AIMS:Circadian syndrome (CircS) is considered a better predictor for cardiovascular disease than the metabolic syndrome (MetS). We aim to examine the associations between CircS and MetS with cognition in Chinese adults. METHOD:We used the data of 8546 Chinese adults aged ≥40 years from the 2011 China Health and Retirement Longitudinal Study. MetS was defined using harmonised criteria. CircS included the components of MetS plus short sleep and depression. The cut-off for CircS was set as ≥4. Global cognitive function was assessed during the face-to-face interview. RESULTS:CircS and MetS had opposite associations with the global cognition score and self-reported poor memory. Compared with individuals without the CircS and MetS, the regression coefficients (95%CI) for global cognition score were -1.02 (-1.71 to -0.34) for CircS alone and 0.52 (0.09 to 0.96) for MetS alone in men; -1.36 (-2.00 to -0.72) for CircS alone and 0.60 (0.15 to 1.06) for MetS alone in women. Having CircS alone was 2.53 times more likely to report poor memory in men (95%CI 1.80-3.55) and 2.08 times more likely in women (95%CI 1.54-2.81). In contrast, having MetS alone was less likely to report poor memory (OR 0.64 (0.49-0.84) in men and 0.65 (0.52-0.81) in women). People with CircS and MetS combined were more likely to have self-reported poor memory. CONCLUSIONS:CircS is a strong and better predictor for cognition impairment than MetS in Chinese middle-aged adults. MetS without short sleep and depression is associated with better cognition.

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.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Background Aging is linked to hypermethylation of CpG sites on promoters and enhancers, along with loss of methylation in intergenic zones. That such changes are not necessarily a continuous process is exemplified by the extensive changes in DNA methylation during development with another significant time of change during adolescence. However, the relation between age and DNA methylation during adult life has not been systematically evaluated. In particular, potential changes in methylation trends in the same CpGs over the years that may occur with aging remain largely unexplored. Methods Here we set out to determine the average trends by age of the CpG sites represented in the Illumina 450 platform, based on data from 2143 subjects of the age range of 20 to 80 years, compiled from 24 different cohorts. Using several mathematical procedures, we initially separated stationary probes from probes whose methylation changes with age. Among the latter, representing ∼20% of the probes, we then focused on the identification of CpG sites with switch points, i.e., a point where a stable trend of change in the age-averaged methylation is replaced by another linear trend. Results Using several mathematical modeling steps, we generated a machine learning model that identified 5175 CpG sites with switch points in age-related changes in the trend of methylation over the years. Switch points reflect acceleration, deceleration or change of direction of the alteration of methylation with age. The 5175 switch points were limited to 2813 genes in three waves, 80% of which were identical in men and women. A medium-size wave was seen in the early forties, succeeded by a dominant wave as of the late fifties, lasting up to 8 years each. Waves appeared∼4-5 years earlier in men. No switch points were detected on CpGs mapped to the X chromosome. Conclusion In non-stationary CpG sites, concomitant switch points in age related changes in methylations can be seen in a defined group of sites and genes, which cluster in 3 age- and sex-specific waves.

BackgroundThe 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.ResultsUsing the Horvath original epigenetic clock, we identified several CpG sites linked to distinct genes that quantitatively explain much of the interpersonal 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.ConclusionsOf 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.

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.

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.

Background: Multiple factors are involved in the pathogenesis of hypertension in obese individuals. Recent studies have reported a strong association between blood pressure (BP) and resting metabolic rate (RMR). However, it is not known whether this relationship exists for systolic BP (SBP) and diastolic BP (DBP) in obese subjects patients with the metabolic syndrome, in whom several homeostatic mechanisms are impaired. Objective: To evaluate the relationship existing between RMR, to SBP and DBP, Fat Body Mass (FBM), Lean Body Mass (LBM), Body Mass Index (BMI), Blood parameters, in obese subjects with the metabolic syndrome. Methods: Sixty three non-diabetic subjects (27 women, 36 men) who fulfilled the ATPIII criteria for the metabolic syndrome, with a mean age of 50.4±12.5 yrs were evaluated. Mean BMI was 34.6±3.9 kg/m²; % FBM- 40.9±6.6 %; and LBM- 59±0.7%. Basal RMR was 1875.2±420.1 cal/day. Baseline assessment also included 24h ambulatory blood pressure monitoring, clinical and biochemical profiling, subcutaneous periumbilical fat biopsy, region-defined body composition with DEXA and carotid intima-media thickness. The intervention targeted all assessed risk factors and was implemented through frequent interactions with dietitians, an endocrinologists, and physiotherapist expert for physical activity. Results: At the baseline assessment RMR was significantly related to mean 24 h systolic blood pressure (r=0.3 p<0.05). There were significant inverse correlation between RMR to %FBM (r=0.45, p<0.05). RMR was also positively related to BMI (r=0.37, p<0.05) and fasting triglycerides (r=0.28, p<0.05). Conclusion: This report extends and strengthens previous findings that RMR is independently related to SBP. Prior to this study, the relationship between RMR and SBP in metabolic obese subjects had not been explored. This study expanded the findings of Brock and colleagues by showing that REE was significantly related to SBP, independent of several possible confounders found in metabolic obesity.

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.

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.

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.

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.

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. 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. 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. ClinicalTrials.gov PRS: NCT03560375 . Last registration date (last update): 06/06/2018. The trial was a-priori registered before actual recruitment of subjects.

Background: With the growing prevalence of obesity, there is also a rise in the incidence of metabolic syndrome (MS). It is characterizes by hyperinsulinemia, increased fasting glucose, hypertriglyceridemia, low HDL, increased waist circumference and hypertension.Insulin-degrading enzyme (IDE) is the major enzyme responsible for insulin degradation among other proteins linked to glucose metabolism such as glucagon. Using genome wide associated studies, IDE was identified as a diabetes susceptibility gene. Furthermore, inhibition of IDE was suggested as therapeutic target for type 2 diabetes. Objectives: Study the difference in IDE levels between healthy and MetS subjects. Characterize metabolic parameters which correlate with IDE.Explore IDE levels in a mouse model of obesity/ insulin resistance. Methods: We developed highly specific anti IDE antibodies with the ability to detect human IDE levels using ELISA. IDE levels were measured in 45 MS subjects and 30 controls. Results: As expected, MS subjects had higher BMI, glucose, triglycerides and insulin levels, with lower HDL levels. IDE levels were higher in MS subjects (average 692 +/-464 vs 420 +/- 232 pg/microliter; p<0.01). We also found a strong correlation between IDE levels and triglyceride levels (r= 0.305; p<0.05), and negative correlation with HDL levels (r= -0.347; p<0.05). This difference remained significant even after multi-variant analysis.Of interest, IDE levels in MS subjects were clearly segregated into two different subgroups, subjects with "normal IDE", with value distribution and mean (n=25; 278+/-156 pg/ul) which were indistinguishable from the normal control group and subjects with high IDE (n=25; 1272+/-757 pg/ul<0.001 for the difference between normal and high IDE). The high IDE MS group was older and had higher glucose levels than the normal IDE MS group (54 +/- 10 vs 45+/-13 years; p=0.01; and (94+/-20 vs 80+/-8 mg/dl; p=0.01; respectively). Conclusions: IDE is higher in MS subjects and is related to age and fasting glucose. Whether or not this is a compensatory mechanism or contributes to disease progression remains to be explored. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

SMECE is a rare thyroid carcinoma (<1%), on the background of Hashimoto's thyroiditis, with a female predominance. SMECE is characterized by inflammatory infiltrate of eosinophils, extensive sclerosis and squamous and glandular differentiation. It is mostly regarded as an aggressive tumor. Most SMECE stain negative with thyroglobulin and positive with p63, but to date lack a pathgnomonic molecular/genetic/epigenetic diagnostic marker. SMECE should be differentiated from salivary mucoepidermoid carcinoma, papillary carcinoma with squamous metaplasia and Hodgkin lymphoma. Here we describe a 42-year-old female that presented with a right-sided thyroid swelling. A total-thyroidectomy was preformed and the pathological report described a tumor of 2.2cm which reached the inked surgical margins at several foci. Staining showed typical features of SMECE. Calcitonin, thyroglobulin stains were negative but cytokeratin staining was positive. No extra-thyroidal extension was seen. Post-operative PET scan and US showed no evidence of residual/recurrence disease during the next 9 years of follow -up. There are about 55 cases of SMECE described in the literature. SMECE was categorized as low-grade tumor but recent reports suggested a more aggressive behavior both locally and occasionally by distant metastasis. In the largest published series nearly half of the cases presented with an extrathyroidal extension and over 1/3 had lymph node metastases. After an average of 4 years follow up, 24% were deceased and 15% were alive with disease. In the present case, despite some involvement of the surgical margins no other aggressive feature was noted. This case then may indicate that a localized tumor, at diagnosis, without extrathyroidal and lymph node involvement may be regarded as a low-grade tumor with a favorable prognosis. Shah A et al - Modern Pathology 2017; 30: 329-339 Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

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 (β = −0.865) and caproic acid (β = −0.423) and reduction in the consumption of dietary vitamin B6 (β = 0.542), calcium (β = 0.335), total carbohydrates (β = 0.239) and total caloric intake (β = 0.238; p < 0.001). Notably, the strongest correlate of the decline in BMI was the increase in dietary potassium intake (β = −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.