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Background Sex hormone-binding globulin (SHBG) is the main transporter of sex hormones in most vertebrates. Low SHBG levels have been linked to increased risk for diabetes and metabolic syndrome. Polymorphisms of the SHBG gene linked to low SHBG protein levels also strongly predicted increased risk of type 2 diabetes, thus raising the possibility that SHBG may play a role in the pathogenesis of insulin resistance and diabetes. Aim To examine whether expression of human SHBG in mice may ameliorate the development of diabetes and metabolic syndrome in response to a high-fat diet (HFD). Methods Transgene mice expressing a human SHBG transgene (SHBG+) (N = 10/11; males/females) and their wild type littermates (N = 12/8; males/females) were fed HFD for 4.5 months. Results HFD induced comparable obesity in control and SHBG+ mice. Male transgenes had higher muscle mass after 2–3.5 months HFD (0.43 ± 0.028 (n = 4) vs 0.38 ± 0.053 g (n = 7), P = 0.05). Fasting blood glucose, as well as insulin or HOMA-IR, was not different in transgenic vs wild-type males after 4–5 months HFD. Female transgenes had higher fasting glucose (152 ± 29 (n = 7) vs 115 ± 27 mg/dL, P = 0.01 (n = 8)), but mean insulin and HOMA-IR were not different. Likewise, insulin tolerance test and intra-peritoneal glucose tolerance test (GTT) were not different. Finally, SHBG+ mice were not different from controls in terms of liver enzymes, serum triglyceride levels and blood pressure. Conclusion In mice with diet-induced obesity, human SHBG did not protect against development of obesity or dysglycemia.

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. Electronic supplementary material The online version of this article (10.1186/s12877-019-1219-7) contains supplementary material, which is available to authorized users.

ObjectiveIt is still uncertain whether mild primary hyperparathyroidism (PHPT) carries the same risk for increased cardiovascular (CV) morbidity as the more severe symptomatic form. In recent years, the even more subtle normocalcemic (NC) variant is being increasingly recognized. We sought to compare the prevalence of CV risk factors in patients with NC- and hypercalcemic (HC)-PHPT, and to examine whether they differ on a battery of non-invasive vascular parameters.Design/subjects/methodsA retrospective study of two cohorts of patients with PHPT in a referral center: 32 subjects with NC-PHPT and 81 subjects with HC-PHPT, compared for the presence of clinical and biochemical risk factors, and CV morbidity. Non-invasive parameters of arterial stiffness (augmentation index; pulse wave velocity; and vascular compliance indices, C1 and C2) were extracted from the data of gender- and age-matched subsets of these patients, and were related to those of a group of matched control subjects.ResultsDespite a similar prevalence of hypertension (∼62%), hyperlipidemia (∼30%), and impaired glucose metabolism in both PHPT groups, CV or cerebrovascular disease was more common in the HC-PHPT group (24.7 vs 3.1%,P=0.007). Arterial stiffness parameters did not differ in the three groups, and were unrelated to serum calcium or parathyroid hormone concentration.ConclusionsNC-PHPT and HC-PHPT subjects exhibit similar high rates of traditional CV risk factors, and have comparable indices of arterial stiffness. The lower clinical CV morbidity observed with NC-PHPT remains unexplained, and requires confirmation. Until then, the CV risk associated with NC-PHPT should not be underestimated.

Although the negative impact of high BMI on the risk of death from all-cause mortality is now well established, there is an apparent decline in the relative added risk of obesity with increasing age (1,2). This has led some experts to conclude that obesity should not necessarily be viewed as a disease in individuals older than 55 years. If such shift in the approach to adiposity during the latter phases of life is prematurely accepted, it may not only discourage attempted weight loss in older subjects, but also promote nutritional and lifestyle indulgence, which is presently difficult enough to overcome. It is the purpose of the present commentary to briefly outline the full spectrum of obesity-related hardships in the elderly. In our opinion, obesity-induced complications amount to real disease, which gravely affects quality of life and limits effective lifespan. The incidence of hypertension, diabetes, and the metabolic syndrome intensifies with age, and aging per se is closely linked to increased prevalence of most of the abnormalities contributing to the metabolic syndrome (3). The incidence of the metabolic syndrome rises with increasing BMI, and a broader waist circumference is more common in men older than 65 years than in younger age-groups (3). The occurrence of the metabolic syndrome reaches peak levels in the 6th decade for men and the 7th decade for women, and a decline is noted only in the 8th decade for men and for some women in different ethnic groups (3). As recently outlined by the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research, older age and obesity are two of the most powerful risk factors for uncontrolled hypertension (4), and high blood pressure, in turn, is a major determinant of mortality and stroke incidence, particularly in senior years. BMI …

The practicality of vigorous lowering of systolic pressure in diabetes to

Peroxisome proliferator-activated receptor-α is widely distributed in the vasculature where it is believed to exert pleiotropic antiatherogenic effects. Its role in the regulation of blood pressure is still unresolved; however, some evidence suggests that it may affect the renin-angiotensin system. We investigated its role in angiotensin II–induced hypertension in the Tsukuba hypertensive mouse (THM). This is a model of hypertension and atherosclerosis because of high angiotensin II and aldosterone levels as a result of the transgenic expression of the entire human renin-angiotensin system. Making the THM animals deficient in Peroxisome proliferator-activated receptor-α (THM/PPARKO) totally abolished hypertension and myocardial hypertrophy. This was accompanied by a reduction in plasma human active renin in THM/PPARKO mice compared with THM animals from 3525±128 mU/L to 1910±750 mU/L ( P P =0.003). In the THM/PPARKO mice, the extent of atherosclerosis at the aortic sinus after a 12-week period on an atherogenic diet was decreased by >80%. In addition, the spontaneous formation of foam cells from peritoneal macrophages, a blood pressure–independent event, was reduced by 92% in the THM/PPARKO mice, suggesting protection from the usual oxidative stress in these animals, possibly because of lower prevailing angiotensin II levels. Finally, chronic fenofibrate treatment further elevated blood pressure in THM animals but not in THM/PPARKO animals. Taken together, these data indicate that peroxisome proliferator-activated receptor-α may regulate the renin-angiotensin system. They raise the possibility that its activation may aggravate hypertension and hasten atherosclerosis in the context of an activated renin-angiotensin system.

Background Late Onset Tay- Sachs disease (LOTS) is a rare neurodegenerative lysosomal storage disease which results from mutations in the gene encoding the α subunit (HEXA) of β-hexosaminidase enzyme (HexA). At the present time, no effective treatment exists for LOTS and other neurodegenerative diseases involving the central nerve system (CNS). Pyrimethamine (PMT) was previously shown to act as a HexA chaperone in human fibroblasts in vitro carrying some (e.g., αG269S), but not all LOTS-related mutations. The present study assessed the effect of cyclic, low dose and long term pyrimethamine treatment on HexA in subjects with LOTS. Methods In an open label trial in 4 LOTS patients, PMT was initiated at an average daily dose of ~2.7 mg and administered cyclically guided by blood lymphocyte HexA activity for a mean duration of 82.8 (±22.5; SD) weeks (~1.5 year). Results HexA activity rose in all subjects, with a mean peak increase of 2.24 folds (±0.52; SD) over baseline activity (range 1.87-3). The mean treatment time required to attain this peak was of 15.7 (±4.8; SD) weeks. Following increase in activity, HexA gradually declined with the continued use of PMT, which was then stopped, resulting in the return of HexA activity to baseline. A second cycle of PMT treatment was then initiated, resulting again in an increase in HexA activity. Three of the patients experienced a measurable neuropsychiatric deterioration whereas one subject remained entirely stable. Conclusions Cyclic low dose of PMT can increase HexA activity in LOTS patients. However, the observed increase is repeatedly transient and not associated with discernible beneficial neurological or psychiatric effects.

In the present issue of The Journal of Clinical Hypertension, Kline and colleagues propose a fundamental change in the diagnostic workup of patients evaluated for potential primary hyperaldosteronism (PH). Traditionally, the diagnosis of PH is predominantly considered in the presence of hypertension with hypokalemia; severe or resistant hypertension; adrenal incidentaloma, particularly when associated with hypertension; and hypertension of early onset, especially in the context of familial hypertension with early cerebrovascular events. That screening for PH should be initiated by the determination of the Aldosterone-Renin Ratio (ARR) is now widely recommended. A high ARR is followed by one of several confirmatory forms of testing, all of which are based on the principle that contrary to physiological control of aldosterone secretion, autonomous aldosterone secretion cannot be properly turned off in response to salt/volume loading or acute reduction in circulating angiotensin II. Although the need for confirmatory testing is widely accepted, views on the most adequate procedure vary. Reflecting this area of disagreement, the Endocrine Society’s guidelines endorse the use of one of several forms of tests: the oral sodium loading test, saline infusion test, fludrocortisone suppression test, or the captopril challenge test. In principle, only individuals with evidence of autonomous aldosterone secretion in any of these tests are presumed to have “true PH” and are thus referred for further evaluation, including computed tomography (CT) or magnetic resonance imaging scans, followed by adrenal venous sampling (AVS). Individuals with unilateral disease, mostly aldosterone-producing adenoma, are usually referred for surgery and are likely to benefit from adrenalectomy, whereas patients with bilateral adrenal hyperplasia are treated medically. In their present article, Kline and coworkers challenge the need for confirmatory testing and offer an alternative single-step, ARR-based approach to the diagnosis of PH, to be directly followed, when a preset critical ARR is surpassed, by adrenal imaging and AVS. Because of the inconsistent performance of the confirmatory tests, the authors abandoned this phase altogether. Having accumulated considerable experience with this approach, this group now submits evidence from a single referral center that a systematic omission of confirmatory testing has virtually no discernible impact on the clinical outcome of patients evaluated for PH. In the course of 6 years (2005–2011), Kline and associates evaluated 83 hypertensive patients whose initial ARR exceeded 550 pmol/L irrespective of their medication status. Patients with resistant hypertension and normal ARR were re-evaluated after the withdrawal of all medications known to affect aldosterone and/or plasma renin activity (PRA) and maintained on doxazocin and either nifedipine or diltiazem, supplemented, when needed, only by oral potassium-containing tablets. In all, 83 patients whose ARR exceeded 550 pmol/L were considered to have PH. All were referred for adrenal CT and AVS, using a protocol in which adrenal vein aldosterone was measured both before and after the administration of 250 lg of cosyntropin (a synthetic derivative of adrenocorticotropic hormone [ACTH]). Patients whose post-ACTH interadrenal aldosterone/cortisol ratio gradient was higher than 3 were considered to have unilateral disease. In terms of outcome, AVS was technically successful in 80 of 83 (96%) of the patients and an unequivocal AVS-based lateralization was established in 48 patients. Notably, 88% of the lateralized patients had a congruent CT finding, whereas unilateral anomalous CT adrenal was seen in

ObjectiveTo assess arterial stiffness in a cohort of hypogonadal males and to investigate the effect of testosterone replacement therapy on arterial properties in this specific group.DesignEighteen male patients with untreated acquired hypogonadism due to either adult-onset idiopathic hypogonadotropic hypogonadism (n=9) or pituitary tumor (n=9) and 12 age-, sex, and weight-matched eugonadal healthy controls were recruited for the study. Arterial properties, plasma glucose, lipid profile, total, and bioavailable testosterone (BT) levels were measured in fasting state. In the hypogonadal subjects, the effect of transdermal testosterone replacement therapy on arterial properties was studied by repeat noninvasive measurements at baseline, as well as 48 h and 90 days following the initiation of treatment.MethodsArterial stiffness was evaluated using applanation tonometry and pulse wave analysis by three different standard devices that assess various measures of arterial stiffness: pulse wave velocity (PWV), augmentation index (AIx), and large/small artery compliance (C1 and C2).ResultsAge- and blood pressure-adjusted PWV was significantly higher in hypogonadal men (8.90±2.29 vs 6.78±1.16 m/s in the control group;P=0.025). Testosterone therapy increased BT level from 2.01±1.04 to 4.68±2.43 and 7.83±6.2 nmol/l after 48 h and 3 months respectively (P=0.001). PWV decreased from 8.9±2.29 to 8.24±1.39 and 8.25±1.82 m/s after 48 h and 3 months of treatment respectively (P=0.03).ConclusionsMale hypogonadism is associated with increased PWV, which is rapidly but incompletely ameliorated by normalization of circulating testosterone levels.

The practicality of vigorous lowering of systolic pressure in diabetes to130 mmHg remains uncertain. Baseline blood pressure data from several recent trials indicate that, in diabetic subjects, there is nearly a fourfold excess in systolic pressure (the difference between baseline pressure and target pressure) over diastolic pressure with respect to the recommended systolic/diastolic target pressure of130/80 mmHg. Additionally, systolic pressure was 2-3 mmHg higher and diastolic pressure was 1-3 mmHg lower in diabetic hypertensive than in nondiabetic hypertensive individuals, which adds approximately 4 mmHg to pulse pressure and also to the difference between the excess systolic and excess diastolic pressure. We attempted to force (titrate both systolic and excess diastolic pressure) systolic and diastolic blood pressure to130/85 mmHg based on Joint National Committee VI guidelines in the setting of a clinical practice in 257 diabetic patients. Although target systolic pressure was attained in a third of this cohort, in 57% of the patients, the attained diastolic pressure wasor=70 mmHg. Patients with final diastolic pressure70 mmHg were older, had a higher prevalence of coronary artery disease, and had higher initial systolic and pulse pressures. Review of achieved blood pressure in studies such as the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) indicates that a significant fraction of the diabetic subjects' diastolic pressure was also driven down to70 mmHg or even60 mmHg. Thus, attempted lowering of blood pressure to target systolic pressure is associated with inordinate lowering of diastolic pressure in a significant number of patients. Whether the benefits of tight systolic control to130 mmHg outweigh the risks of excessive diastolic reduction, especially in older diabetic subjects or diabetic patients with coronary artery disease, remains unresolved.

A 56 year old man presented with deteriorating vision in his right eye and a history of recent weight gain, new onset hypertension, weakness, headaches, and widespread ecchymoses. Visual acuity …