Metabolically Healthy Obesity Is a Misnomer: Components of the Metabolic Syndrome Linearly Increase with BMI as a Function of Age and Gender.

OBJECTIVES: We aimed to examine the relationships between body mass index (BMI) and metabolic syndrome (MS) components as a function of age and gender across weight categories. METHODS: This cross-sectional study included 19,328 subjects who participated in a health-screening program. We analyzed 14,093 apparently healthy subjects with a BMI ≥ 18.5 kg/m2 (ranging from 18.5 to 46 kg/m2). RESULTS: At a BMI of 18.5 kg/m2, 16% of subjects had one or more MS components (MS ≥ 1). The number of MS components increased linearly with BMI. The most prevalent components for MS1-4 were hypertension (in men) and increased waist circumference (in women). Among 6391 non-obese subjects with MS = 0, there was a linear increase in blood pressure, glucose, and triglycerides, as well as a decline in high-density lipoprotein cholesterol, as BMI increased. In 2087 subjects with a BMI ≥ 30 kg/m2, a true normometabolic state (MS = 0) was observed in only 7.5%, declining to less than 1% at a BMI ≥ 36 kg/m2 (ATP criteria). Women were metabolically protected relative to men between the ages of 30 and 50 years. CONCLUSIONS: (A) MS components increase linearly with BMI from the lowest normal BMI and continue to increase with age and BMI; (B) metabolically healthy obesity is rare in subjects with a high BMI and declines with age; (C) hypertension is the most common component in men; and (D) in women, MS components are seen at older ages than in men for the same BMI. Metabolic health declines with age and BMI in nearly all subjects with obesity.

Deconvolution of the epigenetic age discloses distinct inter-personal variability in epigenetic aging patterns.

BACKGROUND: The epigenetic age can now be extrapolated from one of several epigenetic clocks, which are based on age-related changes in DNA methylation levels at specific multiple CpG sites. Accelerated aging, calculated from the discrepancy between the chronological age and the epigenetic age, has shown to predict morbidity and mortality rate. We assumed that deconvolution of epigenetic age to its components could shed light on the diversity of epigenetic, and by inference, on inter-individual variability in the causes of biological aging. RESULTS: Using the Horvath original epigenetic clock, we identified several CpG sites linked to distinct genes that quantitatively explain much of the inter-personal variability in epigenetic aging, with CpG sites related to secretagogin and malin being the most variable. We show that equal epigenetic age in different subjects can result from variable contribution size of the same CpG sites to the total epigenetic age. In a healthy cohort, the most variable CpG sites are responsible for accelerated and decelerated epigenetic aging, relative to chronological age. CONCLUSIONS: Of the 353 CpG sites that form the basis for the Horvath epigenetic age, we have found the CpG sites that are responsible for accelerated and decelerated epigenetic aging in healthy subjects. However, the relative contribution of each site to aging varies between individuals, leading to variable personal aging patterns. Our findings pave the way to form personalized aging cards allowing the identification of specific genes related to CpG sites, as aging markers, and perhaps treatment of these targets in order to hinder undesirable age drifting.

Impaired aldosterone response to ACTH without hypoaldosteronism: An unrecognized secretory pattern in search of clinical implications.

CONTEXT: Aldosterone has been recently characterized as a 'stress hormone'. Stress per se elicits a sizable rise in aldosterone secretion, which could be replicated by the administration of a low dose (0.03-1 µg, IV) of adrenocorticotropic hormone (ACTH). Whether or not the aldosterone response to ACTH could be selectively impaired, that is, in association with intact cortisol response, is presently unknown. OBJECTIVE: To determine whether or not the aldosterone response to low dose of ACTH is impaired in subjects referred to assess the hypothalamic-pituitary-adrenal axis (HPA). DESIGN: Retrospective analysis. SETTING: Outpatient referral endocrine day care centre. PATIENTS: One hundred and ninety-five consecutive subjects who underwent the low dose (1 µg) ACTH test, in whom decreased cortisol reserve was suspected due to former/present glucocorticoid excess, pituitary disease or/and unexplained weakness. MAIN OUTCOME MEASURES: The outcome was the detection of lack of aldosterone response, defined as a rise <111 pmol/l. RESULTS: In all, 46/195 subjects had subnormal aldosterone response as compared with 52/195 subjects showing diminished cortisol response. Nine subjects had combined deficient aldosterone and cortisol response. In the 37 subjects with isolated subnormal aldosterone response common associations were the use of exogenous glucocorticoids, mostly prednisone (n = 16); former Cushing disease (n = 2); nonfunctioning pituitary adenoma (n = 8); hypothyroidism (n = 11); the use of statins (n = 11), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (n = 6), sex steroids in transgenders and orthostatic hypotension (n = 3). Twenty-seven percent (25/93) of the subjects with recent exposure to glucocorticoids had impaired aldosterone response to ACTH. CONCLUSION: Blunted aldosterone response to ACTH in the absence of hypoaldosteronism was seen in ~27% of subjects referred for HPA assessment using the low dose 1 µg ACTH test. Exposure to glucocorticoid excess was often linked to this impairment, independent of the cortisol response to ACTH.

24-h Potassium Excretion Is Associated with Components of the Metabolic Syndrome: Results from a National Survey Based on Urine Collection in Adults.

A balanced diet and weight loss are the first lines of treatment for the prevention of metabolic syndrome (MS). Dietary strategies may include changing the composition of macronutrients, adopting a particular dietary pattern as a Mediterranean diet. However, the role of micronutrients, particularly potassium, in the propensity for or treatment of the syndrome is unclear. The study aimed to examine the relationship between the presence of the MS and its risk factors and the 24-h potassium excretion as the most valid proxy for dietary intake. The analyses were performed as part of the national survey estimating sodium and other electrolytes excretion conducted between 2014-2016 in Israel. The survey included urine collection, anthropometric and blood pressure measurements, and a comprehensive medical questionnaire that included details on the intake of medications that may affect electrolyte secretion. A model was constructed to evaluate the probability for the MS. MS score and its probability were examined in relation to potassium excretion at different levels and in stratification to sex. A total of 581 participants were included in the analysis. The mean potassium excretion was 2818 ± 1417 mg. The prevalence of the MS was 18.5% among participants with above-average potassium excretion and about 10.4% among participants with lower-than-average excretion (p = 0.007). A dose-response relationship was observed between MS score and potassium: the higher the score, the lower was the excretion of potassium. Potassium excretion, rather than sodium excretion, correlated with all components of the MS and even predicted MS independently from other variables. This is the first study based on a national survey showing that potassium consumption, as represented by daily excretion in urine, is inversely related to the presence of MS components after adjustment for several leading variables and careful exclusion of participants taking drugs which may interfere in potassium excretion.

The role of caloric intake in the association of high salt intake with high blood pressure.

Since current recommendations call for a substantial reduction in overall sodium consumption, we tested whether or not these recommendations are implemented in common large subpopulations such as those with abnormal weight or hypertension in the current high sodium, high-calorie nutritional environment. In a national representative cross-sectional survey of the community-dwelling subjects aged 25-65 years conducted in Israel between 2015 and 2017, 582 randomly selected subjects completed health and dietary questionnaires, underwent blood pressure and anthropometric measurements and collected 24-h urine specimens, to assess dietary sodium intake. Overall mean 24-h sodium excretion was 3834 mg, more than double the recommended upper intake for adults < 1500 mg/day. Sodium excretion was directly related to caloric intake and blood pressure and linked to the presence of hypertension and overweight/obesity. The highest sodium excretion was seen in overweight/obese hypertensive subjects. This recent national survey shows a high consumption of sodium in the Israeli population and a dose-response association between caloric intake and urinary sodium excretion, independent of BMI and hypertension. Nevertheless, overweight/obese subjects with hypertension consume (excrete) more sodium than other BMI/ blood pressure-related phenotypes and may thus comprise a target subpopulation for future efforts to reduce sodium intake.

Approach to Obesity in the Older Population.

Until recently, weight loss in older obese people was feared because of ensuing muscle loss and frailty. Facing overall increasing longevity, high rates of obesity in older individuals (age ≥ 65 years) and a growing recognition of the health and functional cost of the number of obesity years, abetted by evidence that intentional weight loss in older obese people is safe, this approach is gradually, but not unanimously, being replaced by more active principles. Lifestyle interventions that include reduced but sufficient energy intake, age-adequate protein and micronutrient intake, coupled with aerobic and resistance exercise tailored to personal limitations, can induce weight loss with improvement in frailty indices. Sustained weight loss at this age can prevent or ameliorate diabetes. More active steps are controversial. The use of weight loss medications, particularly glucagon-like peptide-1 analogs (liraglutide as the first example), provides an additional treatment tier. Its safety and cardiovascular health benefits have been convincingly shown in older obese patients with type 2 diabetes mellitus. In our opinion, this option should not be denied to obese individuals with prediabetes or other obesity-related comorbidities based on age. Finally, many reports now provide evidence that bariatric surgery can be safely performed in older people as the last treatment tier. Risk-benefit issues should be considered with extreme care and disclosed to candidates. The selection process requires good presurgical functional status, individualized consideration of the sequels of obesity, and reliance on centers that are highly experienced in the surgical procedure as well as short-term and long-term subsequent comprehensive care and support.

The Effect of the PCSK9 Inhibitor Evolocumab on Aldosterone Secretion among High Cardiovascular Risk Patients: A Pilot Study.

Elevated low-density lipoprotein (LDL) cholesterol is one of the leading causes of cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce LDL cholesterol levels with subsequent reductions in cardiovascular morbidity. Elevated aldosterone levels are also associated with a greater risk of cardiovascular morbidity. There are currently no published data on the impact of PCSK9 inhibitor monotherapy on the secretion of aldosterone. The aim of this study was to examine the effect of monotherapy with the PSCK9 inhibitor evolocumab on the lipid profile and aldosterone secretion level in high-risk cardiovascular patients. Lipid profile, sodium, potassium, aldosterone, cortisol, plasma renin activity, and adrenocorticotropic hormone (ACTH) levels were analyzed at baseline and after 3 months of evolocumab therapy. Each participant underwent a 250 mcg ACTH stimulation test upon study entry. Eight women and seven men were included in the study. Their median total cholesterol, LDL cholesterol, lipoprotein (a), apolipoprotein B100, and baseline and stimulated aldosterone levels were significantly lower after 3 months of evolocumab therapy. These heretofore unreported findings indicate that reductions in unstimulated and stimulated aldosterone secretion under evolocumab therapy could be associated with reductions in cardiovascular events, a possibility that warrants further investigation.

Improving blood glucose level predictability using machine learning.

This study was designed to improve blood glucose level predictability and future hypoglycemic and hyperglycemic event alerts through a novel patient-specific supervised-machine-learning (SML) analysis of glucose level based on a continuous-glucose-monitoring system (CGM) that needs no human intervention, and minimises false-positive alerts. The CGM data over 7 to 50 non-consecutive days from 11 type-1 diabetic patients aged 18 to 39 with a mean HbA1C of 7.5% ± 1.2% were analysed using four SML models. The algorithm was constructed to choose the best-fit model for each patient. Several statistical parameters were calculated to aggregate the magnitudes of the prediction errors. The personalised solutions provided by the algorithm were effective in predicting glucose levels 30 minutes after the last measurement. The average root-mean-square-error was 20.48 mg/dL and the average absolute-mean-error was 15.36 mg/dL when the best-fit model was selected for each patient. Using the best-fit-model, the true-positive-hypoglycemia-prediction-rate was 64%, whereas the false-positive- rate was 4.0%, and the false-negative-rate was 0.015%. Similar results were found even when only CGM samples below 70 were considered. The true-positive-hyperglycemia-prediction-rate was 61%. State-of-the-art SML tools are effective in predicting the glucose level values of patients with type-1diabetes and notifying these patients of future hypoglycemic and hyperglycemic events, thus improving glycemic control. The algorithm can be used to improve the calculation of the basal insulin rate and bolus insulin, and suitable for a closed loop "artificial pancreas" system. The algorithm provides a personalised medical solution that can successfully identify the best-fit method for each patient.

The effect of circuit resistance training, empagliflozin or "vegeterranean diet" on physical and metabolic function in older subjects with type 2 diabetes: a study protocol for a randomized control trial (CEV-65 trial).

BACKGROUND: Treatment of the older diabetic individual comprises a therapeutic challenge. Currently little scientific evidence exists depicting the best approach to type 2 diabetes treatment in this growing sub-population of patients. The purpose of this study is to assess the effects of a modified plant-based Mediterranean diet ("vegeterranean" diet), circuit resistance training (CRT) and empagliflozin, separately or in combination, on body composition and physical function in older subjects with type 2 diabetes. The rationale for this study is to assess three interventions associated with a negative energy/caloric balance (increased caloric use in exercise, caloric restriction in the "vegeterranean" diet and caloric wasting by glycosuria with empagliflozin), their interaction and effect on body composition and physical function. METHODS: One hundred and twenty men and women ≥65 years of age with type 2 diabetes, and low levels of physical activity will be randomized (1:1:1 manner, gender stratified) for 10 weeks to one of 3 parallel arms: CRT consisting of 3 home sessions/week; ad-libitum plant-based Mediterranean diet (limited consumption of eggs, dairy and fish, avoidance of red meat and poultry) or empagliflozin 10 mg/day. After 10 weeks CRT will be added to the empagliflozin and diet arms for an additional 10 weeks. Allocation concealment and blinding of primary outcome assessors will be implemented. Efficacy will be determined by assessment of lean body mass, body weight, frailty and functional status, sarcopenia, HbA1c and quality of life questionnaires. Safety will be evaluated by routine monitoring of adverse events. This study was approved by the Tel-Aviv Sourasky Medical Center Institutional Review Board. DISCUSSION: The combination and comparison of these diverse interventions to metabolic control may lead to better understanding of their mechanism of action with potential clinical implications in older individuals. Also, this study will provide evidence of the effectiveness of these interventions on delaying the progression from diabetes to sarcopenia and/or frailty. TRIAL REGISTRATION: ClinicalTrials.gov PRS: NCT03560375 . Last registration date (last update): 06/06/2018. The trial was a-priori registered before actual recruitment of subjects.

Increment in Dietary Potassium Predicts Weight Loss in the Treatment of the Metabolic Syndrome.

BACKGROUND: In the treatment of obesity/metabolic syndrome, dietary measures traditionally focus on reducing carbohydrate/fat-related caloric intake. The possibility that changes in potassium consumption may be related to the achieved weight loss has not been previously explored. METHODS: Sixty-eight participants, with a mean age of 51.6 ± 11.0 years (F/M-30/38), who fulfilled the ATPIII criteria for the metabolic syndrome (MS) were enrolled into a 1-year intensive multidisciplinary program. Nutritional recommendation consisted of a moderate low calorie/high protein Mediterranean diet. Baseline assessment included clinical and biochemical profiling, and body composition. Nutritional components were registered over 7 days before and at the end of 1 year of treatment. RESULTS: Mean baseline body mass index (BMI) was 35 ± 4 kg/m², which declined by 9.4 ± 0.1% after one year of combined intervention. Linear stepwise regression analysis revealed that 45% of the predicted variance of the % decline in BMI was related to increased consumption of dietary potassium (ß = -0.865) and caproic acid (ß = -0.423) and reduction in the consumption of dietary vitamin B6 (ß = 0.542), calcium (ß = 0.335), total carbohydrates (ß = 0.239) and total caloric intake (ß = 0.238; p < 0.001). Notably, the strongest correlate of the decline in BMI was the increase in dietary potassium intake (ß = -0.865). Subjects whose achieved decrease in BMI was above the average (n = 30) increased potassium intake by 25% as compared to an increase in dietary potassium intake of only 3% by those whose decline in BMI was below the average (n = 36; p < 0.05). The change in dietary potassium was related to the percent increase in dietary protein (r = 0.433; p < 0.001). CONCLUSION: An increase in dietary potassium consumption is a previously unrecognized predictor of the achieved reduction in BMI in a weight-loss-oriented multidisciplinary intervention in obesity/MS. Prospective trials are underway to confirm this post-hoc finding.

Increase of body mass index and waist circumference predicts development of metabolic syndrome criteria in apparently healthy individuals with 2 and 5 years follow-up.

BACKGROUND: The metabolic syndrome (MetS) is associated with overweight and abdominal obesity. Our aim was to use longitudinal measurements to provide clinically relevant information on the relative influence of changes in body mass index (BMI), waist circumference (WC), and weekly physical exercise duration on the development of each of the MetS components. METHODS: We analyzed data collected at the Tel-Aviv Medical Center Inflammation Survey (TAMCIS). Apparently healthy individuals with two consecutive visits that were not treated for any metabolic criteria were included in this study. We analyzed the influence of changes in BMI, WC, and time engaged in physical exercise on the change in each of the components of the metabolic syndrome using linear regressions. RESULTS: Included were 7532 individuals (5431 men, 2101 women) with 2 years follow-up. Participants who gained two BMI points, had the mean number of criteria increase from 1.07 to 1.52, while participants who lost two BMI points, decreased from 1.64 to 1.16. A long-term analysis over 5 years showed similar results. Furthermore, an increase in WC was independently associated with increased severity of each of the other components, when controlling for increase in BMI. Increase in weekly exercise duration had a small but statistically significant favorable effect on blood triglycerides and HDL levels, but not on blood pressure or HbA1C. CONCLUSIONS: Changes in BMI and WC are highly associative with the likelihood and severity of the MetS independently of the baseline levels, suggesting that obese individuals can substantially improve their MetS prognosis by losing both body weight and abdominal fat.

Severe central obesity or diabetes can replace weight loss in the detection of frailty in obese younger elderly - a preliminary study.

PURPOSE: Unwanted weight loss is one of the established criteria for the diagnosis of frailty. However, the relevance of this criterion to detect frailty in obese older adults has not been assessed. In particular, with the exception of malignancy, unwanted weight loss is not commonly seen in older obese subjects. Therefore, we tested the possibility that some obesity phenotypes and/or diabetes might be more useful in the detection of frailty in this setting. PATIENTS AND METHODS: A preliminary cross-sectional study of 50 consecutive subjects was conducted at The Institute of Endocrinology, Metabolism and Hypertension, Tel-Aviv Sourasky Medical Center. Inclusion criteria were: young elderly (aged 65-75 years), with general and/or abdominal obesity, without cancer. Frailty was assessed directly using the Fried model, the five-item fatigue, resistance, ambulation, illnesses, and loss of weight (FRAIL) scale. Eventually, in the assessment of frailty, the weight loss criterion was replaced by one or several of obesity/diabetes-related variables each time: severity of obesity by body mass index, waist circumference (and their interaction), body fat, and diabetes. The receiver operating characteristic curves for functional impairment indices were plotted to compare the usefulness of the frailty accepted and adjusted models. RESULTS: The prevalence of frailty and pre-frailty in this cohort were 7/50 (14%) and 27/50 (54%), respectively, but unwanted weight loss was seen in three subjects (6%) only. The level of abdominal obesity had the strongest correlation with functional score (r=0.292, P<0.05). Frailty models which included either severe abdominal obesity or diabetes in lieu of unwanted weight loss had good sensitivity rates per each frailty score as compared with the original Fried model. CONCLUSION: For detecting and/or screening for the frailty syndrome in obese young elderly, the level of abdominal obesity or diabetes may provide a useful marker.

Cognitive impairment and the association between frailty and functional deficits are linked to abdominal obesity in the elderly.

OBJECTIVE: To evaluate whether specific obesity phenotypes in community-dwelling elderly: (a) affect differently the relationship between frailty and functional impairment and (b) are related to cognitive impairment. STUDY DESIGN: A post-hoc cross-sectional analysis of the last Israeli national health and nutrition survey of the elderly (≥ 65 yrs.; n = 1619). MAIN OUTCOME MEASURES: We implemented a previously validated frailty model based on frailty-related variables that were obtained in the survey. Mild cognitive impairment was defined using the Mini-Mental State Examination (a score <24 and >17). The Katz's scale of activities of daily living was used for functional assessment. Data were clustered according to different obesity phenotypes using measured body mass index (BMI) and waist circumference (WC). RESULTS: The link between frailty and disability was most prominent in subjects with abdominal obesity who were non-obese by BMI: compared with non-obese subjects as defined by WC and BMI, the odds ratio (OR) for functional limitations in this phenotype was 8.34 (95 % CI, 2.14-32.48) for pre-frail subjects and 69.26 (10.58-453.55) for frail subjects. The rate of cognitive impairment was 3.3 times higher (p = .023) in women who were obese by WC but not by BMI. CONCLUSIONS: In elderly people with a large WC and BMI < 30 kg/m2, disability is more tightly linked to frailty than for any other form of obesity. Cognitive impairment was more prominent in women with central obesity and BMI < 30 kg/m2 than in the other anthropometric phenotypes. WC should be used for early detection of individuals at risk of progression of frailty to functional incapacity.

Vertebral Fractures Following Denosumab Discontinuation in Patients with Prolonged Exposure to Bisphosphonates.

Denosumab (DMAB) efficacy for treatment of osteoporosis was demonstrated in a pivotal trial with a reduction in vertebral and hip fractures during 3 years, and fracture risk reduction was sustained up to 10 years in an extension study. DMAB causes potent yet reversible inhibition of bone resorption. Bone density declines rapidly upon discontinuation and bone turnover markers increase above baseline in a rebound fashion. Spontaneous multiple vertebral fractures after DMAB discontinuation were recently reported. Prior treatment with bisphosphonates (BP) was postulated to decrease the risk for this alarming phenomenon. We aimed to describe our experience of fractures following DMAB withdrawal with special attention to past history of osteoporosis treatment. A phone survey of physicians engaged in bone metabolism from nine hospitals in Israel was performed. Clinical data of the patients presenting with vertebral fractures upon DMAB discontinuation were summarized and compared to the previously published cases. Nine elderly (74.2 ± 5.3 years) female patients were identified. Most patients had a prolonged prior exposure to BP (7.4 ± 3.2 years). All but one sustained osteoporotic fractures prior to DMAB initiation and their FRAX scores were high. Thirty-six vertebral fractures were identified in nine patients. Eight patients presented with multiple fractures, and most fractures were spontaneous. In line with the previous reports, the timing and severity of the fractures raise concern of DMAB discontinuation effect. Prolonged BP exposure in most of our patients challenges the protective effect hypothesis. Care providers, patients, and regulatory authorities should be aware of the possible risk of DMAB treatment interruption.

Circuit resistance training is an effective means to enhance muscle strength in older and middle aged adults: A systematic review and meta-analysis.

BACKGROUND: Physical exercise, particularly resistance training (RT), is proven treatment to reduce the accelerated decline in muscle strength exhibited by older adults, but its effect is hindered by low adherence rate, even under well-structured programs. OBJECTIVE AND DATA SOURCES: We investigated the efficacy of circuit resistance training (CRT) on muscle strength, lean mass and aerobic capacity in older adults based on report in MEDLINE, EMBASE, ClinicalTrials.gov and Cochrane electronic (through 8/2016). STUDY ELIGIBILITY CRITERIA: middle and older aged men and/or women who followed a structured program, assigned to CRT. STUDY APPRAISAL AND SYNTHESIS METHODS: Out of 237 originally identified articles, 10 articles were included with a total of 362 patients with mean: age -64.5±7.4 years; 3±1.15 sessions/week; session duration 41.8±15.9min. RESULTS: Upper body strength modestly increased, by 1.14kg (95% CI; 0.28-2.00), whereas larger increment was seen in lower body strength (11.99; 2.92-21.06). Higher program volume (>24 sessions) positively influenced upper body strength and aerobic capacity. LIMITATIONS: (1) variability in the studies' validity; (2) relatively low number of studies. CONCLUSION: CRT is a valid alternative to conventional RT. Its shorter duration and lower intensity relative to traditional RT, may increase adherence to training in older adults.

GENDER DETERMINES SERUM FREE CORTISOL: HIGHER LEVELS IN MEN.

OBJECTIVE: Because only the free fraction of serum cortisol can readily access glucocorticoid receptors, we investigated whether or not a gender-related difference in serum free cortisol (FC) exists in the basal and adrenocorticotropic hormone (ACTH)-stimulated state. METHODS: Serum total cortisol (TC) and FC were measured in 323 subjects (175 men; 148 women). Additionally, the low-dose 1-µg ACTH test was performed in 56 subjects (30 women, 26 men). Subjects were healthy volunteers, recruited in a preventive medicine screening program and an outpatient clinic. RESULTS: Overall, basal serum TC and FC level were ~18 and ~33%, respectively, higher in men than in women (TC, 14.5 ± 0.33 µg/dL vs. 12.3 ± 0.33 µg/dL; P<.0001; FC, 0.68 ± 0.02 µg/dL vs. 0.51 ± 0.02 µg/dL; P<.0001). The higher FC in men relative to women was apparent across a wide age range (17 to 86 years) and persisted after adjustment for age and body mass index. The FC fraction (%FC, out of TC) was concordantly higher in men (5.4 ± 0.09% vs. 4.8 ± 0.3%; P = .046). FC was not related to the estimated menopausal status (women age below and above 47, 50, or 53 years). ACTH-stimulated FC levels were significantly higher in men compared to women, as reflected by the area under the response curve (49.4 ± 3.4 µg × min vs. 39.6 ± 2.2 µg × min; P = .0014). CONCLUSION: Gender is an unrecognized determinant of serum FC in humans. The possibility of lifelong exposure to the higher bioactive fraction of cortisol under basal conditions or daily stress involving ACTH stimulation should be further investigated in the context of gender-related phenotypic features such as "android" (visceral) fat deposition and longevity. ABBREVIATIONS: ACTH = adrenocorticotropic hormone BMI = body mass index CBG = cortisol-binding globulin FC = free cortisol HPA = hypothalamic-pituitary-adrenal TC = total cortisol.

Angiotensin 1-7 Is a Negative Modulator of Aldosterone Secretion In Vitro and In Vivo.

Angiotensin (1-7) [Ang 1-7] is a 7 amino acid peptide generated predominantly from Ang II by the action of Ang-converting enzyme 2. We previously showed that Ang 1-7 reduced plasma aldosterone and plasma renin activity in high fructose-fed rats, and that the reduction in circulating aldosterone seemed to accord a parallel reduction in plasma renin activity. Here, we tested the possibility that Ang 1-7 affects aldosterone secretion acting directly in glomerulosa cells. First, as detected by immunofluorescence, the receptor for Ang 1-7, Mas1 is localized predominantly at the rat adrenal subcapsular region. Second, in isolated rat glomerulosa cells incubates, Ang 1-7 attenuated the aldosterone response to Ang II, with the strongest effect seen on Ang II (10(-9) M) (control 22±2.5 pg/10(5) cells; Ang II [10(-9) M] 189±11 pg/10(5) cells; Ang II [10(-9) M]+Ang 1-7 [10(-6) M] 33±3.6 pg/10(5) cells; P<0.001) and the largest effect on adrenocorticotropic hormone (10(-8) M) (control 30±3.4 pg/10(5) cells; ACTH [10(-8) M] 409±32.5 pg/10(5) cells; ACTH [10(-8) M]+Ang 1-7 [10(-6) M] 280±12.5 pg/10(5) cells; P<0.001). In contrast, Ang 1-7 did not affect the aldosterone response to potassium (K(+)). In rats subjected to a low-salt diet for 7 days, continuous infusion of Ang 1-7 (576 µg/kg per day) resulted in a lesser rise in aldosterone (salt deplete+Ang 1-7, 16.4±4.8 ng/dL) compared with rats receiving vehicle (salt deplete+vehicle, 27.6±5.3 ng/dL; P<0.01) but did not modify plasma renin activity. Taken together, these results indicate that Ang 1-7 can act as a negative modulator of aldosterone secretion in vitro and in vivo.

Muscle function and fat content in relation to sarcopenia, obesity and frailty of old age--An overview.

BACKGROUND AND AIM: In western countries, the proportion of people over age 60 is increasing faster than any other group. This is linked to higher rates of obesity. Older age, co-morbidities and obesity are all associated with frailty syndrome. In the core of both frailty and sarcopenia there are dysfunction and deterioration of the muscle and the fat tissues. This overview interlinks the phenotypes presented in older adults such as sarcopenia and frailty-alone and with relation to obesity, muscle function and fat tissue accumulation. RECENT FINDINGS: Observational studies have well described the loss of muscle mass and strength through the years of adult life, both components of frailty and sarcopenia. They have shown that these changes are associated with dysmetabolism and functional deterioration, independent of common explanatory variables. In the metabolic mechanism core of this link, insulin resistance and higher ectopic fat accumulation may play a role. Basic experiments have partially validated this hypothesis. Whether there is a synergistic effect of obesity and frailty phenotype on morbidity risk is still questionable and currently under investigation; however, few cohort studies have shown that the frail-obese or sarcopenic-obese group have higher probability for metabolic complications. SUMMARY: Muscle mass loss and fat accumulation in the muscle in the elderly, with or without the presence of obesity, may explain some of the functional and metabolic defects shown in the frail, sarcopenic population.