Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by occurrence of parathyroid tumours and neuroendocrine tumours (NETs) of the pancreatic islets and anterior pituitary. The MEN1 gene, encoding menin, is a tumour suppressor, but its precise role in initiating in vivo tumourigenesis remains to be elucidated. The availability of a temporally controlled conditional MEN1 mouse model would greatly facilitate the study of such early tumourigenic events, and overcome the limitations of other MEN1 knockout models, in which menin is lost from conception or tumour development occurs asynchronously. To generate a temporally controlled conditional mouse model, we crossbred mice with the MEN1 gene floxed by LoxP sites (Men1 L/L), and mice expressing tamoxifen-inducible Cre recombinase under the control of the rat insulin promoter (RIP2-CreER), to establish a pancreatic β-cell-specific NET model under temporal control (Men1 L/L/RIP2-CreER). Men1 L/L/RIP2-CreER mice aged ~3 months were given tamoxifen in the diet for 5 days, and pancreata harvested 2–2.5, 2.9–3.5 and 4.5–5.5 months later. Control mice did not express Cre and did not receive tamoxifen. Immunostaining of pancreata from tamoxifen-treated Men1 L/L/RIP2-CreER mice, compared to control mice, showed at all ages: loss of menin in all islets; increased islet area (>4.2-fold); increased proliferation of insulin immunostaining β-cells (>2.3-fold) and decreased proliferation of glucagon immunostaining α-cells (>1.7-fold). There were no gender and apoptotic or proliferation differences, and extra-pancreatic tumours were not detected. Thus, we have established a mouse model (Men1 L/L/RIP2-CreER) to study early events in the development of pancreatic β-cell NETs.
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K E Lines, R P Vas Nunes, M Frost, C J Yates, M Stevenson, and R V Thakker
Hershel Raff and Hariprasad Trivedi
Patients with end-stage renal disease (ESRD) can display the features of endogenous hypercortisolism but are difficult to evaluate for Cushing's syndrome. We evaluated the circadian rhythm of plasma compared with salivary cortisol in subjects with ESRD.
Plasma and salivary cortisol and plasma ACTH samples were drawn frequently over 24 h in an inpatient research unit in stable ESRD subjects on daytime chronic hemodialysis (n=16) vs controls (n=8).
Plasma cortisol was measured every 2 h from 0800 to 0600 h the following day. Salivary cortisol was measured every 2 h, except between 2400 and 0400 h (sleep time). Plasma ACTH measured in a subset of samples and C-reactive protein (CRP) was measured as a marker of a subclinical inflammatory state in all subjects.
ESRD subjects had a discernable circadian rhythm in plasma and salivary cortisol, but with a significantly higher nadir (1800–2400 h) compared with the controls (P=0.016–<0.001). After excluding four ESRD subjects without a normal circadian rhythm, the ESRD subjects still had higher nadir plasma and salivary cortisol and plasma ACTH compared with controls. There was no difference in the correlation of salivary and plasma cortisol in control vs ESRD subjects. ESRD subjects had higher CRP levels compared with controls.
ESRD subjects had increased late-night plasma and salivary cortisol and plasma ACTH levels. Late-night salivary cortisol is a reliable index of plasma cortisol in ESRD patients.
Eva O Melin, Jonatan Dereke, Maria Thunander, and Magnus Hillman
Depression has been associated with diabetic retinopathy and increased plasma levels of galectin-3, a lectin expressed in activated macrophages. Increased levels of sCD163, the soluble form of a macrophage expressed scavenger receptor involved in several inflammatory processes, have been demonstrated in the vitreous of the eye in type 1 diabetes (T1D) patients with severe diabetic retinopathy. The aim was to explore whether circulating sCD163 was associated with diabetic retinopathy, depression and/or galectin-3 in T1D patients, controlling for gender, metabolic factors, other diabetes complications, life style and medication.
Two hundred eighty-seven T1D patients, men 56%, age 18–59 years, diabetes duration ≥1 year, were consecutively recruited from one specialist diabetes clinic. Depression was assessed by Hospital Anxiety and Depression Scale-Depression subscale. Blood samples, anthropometrics and blood pressure values were collected, supplemented with data from electronic medical records and the Swedish National Diabetes Registry. High plasma sCD163 was defined as ≥0.575 mg/L (corresponding to the 80th percentile) and high plasma galectin-3 as ≥4.659 µg/L (corresponding to the 95th percentile).
The prevalence of depression was 10%, antidepressant medication 8%, diabetic retinopathy 72%, high sCD163 20% and high galectin 3 5%. High galectin-3 (AOR 9.7), antidepressants (AOR 3.8), diabetic retinopathy (AOR 2.4) and systolic blood pressure (per mmHg) (AOR 1.03) were associated with high sCD163.
This is the first study to show that circulating sCD163 was independently associated with galectin-3, the use of antidepressants and diabetic retinopathy, in patients with T1D. Depression was not associated with sCD163.
Lia Ferreira, João Silva, Susana Garrido, Carlos Bello, Diana Oliveira, Hélder Simões, Isabel Paiva, Joana Guimarães, Marta Ferreira, Teresa Pereira, Rita Bettencourt-Silva, Ana Filipa Martins, Tiago Silva, Vera Fernandes, Maria Lopes Pereira, and Adrenal Tumors Study Group of the Portuguese Society of Endocrinology
Primary adrenal insufficiency (PAI) is a rare but severe and potentially life-threatening condition. No previous studies have characterized Portuguese patients with PAI.
To characterize the clinical presentation, diagnostic workup, treatment and follow‐up of Portuguese patients with confirmed PAI.
This multicentre retrospective study examined PAI patients in 12 Portuguese hospitals.
We investigated 278 patients with PAI (55.8% were females), with a mean age of 33.6 ± 19.3 years at diagnosis. The most frequent presenting clinical features were asthenia (60.1%), mucocutaneous hyperpigmentation (55.0%) and weight loss (43.2%); 29.1% of the patients presented with adrenal crisis. Diagnosis was established by high plasma ACTH and low serum cortisol in most patients (43.9%). The most common aetiology of PAI was autoimmune adrenalitis (61.0%). There were 38 idiopathic cases. Autoimmune comorbidities were found in 70% of the patients, the most frequent being autoimmune thyroiditis (60.7%) and type 1 diabetes mellitus (17.3%). Seventy-nine percent were treated with hydrocortisone (mean dose 26.3 ± 8.3 mg/day) mostly in three (57.5%) or two (37.4%) daily doses. The remaining patients were treated with prednisolone (10.1%), dexamethasone (6.2%) and methylprednisolone (0.7%); 66.2% were also on fludrocortisone (median dose of 100 µg/day). Since diagnosis, 33.5% of patients were hospitalized for disease decompensation. In the last appointment, 17.2% of patients had complaints (7.6% asthenia and 6.5% depression) and 9.7% had electrolyte disturbances.
This is the first multicentre Portuguese study regarding PAI. The results emphasize the need for standardization in diagnostic tests and etiological investigation and provide a framework for improving treatment.
Eva Olga Melin, Magnus Hillman, and Mona Landin-Olsson
To explore associations between high midnight salivary cortisol (MSC) secretion and high blood pressure (BP) in type 1 diabetes (T1D).
Cross-sectional study of 196 adult patients with T1D (54% men). Associations between high MSC (≥9.3 nmol/L) and high systolic BP (>130 mmHg), and high diastolic BP (>80 mmHg) were explored for all patients, users and non-users of antihypertensive drugs (AHD). Adjustments were performed for age, sex, diabetes-related variables, p-creatinine, smoking, physical inactivity, depression and medication.
The prevalence of high MSC differed between patients with high and low systolic BP in all 196 patients: 39 vs 13% (P = 0.001); in 60 users of AHD: 37 vs 12% (P = 0.039), and in 136 non-users of AHD: 43 vs 13% (P = 0.012). Significant associations with high systolic BP were for all patients: physical inactivity (adjusted odds ratio (AOR) 6.5), high MSC (AOR 3.9), abdominal obesity (AOR 3.7), AHD (AOR 2.9), age (per year) (AOR 1.07), and p-creatinine (per µmol/L) (AOR 1.03); for 60 users of AHD: high MSC (AOR 4.1) and age (per year) (AOR 1.11); for 136 non-users of AHD: abdominal obesity (AOR 27.4), physical inactivity (AOR 14.7), male sex (AOR 9.0), smoking (AOR 7.9), and age (per year) (AOR 1.08). High MSC was not associated with high DBP.
In adult patients with T1D, high systolic BP was associated with physical inactivity, high MSC secretion, abdominal obesity, p-creatinine, age, and AHD, the latter indicating treatment failure.
Yu Lin, Yingying Zhang, Lei Xu, Wei Long, Chunjian Shan, Hongjuan Ding, Lianghui You, Chun Zhao, and Zhonghua Shi
Gestational diabetes mellitus (GDM)-induced macrosomia is predominantly characterized by fat accumulation, which is closely related to adipocyte differentiation. An unknown long noncoding RNA RP11-290L1.3, referred to as RP11, was identified to be dramatically upregulated in the umbilical cord blood of women with GDM-induced macrosomia in our previous study. We conducted this study to identify the function of RP11 in GDM-induced macrosomia.
The effects of RP11 gain- and loss-of-function on HPA-v (human preadipocytes-visceral) adipogenesis were determined with lentivirus mediated cell transduction. The mRNA and protein expression levels of adipogenesis makers were evaluated by qPCR/Western blot. Then, we performed the microarray and pathway analysis to explore the possible mechanisms by which RP11 regulates adipogenesis.
Overexpression of RP11 significantly enhanced adipocyte differentiation and increased the mRNA and protein expression levels of adipogenesis makers, such as PPARγ, SREBP1c, and FASN by qPCR/Western blot. Knockdown of RP11 showed opposite effects. Microarray and pathway analysis showed, after RP11 knockdown, 1612 genes were upregulated, and 583 genes were down-regulated which were found to be mainly involved in metabolic pathways, insulin signaling pathway and MAPK signaling pathway.
In conclusion, the unknown lncRNA RP11 serves as a positive factor on preadipocyte differentiation which could shed light on fetal fat accumulation in GDM.
Lukas Engler, Christian Adolf, Daniel A Heinrich, Anna-Katharine Brem, Anna Riester, Anna Franke, Felix Beuschlein, Martin Reincke, Axel Steiger, and Heike Künzel
Primary aldosteronism is a natural model for chronic aldosterone excess in humans and associated with symptoms of anxiety and depression. Cognitive deficits are inherent to the symptomatology of depression and anxiety disorders. Mineralocorticoid receptors and aldosterone appear to play a role in memory. Aldosterone was additionally supposed to be a risk factor for cognitive decline in patients with essential hypertension. The objective of this study was to investigate possible effects of chronically high aldosterone concentrations on cognitive function. A range of cognitive dimensions were assessed in 19 patients (9 males, 10 females); mean age 47.1 (12.5) under standardized treatment and several rating scales for anxiety, depression, quality of life and sleep were administered. Cognitive parameters were compared to standard norms from a large, healthy standardization sample. Patients showed increased levels of anxiety and depression without meeting diagnostic criteria for a disorder. Besides a numerically lower attention score, patients did not show any significant differences in the cognitive dimensions. Anxiety and depression were negatively correlated with quantitative performance in males. In females, a negative correlation between sleep disturbances and abstract reasoning and a positive correlation with quantitative performance were found. Our data showed no specific effect of chronic aldosterone in the tested cognitive parameters overall at least in younger patients, but they indicate sexually dimorphic regulation processes.
Filippo Ceccato, Elisa Selmin, Chiara Sabbadin, Miriam Dalla Costa, Giorgia Antonelli, Mario Plebani, Mattia Barbot, Corrado Betterle, Marco Boscaro, and Carla Scaroni
Introduction and Aim
The purpose of replacement therapy in adrenal insufficiency (AI) is mimicking endogenous cortisol levels as closely as possible: dual release hydrocortisone (DR-HC) has been introduced to replicate the circadian cortisol rhythm. Multiple daily saliva collections could be used to assess the cortisol rhythm during real life: our aim was to study the salivary cortisol profile in AI.
Materials and Methods
We prospectively evaluated, in an observational study, 18 adult outpatients with AI (11 primary and 7 secondary AI), switched from conventional treatment (conv-HC, 25 mg/day) to the same dose of DR-HC. We collected six samples of saliva in a day, measuring cortisol (F) and cortisone (E) with LC-MS/MS. Forty-three matched healthy subjects served as controls.
F levels were similar in the morning (and higher than controls) in patients treated with conv-HC or DR-HC; otherwise F levels and exposure were lower in the afternoon and evening in patients with DR-HC, achieving a cortisol profile closer to healthy controls. Daily cortisol exposure, measured with area under the curve, was lower with DR-HC. Morning F and E presented sensitivity and specificity >90% to diagnose AI (respectively threshold of 3 and 9.45 nmol/L). Total cholesterol and HbA1c levels reduced with DR-HC.
Salivary cortisol daily curve could be used as a new tool to assess the cortisol profiles in patients treated with conv-HC and DR-HC. A lower daily cortisol exposure was achieved with DR-HC (despite the same HC dose), especially in the afternoon-evening.
Sheila Leone, Lucia Recinella, Annalisa Chiavaroli, Claudio Ferrante, Giustino Orlando, Michele Vacca, Roberto Salvatori, and Luigi Brunetti
Growth hormone-releasing hormone (GHRH) plays an important role in brain functions. The aim of this study was to examine cognitive functions and emotional behaviour in a mouse model of isolated GH deficiency due to bi-allelic ablation of the GHRH gene (GHRH knockout, GHRHKO).
Learning, memory and emotional behaviour were evaluated using a series of validated tests (Morris water maze, eight-arm radial maze, open field, elevated plus maze test, forced swim tests) in 2-, 5- and 12-month-old male mice either homozygous (−/−) or heterozygous (+/−) for the GHRHKO allele.
Compared with age-matched +/− mice, −/− mice showed decreased cognitive performance in Morris water maze and eight-arm radial maze tests. By comparing the effects of aging in each genotype, we observed an age-related impairment in test results in +/− mice, while in −/− mice a significant decline in cognitive function was found only in 12 months compared with 2-month-old mice, but no difference was found between 5 months old vs 2 months old. −/− mice showed increased exploration activity compared to age-matched +/− controls, while both strains of mice had an age-related decrease in exploration activity. When evaluated through open field, elevated plus maze and forced swim tests, −/− mice demonstrated a decrease in anxiety and depression-related behaviour compared to age-matched +/− controls.
Our results suggest that homozygous ablation of GHRH gene is associated with decreased performance in learning and memory tests, possibly linked to increased spontaneous locomotor activity. In addition, we observed an age-related decline in cognitive functions in both genotypes.
Sirazum Choudhury, Tricia Tan, Katharine Lazarus, and Karim Meeran
The introduction of adrenocortical extract in 1930 improved the life expectancy of hyhpoadrenal patients, with further increases seen after the introduction of cortisone acetate from 1948. Most patients are now treated with synthetic hydrocortisone, and incremental advances have been made with optimisation of daily dosing and the introduction of multidose regimens. There remains a significant mortality gap between individuals with treated hypoadrenalism and the general population. It is unclear whether this gap is a result of glucocorticoid over-replacement, under-replacement or loss of the circadian and ultradian rhythm of cortisol secretion, with the risk of detrimental excess glucocorticoid exposure at later times in the day. The way forwards will involve replacement of the diurnal cortisol rhythm with better glucocorticoid replacement regimens. The steroid profile produced by both prednisolone and dual-release hydrocortisone (Plenadren), provide a smoother glucocorticoid profile of cortisol than standard oral multidose regimens of hydrocortisone and cortisone acetate. The individualisation of prednisolone doses and lower bioavailability of Plenadren offer reductions in total steroid exposure. Although there is emerging evidence of both treatments offering better cardiometabolic outcomes than standard glucocorticoid replacement regimens, there is a paucity of evidence involving very low dose prednisolone (2–4 mg daily) compared to the larger doses (~7.5 mg) historically used. Data from upcoming clinical studies on prednisolone will therefore be of key importance in informing future practice.