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Defective insulin processing is associated with obesity and diabetes. Prohormone convertase 1/3 (PC1/3) is an endopeptidase required for the processing of neurotransmitters and hormones. PC1/3 deficiency and genome-wide association studies relate PC1/3 with early onset obesity. Here, we find that deletion of PC1/3 in obesity-related neuronal cells expressing proopiomelanocortin mildly and transiently change body weight and fail to produce a phenotype when targeted to Agouti-related peptide- or nestin-expressing tissues. In contrast, pancreatic β cell-specific PC1/3 ablation induces hyperphagia with consecutive obesity despite uncontrolled diabetes with glucosuria. Obesity develops not due to impaired pro-islet amyloid polypeptide processing but due to impaired insulin maturation. Proinsulin crosses the blood-brain-barrier but does not induce central satiety. Accordingly, insulin therapy prevents hyperphagia. Further, islet PC1/3 expression levels negatively correlate with body mass index in humans. In this work, we show that impaired PC1/3-mediated proinsulin processing, as observed in human prediabetes, promotes hyperphagic obesity. Defective insulin secretion is observed early in the development of diabetes. Here the authors report that β cell-specific deficiency of the insulin prohormone convertase 1/3 (PC1/3) leads not only to hyperglycemia, but also to hyperphagic obesity in mice.

Increased motor fatigability is a symptom of many neuromuscular and neurodegenerative disorders. However, it is difficult to pinpoint pathological motor fatigability, since the phenomena has not yet been fully characterized in the healthy population. In this study, we investigate how motor fatigability differs across age. Given that many disorders involve supraspinal components, we characterize motor fatigability with a paradigm that has previously been associated with supraspinal mechanisms. Finger tapping at maximal speed results in a rapid decrease in movement speed, which is a measure of motor fatigability. We collected finger tapping data in a field experiment from the general population with a smartphone app, and we investigated age differences in maximal tapping speed, as well as the decrease in tapping speed for the index, middle, and little fingers. We found that the maximal tapping speed differed significantly between young (18-30 years,  = 194) and aged (50-70 years, = 176), whereas the fatigability-induced relative decrease in movement speed did not differ between the age groups (average decrease: 17.0% ± 6.9% (young) vs. 16.5% ± 7.5% (aged) decrease). Furthermore, tapping speed and motor fatigability depended on which finger was used. These findings might relate to dexterity, with more dexterous movements being more resistant to fatigue. In this study, we provide a characterization of motor fatigability in the general population which can be used as a comparison for clinical populations in the future.

Gestational diabetes mellitus (GDM) is one of the most common diseases associated with pregnancy, however, the underlying mechanisms remain unclear. Based on the well documented role of inflammation in type 2 diabetes, the aim was to investigate the role of inflammation in GDM. We established a mouse model for GDM on the basis of its two major risk factors, obesity and aging. In these GDM mice, we observed increased Interleukin-1β (IL-1β) expression in the uterus and the placenta along with elevated circulating IL-1β concentrations compared to normoglycemic pregnant mice. Treatment with an anti-IL-1β antibody improved glucose-tolerance of GDM mice without apparent deleterious effects for the fetus. Finally, IL-1β antagonism showed a tendency for reduced plasma corticosterone concentrations, possibly explaining the metabolic improvement. We conclude that IL-1β is a causal driver of impaired glucose tolerance in GDM.

Activity and selectivity assessment of new bi-aryl amide 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) inhibitors, prepared in a modular manner via Suzuki cross-coupling, are described. Several compounds inhibiting 11β-HSD1 at nanomolar concentrations were identified. Compounds 2b, 3e, 7b and 12e were shown to selectively inhibit 11β-HSD1 over 11β-HSD2, 17β-HSD1 and 17β-HSD2. These inhibitors also potently inhibited 11β-HSD1 activity in intact HEK-293 cells expressing the recombinant enzyme and in intact primary human keratinocytes expressing endogenous 11β-HSD1. Moreover, compounds 2b, 3e and 12e were tested for their activity in human skin biopsies. They were able to prevent, at least in part, both the cortisone- and the UV-mediated decreases in collagen content. Thus, inhibition of 11β-HSD1 by these compounds can be further investigated to delay or prevent UV-mediated skin damage and skin aging.

Aldosterone is the main mineralocorticoid hormone controlling sodium balance, fluid homeostasis, and blood pressure by regulating sodium reabsorption in the aldosterone-sensitive distal nephron (ASDN). Germline loss-of-function mutations of the mineralocorticoid receptor (MR) in humans and in mice lead to the “renal” form of type 1 pseudohypoaldosteronism (PHA-1), a case of aldosterone resistance characterized by salt wasting, dehydration, failure to thrive, hyperkalemia, and metabolic acidosis. To investigate the importance of MR in adult epithelial cells, we generated nephron-specific MR knockout mice (MR Pax8/LC1 ) using a doxycycline-inducible system. Under standard diet, MR Pax8/LC1 mice exhibit inability to gain weight and significant weight loss compared to control mice. Interestingly, despite failure to thrive, MR Pax8/LC1 mice survive but develop a severe PHA-1 phenotype with higher urinary Na + levels, decreased plasma Na + , hyperkalemia, and higher levels of plasma aldosterone. This phenotype further worsens and becomes lethal under a sodium-deficient diet. Na + /Cl − co-transporter (NCC) protein expression and its phosphorylated form are downregulated in the MR Pax8/LC1 knockouts, as well as the αENaC protein expression level, whereas the expression of glucocorticoid receptor (GR) is increased. A diet rich in Na + and low in K + does not restore plasma aldosterone to control levels but is sufficient to restore body weight, plasma, and urinary electrolytes. In conclusion, MR deletion along the nephron fully recapitulates the features of severe human PHA‐1. ENaC protein expression is dependent on MR activity. Suppression of NCC under hyperkalemia predominates in a hypovolemic state.

Abstract Context Mammalian target of rapamycin complex 1 (mTORC1) activity is often increased in the adrenal cortex of patients with primary aldosteronism (PA), and mTORC1 inhibition decreases aldosterone production in adrenocortical cells, suggesting the mTORC1 pathway as a target for treatment of PA. Objective To investigate the effect of mTORC1 inhibition on adrenal steroid hormones and hemodynamic parameters in mice and in patients with PA. Design (i) Plasma aldosterone, corticosterone, and angiotensin II (Ang II) were measured in mice treated for 24 hours with vehicle or rapamycin. (ii) Plasma aldosterone levels after a saline infusion test, plasma renin, and 24-hour urine steroid hormone metabolome and hemodynamic parameters were measured during an open-label study in 12 patients with PA, before and after 2 weeks of treatment with everolimus and after a 2-week washout. Main Outcome Measures (i) Change in plasma aldosterone levels. (ii) Change in other steroid hormones, renin, Ang II, and hemodynamic parameters. Results Treatment of mice with rapamycin significantly decreased plasma aldosterone levels (P = 0.007). Overall, treatment of PA patients with everolimus significantly decreased blood pressure (P < 0.05) and increased renin levels (P = 0.001) but did not decrease aldosterone levels significantly. However, prominent reduction of aldosterone levels upon everolimus treatment was observed in four patients. Conclusion In mice, mTORC1 inhibition was associated with reduced plasma aldosterone levels. In patients with PA, mTORC1 inhibition was associated with improved blood pressure and renin suppression. In addition, mTORC1 inhibition appeared to reduce plasma aldosterone in a subset of patients. Systemic mammalian target of rapamycin complex 1 inhibition decreases plasma aldosterone levels in mice and in a subset of patients with primary aldosteronism.

To estimate the health economic impact of osteosynthesis (OS) in fracture care over six decades in 17 high-income countries. Applying a decision tree model, we assumed a hypothetical absence of OS and compared OS (intervention) with conservative treatment (CONS; comparator). We included patients with femur, tibia and radius fractures (age <65 years) and for proximal femur fractures also elderly patients (≥70 years). We estimated savings in direct and indirect costs of 855 billion Swiss francs in the working age population in addition to 4.6 million years of life gained. In the elderly population, 69 billion Swiss francs were saved in direct costs of proximal femur fractures in addition to 73 million years of life gained. OS contributed to maximize health gains of society.

Context: Mammalian target of rapamycin complex 1 (mTORCI) activity is often increased in the adrenal cortex of patients with primary aldosteronism (PA), and mTORC1 inhibition decreases aldosterone production in adrenocortical cells, suggesting the mTORC1 pathway as a target for treatment of PA. Objective: To investigate the effect of mTORC1 inhibition on adrenal steroid hormones and he-modynamic parameters in mice and in patients with PA. Design: (i) Plasma aldosterone, corticosterone, and angiotensin II (Ang II) were measured in mice treated for 24 hours with vehicle or rapamycin. (ii) Plasma aldosterone levels after a saline infusion test, plasma renin, and 24-hour urine steroid hormone metabolome and hemodynamic parameters were measured during an open-label study in 12 patients with PA, before and after 2 weeks of treatment with everolimus and after a 2-week washout. Main Outcome Measures: (i) Change in plasma aldosterone levels. (ii) Change in other steroid hormones, renin, Ang II, and hemodynamic parameters. Results: Treatment of mice with rapamycin significantly decreased plasma aldosterone levels (P = 0.007). Overall, treatment of PA patients with everolimus significantly decreased blood pressure (P < 0.05) and increased renin levels (P = 0.001) but did not decrease aldosterone levels significantly. However, prominent reduction of aldosterone levels upon everolimus treatment was observed in four patients. Conclusion: In mice, mTORCI inhibition was associated with reduced plasma aldosterone levels. In patients with PA, mTORC1 inhibition was associated with improved blood pressure and renin suppression. In addition, mTORC1 inhibition appeared to reduce plasma aldosterone in a subset of patients. (J Clin Endocrinol Metab 104: 4703-4714, 2019)

Background Several studies found mid-regional pro-adrenomedullin (ProADM), the prohormone of the cardiovascular protein adrenomedullin, to be strongly associated with short-term mortality, mostly in the inpatient setting. We evaluated associations of ProADM levels with 10-year mortality in community-dwelling primary care patients with respiratory tract infections. Methods This is a post-hoc analysis using clinical and biomarker data of 134 primary care patients with respiratory tract infections. ProADM was measured on admission and after 7 days in batch-analysis. 10-year follow-up data was collected by GP, patient and relative tracing through phone interviews. We calculated Cox regression models and area under the receiver operating characteristics curves to assess associations of ProADM with 10-year all-cause mortality. Results During the 10-year follow-up 6% of included patients died. Median baseline ProADM blood levels (nmol/l) were significantly higher in non-survivors compared to survivors (0.5, IQR 0.4–1.3; vs. 0.2, IQR 0.1–0.5; p  = 0.02) and showed a significant association with 10-year all-cause mortality in an age-adjusted cox regression model (HR: 2.5, 95%-CI: 1.0–6.1, p  = 0.04). ProADM levels on day 7 showed similar results. Conclusions This posthoc analysis found an association of elevated ProADM blood levels and 10-year all-cause mortality in a primary care cohort with respiratory tract infections. Due to the methodological limitations including incomplete data regarding follow-up information and biomarker measurement, this study warrants validation in future larger studies. Trial registration Current Controlled Trials, SRCTN73182671

Activity and selectivity assessment of new bi-aryl amide 11[beta]-hydroxysteroid dehydrogenase 1 (11[beta]-HSD1) inhibitors, prepared in a modular manner via Suzuki cross-coupling, are described. Several compounds inhibiting 11[beta]-HSD1 at nanomolar concentrations were identified. Compounds 2b, 3e, 7b and 12e were shown to selectively inhibit 11[beta]-HSD1 over 11[beta]-HSD2, 17[beta]-HSD1 and 17[beta]-HSD2. These inhibitors also potently inhibited 11[beta]-HSD1 activity in intact HEK-293 cells expressing the recombinant enzyme and in intact primary human keratinocytes expressing endogenous 11[beta]-HSD1. Moreover, compounds 2b, 3e and 12e were tested for their activity in human skin biopsies. They were able to prevent, at least in part, both the cortisone- and the UV-mediated decreases in collagen content. Thus, inhibition of 11[beta]-HSD1 by these compounds can be further investigated to delay or prevent UV-mediated skin damage and skin aging.