Treatment of Primary Aldosteronism with mTORC1 Inhibitors

mTORC1 activity is often increased in the adrenal cortex of patients with primary aldosteronism and mTORC1 inhibition decreases aldosterone production in adrenocortical cells, suggesting the mTORC1 pathway as a possible target for treatment of primary aldosteronism.; To investigate the effect of mTORC1 inhibition on adrenal steroid hormones and hemodynamic parameters in mice and in patients with primary aldosteronism.; (i) Plasma aldosterone, corticosterone and angiotensin II were measured in mice treated for 24 hours with vehicle or rapamycin. (ii) Plasma aldosterone levels after a saline infusion test, plasma renin, 24-hour urine steroid hormone metabolome and hemodynamic parameters were measured during an open-label study in 12 patients with primary aldosteronism before and after two-weeks of treatment with everolimus and after a two-week washout period.; (i) Change in plasma aldosterone levels. (ii) Change in other steroid hormones, renin, angiotensin II and hemodynamic parameters.; Treatment of mice with rapamycin significantly decreased plasma aldosterone levels (P = 0.007). Overall, treatment of primary aldosteronism patients with everolimus significantly decreased blood pressure (P < 0.05) and increased renin levels (P = 0.001) but did not lead to a significant reduction in aldosterone levels. However, prominent reduction of aldosterone levels upon everolimus treatment was observed in 4 out of 12 patients.; In mice, mTORC1 inhibition was associated with reduced plasma aldosterone levels. In patients with primary aldosteronism, 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

Arachidonic acid inhibition of the NLRP3 inflammasome is a mechanism to explain the anti-inflammatory effects of fasting.

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Randomized, double-blind, placebo-controlled crossover trial of once daily empagliflozin 25 mg for the treatment of postprandial hypoglycaemia after Roux-en-Y gastric bypass.

Aims To investigate the effect of empagliflozin on glucose dynamics in individuals suffering from postbariatric hypoglycaemia (PBH) after Roux-en-Y gastric bypass (RYGB). Methods Twenty-two adults with PBH after RYGB were randomized to empagliflozin 25 mg or placebo once daily over 20 days in a randomized, double-blind, placebo-controlled, crossover trial. The primary efficacy outcome was the amplitude of plasma glucose excursion (peak to nadir) during a mixed meal tolerance test (MMTT). Outcomes of the outpatient period were assessed using continuous glucose monitoring (CGM) and an event-tracking app. Results The amplitude of glucose excursion during the MMTT was 8.1±2.4 mmol/L with empagliflozin vs 8.1±2.6 mmol/L with placebo (mean±SD, p=0.807). CGM-based mean amplitude of glucose excursion (MAGE) during the 20 day-period was lower with empagliflozin than placebo (4.8±1.3 vs 5.2±1.6. p=0.028). Empagliflozin reduced the time spent with CGM values >10.0 mmol/L (3.8±3.5 % vs. 4.7±3.8 %, p =0.009), but not the time spent with CGM values <3.0 mmol/L (1.7±1.6 % vs. 1.5±1.5 %, p=0.457). No significant difference was observed in the quantity and quality of recorded symptoms. Eleven adverse events occurred with empagliflozin (three drug-related) and six with placebo. Conclusions Empagliflozin 25 mg reduces glucose excursions but not hypoglycaemia in individuals with PBH

Randomized, Double-Blind, Placebo-Controlled Crossover Trial of Once Daily Empagliflozin 25 mg for the Treatment of Postprandial Hypoglycemia After Roux-en-Y Gastric Bypass

Aims: To investigate the effect of empagliflozin on glucose dynamics in individuals suffering from postbariatric hypoglycemia (PBH) after Roux-en-Y gastric bypass (RYGB). Methods: Twenty-two adults with PBH after RYGB were randomized to empagliflozin 25 mg or placebo once daily over 20 days in a randomized, double-blind, placebo-controlled, crossover trial. The primary efficacy outcome was the amplitude of plasma glucose excursion (peak to nadir) during a mixed-meal tolerance test (MMTT). Outcomes of the outpatient period were assessed using continuous glucose monitoring (CGM) and an event-tracking app. Results: The amplitude of glucose excursion during the MMTT was 8.1 ± 2.4 mmol/L with empagliflozin versus 8.1 ± 2.6 mmol/L with placebo (mean ± standard deviation, P = 0.807). CGM-based mean amplitude of glucose excursion during the 20-day period was lower with empagliflozin than placebo (4.8 ± 1.3 vs. 5.2 ± 1.6. P = 0.028). Empagliflozin reduced the time spent with CGM values >10.0 mmol/L (3.8 ± 3.5% vs. 4.7 ± 3.8%, P = 0.009), but not the time spent with CGM values <3.0 mmol/L (1.7 ± 1.6% vs. 1.5 ± 1.5%, P = 0.457). No significant difference was observed in the quantity and quality of recorded symptoms. Eleven adverse events occurred with empagliflozin (three drug-related) and six with placebo. Conclusions: Empagliflozin 25 mg reduces glucose excursions but not hypoglycemia in individuals with PBH

Canakinumab in patients with COVID-19 and type 2 diabetes - A multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND: Patients with type 2 diabetes and obesity have chronic activation of the innate immune system possibly contributing to the higher risk of hyperinflammatory response to SARS-CoV2 and severe COVID-19 observed in this population. We tested whether interleukin-1β (IL-1β) blockade using canakinumab improves clinical outcome. METHODS: CanCovDia was a multicenter, randomised, double-blind, placebo-controlled trial to assess the efficacy of canakinumab plus standard-of-care compared with placebo plus standard-of-care in patients with type 2 diabetes and a BMI > 25 kg/m$^{2}$ hospitalised with SARS-CoV2 infection in seven tertiary-hospitals in Switzerland. Patients were randomly assigned 1:1 to a single intravenous dose of canakinumab (body weight adapted dose of 450-750 mg) or placebo. Canakinumab and placebo were compared based on an unmatched win-ratio approach based on length of survival, ventilation, ICU stay and hospitalization at day 29. This study is registered with ClinicalTrials.gov, NCT04510493. FINDINGS: Between October 17, 2020, and May 12, 2021, 116 patients were randomly assigned with 58 in each group. One participant dropped out in each group for the primary analysis. At the time of randomization, 85 patients (74·6 %) were treated with dexamethasone. The win-ratio of canakinumab vs placebo was 1·08 (95 % CI 0·69-1·69; p = 0·72). During four weeks, in the canakinumab vs placebo group 4 (7·0%) vs 7 (12·3%) participants died, 11 (20·0 %) vs 16 (28·1%) patients were on ICU, 12 (23·5 %) vs 11 (21·6%) were hospitalised for more than 3 weeks, respectively. Median ventilation time at four weeks in the canakinumab vs placebo group was 10 [IQR 6.0, 16.5] and 16 days [IQR 14.0, 23.0], respectively. There was no statistically significant difference in HbA1c after four weeks despite a lower number of anti-diabetes drug administered in patients treated with canakinumab. Finally, high-sensitive CRP and IL-6 was lowered by canakinumab. Serious adverse events were reported in 13 patients (11·4%) in each group. INTERPRETATION: In patients with type 2 diabetes who were hospitalised with COVID-19, treatment with canakinumab in addition to standard-of-care did not result in a statistically significant improvement of the primary composite outcome. Patients treated with canakinumab required significantly less anti-diabetes drugs to achieve similar glycaemic control. Canakinumab was associated with a prolonged reduction of systemic inflammation. FUNDING: Swiss National Science Foundation grant #198415 and University of Basel. Novartis supplied study medication

Patient involvement to inform the design of a clinical trial in postbariatric hypoglycemia

Postbariatric hypoglycemia is a major medical complication after bariatric surgery for which no approved medical therapy exists. The exact mechanisms still need to be identified and clinical studies are mostly focusing on physiological changes and hardly reflect patients' needs. In this study, we try to identify the most patient-relevant outcome for a clinical trial for a novel treatment for postbariatric hypoglycemia. We did a literature search and developed questionnaires (in German) for patients to identify the most patient-relevant outcome parameter

Hypothyroidism manifesting as multiple cranial neuropathies: a case report

The clinical picture of hypothyroidism, including neurological symptoms, can be multiform, which may delay or hamper the correct diagnosis.; We present an uncommon clinical presentation of a 38-year-old Caucasian man with mild facial palsy on the left side, uvular deviation to the left with preserved gag reflex, tongue deviation to the left, lingual dysarthria, and xerosis by severe hypothyroidism. Blood tests on admission showed elevated serum creatinine of 151 μmol/L (glomerular filtration rate 47 ml/min/1.7 CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration equation]), increased creatinine phosphokinase activity (1243 U/L), markedly elevated thyroid-stimulating hormone (292.2 mIU/L), low free thyroxine level (1.1 pmol/L), and free triiodothyronine level below the limit of detection (< 0.4 pmol/L). Results of brain magnetic resonance imaging and renal ultrasound were unremarkable. Lumbar puncture revealed a normal cell count in cerebrospinal fluid, with an increased protein level of 758 mg/L and a cerebrospinal fluid/serum albumin ratio of 10.5 × 10; - 3; /L (reference range < 6.7). Further diagnostic workup did not reveal any inflammatory or infectious systemic pathologies as an underlying cause. The patient's neurological symptoms, as well as laboratory findings including renal function, creatinine phosphokinase, and initially altered blood lipid levels, normalized with levothyroxine substitution.; Multiple cranial neuropathy is an uncommon clinical finding in hypothyroidism, which is an important differential diagnosis in the workup of new neurological deficits

Brunner's Gland Hyperplasia in a Patient after Roux-Y Gastric Bypass: An Important Pitfall in GLP-1 Receptor Imaging.

Severe cases of postprandial hypoglycaemia after bariatric surgery can be a diagnostic and therapeutic challenge. The diagnostic role of 68Ga-DOTA-Exendin-4 PET/CT in postbariatric hypoglycaemia for further treatment decisions is unclear. We present a case of a 50-year-old woman with frequent and severe postprandial hypoglycaemic (≤2.5 mmol/L) episodes starting three years after Roux-Y gastric bypass. Despite strict dietary adherence and several medical therapies, the patient remained severely affected, and 68Ga-DOTA-Exendin-4 PET/CT was performed to exclude atypical presentation of an insulinoma or nesidioblastosis. No pancreatic abnormalities were found, but intensive tracer accumulation in the first and second part of the duodenum was detected, which proved to be hyperplastic Brunner's glands on histology and were strongly positive for the glucagon-like peptide-1 receptor. This case provides histopathological verification that duodenal 68Ga-DOTA-Exendin-4 uptake is caused by uptake in Brunner's glands and points to a potential relationship between bariatric surgery and Brunner's glands

Medullary thyroid cancer with ectopic Cushing's syndrome: A multicentre case series

OBJECTIVE Ectopic Cushing's syndrome (ECS) induced by medullary thyroid cancer (MTC) is rare, and data on clinical characteristics, treatment and outcome are limited. DESIGN Retrospective cohort study in three German and one Swiss referral centres. PATIENTS Eleven patients with MTC and occurrence of ECS and 22 matched MTC patients without ECS were included. MEASUREMENTS The primary endpoint of this study was the overall survival (OS) in MTC patients with ECS versus 1:2 matched MTC patients without ECS. RESULTS The median age at diagnosis of ECS was 59 years (range: 35-81) and the median time between initial diagnosis of MTC and diagnosis of ECS was 29 months (range: 0-193). Median serum morning cortisol was 49 µg/dl (range: 17-141, normal range: 6.2-18). Eight (73%) patients received treatment for~ECS. Treatment of ECS consisted of bilateral adrenalectomy (BADX) in four (36%) patients and adrenostatic treatment in eight (73%) patients. One patient received treatment with multityrosine kinase inhibitor (MKI) to control hypercortisolism. All patients experienced complete resolution of symptoms of Cushing's syndrome and biochemical control of hypercortisolism. Patients with ECS showed a shorter median OS of 87 months (95% confidence interval 95{\%} CI: 64-111) than matched controls (190 months, 95{\%} CI: 95-285). Of the nine deaths, four were related to progressive disease (PD). Four patients showed PD as well as complications and comorbidities of hypercortisolism before death. CONCLUSION This study shows that ECS occurs in advanced stage MTC and is associated with a poor prognosis. Adrenostatic treatment and BADX were effective systemic treatment options in patients with MTC and ECS to control their hypercortisolism. MKI treatment achieved complete remission of hypercortisolism and sustained tumour control in one treated case

Pitfalls in the Detection of Insulinomas With Glucagon-Like Peptide-1 Receptor Imaging.

PURPOSE Physiological pancreaticoduodenal uptake of radiolabeled exendin-4 in Brunner glands of the proximal duodenum is the most common pitfall for false interpretation of glucagon-like peptide-1 receptor (GLP-1R) imaging. The aim of this study was to analyze the pancreaticoduodenal uptake in GLP-1R PET/CT and SPECT/CT images and to identify additional potential reading pitfalls in patients with suspected insulinoma. METHODS A post hoc analysis of a prospective study, including 52 consecutive patients, was performed. All patients underwent 1 Ga-exendin-4 PET/CT and 2 In-exendin-4 SPECT/CT scans (4 and 72 hours postinjection) in a randomized crossover order. Three board-certified nuclear medicine physicians read all scans independently. They were unaware of other results. Reference standard was surgery with histopathological confirmation of an insulinoma/nesidioblastosis and normalization of blood glucose levels after surgery. RESULTS There were no false-positive readings. However, there were a number of false-negative PET/CT and SPECT/CT readings, respectively: (1) due to false interpretation of uptake in the pancreaticoduodenal region (falsely interpreted as physiological uptake in Brunner glands instead of an insulinoma in 0.6% vs 9.0%), (2) due to ectopic insulinoma (0% vs 2.6%), (3) due to small insulinoma (1.9% vs 5.1%), (4) due to insulinoma overlap with kidneys (1.9% vs 4.5%), and (5) due to nesidioblastosis (0.6% and 1.9%). Pitfalls were identified in all GLP-1R PET/CT and SPECT/CT scans. CONCLUSIONS Peripancreatic uptake, small size of an insulinoma, insulinoma overlap with kidneys, and presence of nesidioblastosis are potential pitfalls in GLP-1R imaging, which can lead to false reading results