks was conducted. Outcome measures included plasma renin activity (PRA), serum and urinary aldosterone, mean arterial pressure (MAP) before and after an infusion of angiotensin II, and renal plasma flow (RPF) via para-aminohippurate clearance. Results: Despite an increase in 1,25(OH)2D with calcitriol administration (45.4 to 61.8 pg/ml, p = 0.03) and no change with placebo, there were no significant differences in PRA, serum or urinary aldosterone, baseline and angiotensin II-stimulated MAP, or basal and angiotensin II-stimulated RPF between interventions. Conclusion: In this randomized and placebo-controlled study in participants with T2DM without CKD, calcitriol therapy to raise 1,25(OH)2D levels, when compared with placebo, did not significantly change circulating RAS activity or vascular hemodynamics.

Background: Prior studies suggest that renin-angiotensin-aldosterone system (RAAS) inhibitors decrease parathyroid hormone (PTH) secretion. Objective: To evaluate the effect of angiotensin-converting enzyme inhibitors (ACEi) on serum PTH in participants with and without primary hyperparathyroidism (P-HPT). Methods: An open-label, single-arm, pilot study whereby participants with and without P-HPT had PTH were evaluated before and after 1 week of maximally tolerated lisinopril therapy. Results: A total of 12 participants with, and 15 participants without, P-HPT successfully completed the protocol. Following 1 week of lisinopril, participants with P-HPT had a decrease in systolic blood pressure (SBP) (−6.4 mmHg, P < 0.01), an increase in plasma renin activity (PRA) (+1.50 ng/mL/h, P = 0.06), and a decrease in PTH (79.5 (21.6) to 70.9 (19.6) pg/mL, ∆ = −8.6 pg/mL, P = 0.049); however, serum and urine calcium did not change. In contrast, although 1 week of lisinopril significantly decreased SBP and increased PRA among participants without P-HPT, there were no changes in PTH or calcium. Conclusion: In this short pilot investigation, 1 week of maximally titrated ACEi did not impact PTH in participants without P-HPT, but resulted in a modest and marginally significant reduction of PTH but not calcium, among participants with P-HPT. This trial is registered with ClinicalTrials.gov NCT01691781.