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Aims/hypothesis Wolfram syndrome is a rare autosomal recessive disorder caused by pathogenic variants in the WFS1 gene. It is characterised by insulin-dependent diabetes mellitus, optic nerve atrophy, diabetes insipidus, hearing loss and neurodegeneration. Considering the unmet treatment need for this orphan disease, this study aimed to evaluate the therapeutic potential of glucagon-like peptide 1 receptor (GLP-1R) agonists under wolframin (WFS1) deficiency with a particular focus on human beta cells and neurons. Methods The effect of the GLP-1R agonists dulaglutide and exenatide was examined in Wfs1 knockout mice and in an array of human preclinical models of Wolfram syndrome, including WFS1-deficient human beta cells, human induced pluripotent stem cell (iPSC)-derived beta-like cells and neurons from control individuals and individuals affected by Wolfram syndrome, and humanised mice. Results Our study shows that the long-lasting GLP-1R agonist dulaglutide reverses impaired glucose tolerance in WFS1-deficient mice, and that exenatide and dulaglutide improve beta cell function and prevent apoptosis in different human WFS1-deficient models including iPSC-derived beta cells from people with Wolfram syndrome. Exenatide improved mitochondrial function, reduced oxidative stress and prevented apoptosis in Wolfram syndrome iPSC-derived neural precursors and cerebellar neurons. Conclusions/interpretation Our study provides novel evidence for the beneficial effect of GLP-1R agonists on WFS1-deficient human pancreatic beta cells and neurons, suggesting that these drugs may be considered as a treatment for individuals with Wolfram syndrome. Graphical abstract

Subclinical hyperthyroidism is a common clinical entity, defined by serum TSH below the reference range, with normal FT4 and FT3 levels in an asymptomatic patient. Whether or not subclinical hyperthyroidism should be treated remains a matter of debate. Cross-sectional and longitudinal population-based studies demonstrate association of subclinical hyperthyroidism with risk of atrial fibrillation and osteoporosis, and with cardiovascular and all-cause mortality. However, there are no randomized clinical trials addressing whether long-term health outcomes are improved by treating subclinical hyperthyroidism; in the absence of evidence one way or the other, it seems appropriate to use decision trees taking account of TSH concentration and presence of risk factors (age>65 years or post-menopause, osteoporosis and cardiac disease).

DNAJC3, also known as P58IPK, is an Hsp40 family member that interacts with and inhibits PKR-like ER-localized eIF2α kinase (PERK). Dnajc3 deficiency in mice causes pancreatic β-cell loss and diabetes. Loss-of-function mutations in DNAJC3 cause early-onset diabetes and multisystemic neurodegeneration. The aim of our study was to investigate the genetic cause of early-onset syndromic diabetes in two unrelated patients, and elucidate the mechanisms of β-cell failure in this syndrome., info:eu-repo/semantics/published

Type 2 diabetes is a common complex disease. Relatively little is known about the underlying pathophysiology. Mild islet inflammation has been suggested to play a pathogenic role; here we review the available evidence. Mild islet inflammation is histologically detected in pancreas sections of type 2 diabetic patients. In experimental models, it can be triggered by excess nutrients, amyloid, lipopolysaccharide, and endoplasmic reticulum and oxidative stress. Transcriptome studies do not consistently identify pro-inflammatory gene expression signatures in type 2 diabetic islets, and genetic evidence calls into question the causality of inflammation. Several anti-inflammatory medications confer a modest glucose-lowering effect, supporting the role for inflammation in type 2 diabetes. Whether these anti-inflammatory therapies target inflammation in islets or in other metabolically relevant tissues remains unknown., SCOPUS: re.j, info:eu-repo/semantics/published

Primary pigmented nodular adrenal disease (PPNAD) accounts for,1% of ACTH-independent Cushing syndrome. We describe the case of twin female patients with PPNAD who both had sustainable disease control after unilateral adrenalectomy, which corroborates current evidence in favor of unilateral adrenalectomy for a subset of patients with PPNAD. Patient A presented with a 10-kg weight gain over the past year and facial plethora. Diagnostic evaluation revealed abolition of normal cortisol rhythm with suppressed ACTH levels, normal adrenal CT and MRI imaging and a slightly left-predominant adrenal uptake on 131I iodomethyl norcholesterol scintigraphy coupled with single-photon emission CT/ CT. PPNAD was confirmed after genetic testing revealed a known pathogenic PRKA1A mutation (c.709 (-7-2) del6). At that time, her twin sister (patient B) was asymptomatic. Patient A underwent successful unilateral adrenalectomy and histology confirmed PPNAD. Two years after initial onset of symptoms in patient A, patient B was seen for the same subtle symptoms of progressive weight gain. Diagnostic test results were identical, revealing the same clinical features and mutational status as patient A. Patient B also underwent unilateral adrenalectomy with a favorable outcome. Follow-up 3 years after surgery for patient A and 18 months for patient B showed sustained disease control without recurrence and uncompromised quality of life, with no adrenal insufficiency having occurred. Unilateral adrenalectomy can be a successful therapeutic approach for patients with PPNAD with a mild phenotype without the risk and the inconvenience of subsequent adrenal insufficiency, which alters quality of life., SCOPUS: ar.j, info:eu-repo/semantics/published

Subclinical hyperthyroidism (SCH) is common and is characterized by laboratory findings of a persistently low TSH level and normal FT4 and FT3 values. The interpretation of studies on the clinical significance of SCH have been complicated by the fact that the degree and etiology of SCH varies, but research has suggested that it is associated with osteoporosis, weight changes, adverse cardiovascular effects including an increased risk of atrial fibrillation, and an increased all-cause mortality rate. We discuss SCH and review the literature on its suspected cardiovascular effects, which are more likely to be seen in the elderly and in patients with more significant degrees of TSH suppression. We then discuss SCH treatment options in detail and suggest an algorithm for the management of SCH that takes into consideration the TSH level and the presence of clinical risk factors., SCOPUS: re.j, info:eu-repo/semantics/published

Neonatal diabetes is caused by single gene mutations affecting fundamental β-cell function pathways. 20% of cases of neonatal diabetes remain genetically unexplained. Our aim was to explore the genetic basis of a syndrome characterized by neonatal diabetes, microcephaly and epilepsy, present in 2 unrelated patients. The Turkish and Indian patients were born to consanguineous parents. Using whole genome sequencing, we found that they had homozygous likely deleterious variants (missense, p.(Ala181Val) and in-frame deletion p.(Lys106del)) in YIPF5. We then performed replication studies in 112 patients with neonatal diabetes by targeted next generation sequencing. These identified 2 homozygous YIPF5 mutations (p.(Trp218Arg) and p.(Ile98Ser)) in 3 patients (2 siblings) with early-onset diabetes, epilepsy and microcephaly. In functional studies, YIPF5 was expressed in human islets and fetal brain cortex, as evaluated by qPCR and in situ hybridization. Because YIPF5 is involved in endoplasmic reticulum (ER)-to-Golgi trafficking, we examined the impact of YIPF5 loss-of-function on β-cell survival during ER stress. YIPF5 was silenced in the human β-cell line EndoC-βH1 and in human islets. YIPF5 silencing sensitized β cells to apoptosis induced by the ER stressors thapsigargin and brefeldin A. The ER stressors enhanced CHOP, BiP and spliced XBP1 expression in YIPF5-depleted cells, indicating increased ER stress signaling. Expression of the proapoptotic proteins PUMA and DP5 was also enhanced by YIPF5 silencing. CHOP and DP5 knockdown partially protected YIPF5-deficient cells from apoptosis, suggesting that they mediate apoptosis. In conclusion, homozygous loss-of-function mutations in YIPF5 are a novel cause of early-onset diabetes, microcephaly and epilepsy. This syndrome unveils a critical role of YIPF5 and ER-to-Golgi trafficking in the function and survival of human β-cells and neurons. Disclosure M. Lytrivi: None. E. De Franco: Other Relationship; Self; Novo Nordisk Foundation. K.A. Patel: None. M. Igoillo Esteve: None. C. Cosentino: None. M.N. Wakeling: None. B. Haliloglu: None. M. Yildiz: None. T. Godbole: None. A.T. Hattersley: None. M. Cnop: None. Funding Fonds Erasme for Medical Research; European Union (667191); Fonds National de la Recherche Scientifique; Brussels-Capital Region Innoviris

Objective The effects of endogenous subclinical hyperthyroidism (eSCH) on heart and bone have been well documented. There are only limited data available regarding the impact of eSCH on weight regulation and lipid metabolism. Our aim was to evaluate the changes in body weight and metabolic parameters after total thyroidectomy in patients with preoperative eSCH compared with preoperative euthyroid patients (EUT). Design A retrospective study of 505 patients who underwent total thyroidectomy for benign multinodular goiter in an academic hospital in Brussels (Belgium) was performed. Patients measurements Two hundred and twenty-five patients were included (eSCH group: n=74; EUT group: n=151). The mean follow-up time was 26.1 ± 0.8 months and was similar in both groups. Results Absolute BMI gain was significantly greater in the eSCH group than in the EUT group (1.11 ± 0.17 vs. 0.33 ± 0.13 kg/m2; p=0.003). A significant increase in LDL cholesterol was observed in the eSCH group (16.1 ± 3.8 mg/dl; p

Glucose entropy was inversely correlated with insulin resistance in a series of non-diabetic individuals with low glucose variability. In long-standing type 1 diabetes, the inverse correlation between glucose entropy and insulin resistance is preserved, as lower glucose entropy is associated with higher BMI.

SummaryObjective The use of thyroid lobectomy in the treatment of unilateral, benign nodules is limited by the potential of nodular recurrence in the remaining lobe. This study aimed to assess the rate and clinical impact of nodular recurrence in the contralateral lobe after thyroid lobectomy and to identify predictive factors of recurrence. Design Single-centre retrospective study. Patients Records of patients that underwent lobectomy for unilateral thyroid nodules between 1991 and 2010 were reviewed and 270 patients were included. Exclusion criteria were: presence of contralateral nodule(s) ≥5 mm on preoperative ultrasound, diagnosis of cancer necessitating completion thyroidectomy or pseudonodules. Recurrence was defined as the occurrence of nodule(s) ≥5 mm in the remaining lobe on at least one postoperative ultrasound. A set of clinical, imaging, histological and biochemical parameters was tested as predictors of recurrence using logistic regression. Results After a median follow-up of 78 months (range, 12–277 months), the global recurrence rate was 42% and recurrence of nodules of a size ≥1 cm occurred in 19%. Reoperation rate was 1·1%. 90% of patients were treated postoperatively by levothyroxine. Median time to nodular recurrence was 4 years. Preoperative contralateral lobe volume and resected thyroid weight were identified as significant predictors of recurrence (P = 0·045 and P = 0·03 respectively). Conclusions Thyroid lobectomy is an effective therapeutic strategy for unilateral, benign nodules, resulting in a low rate of clinically relevant nodular relapse in a mildly iodine-deficient area. Patients with uninodular disease and a contralateral lobe of normal size are particularly good candidates for lobectomy.

Aberrant expression of serotonin receptors in an aldosterone- and cortisol-producing adenoma Introduction Aberrant expression of serotonin receptors has been described to be involved in the pathophysiology of both aldosterone-producing and cortisol-producing adrenal adenomas. Case report A 46-year-old woman was referred for evaluation of severe hypertension associated with hypokalaemia. Primary aldosteronism with concurrent subclinical Cushing’s syndrome was diagnosed. A CT-scan identified a lesion of 4 cm in the right adrenal gland and a second lesion of 1 cm in the left adrenal gland, both displaying benign imaging phenotype. Following dexamethasone suppression, we explored the potential aberrant expression of serotonin receptors in the adrenal cortex by intravenous administration of metoclopramide, a serotonin type 4 receptor (5-HT4-R) agonist. This led to abnormal cortisol increase and physiological response of aldosterone in peripheral blood. Adrenal venous sampling was then performed in basal conditions and after metoclopramide stimulation. An increase in cortisol level was observed in the left adrenal vein after stimulation. 131I-19-Iodocholesterol scintigraphy showed intense radiotracer uptake in the right adrenal mass and weak uptake in the contralateral mass. Right laparoscopic adrenalectomy was performed. Histological examination revealed an adrenocortical adenoma. In vitro, cultured adrenocortical cells derived from the tumoural tissue exhibited aldosterone and cortisol co-secretion. Administration of 5-HT or metoclopramide to the cells induced a dose-dependent increase in cortisol production. These effects were inhibited by concomitant administration of the 5-HT4-R antagonist GR113808. Incubation of tumour tissue fragments with 5-HT induced a significant increase in aldosterone production which was abrogated in the presence of GR113808. These data were suggestive of aberrant expression of 5HT4-R in the tumoural tissue. Conclusion We report a rare case of an aldosterone- and cortisol-co-producing adenoma in a patient with severe hypertension and bilateral adrenal masses exhibiting an abnormal plasma cortisol response to metoclopramide. In vitro studies revealed enhanced sensitivity of the tumour tissue to 5-HT indicative of illicit expression of 5-HT4 receptors.

We present the case of an 82-year-old man admitted to our hospital for muscle weakness. He was under simvastatin 20 mg per day and was given pulse itraconazole therapy 8 days before the onset of symptoms for onychomycosis. He developed severe rhabdomyolysis inducing an acute renal failure necessitating renal replacement therapy. He eventually fully recovered. Given the possible concurrent use of simvastatin and itraconazole, awareness of this potential interaction is clinically important.

Introduction Les regimes alimentaires riches en gras satures contribuent a la defaillance de la cellule β dans le diabete de type 2 (DT2). Le palmitate induit le stress du reticulum endoplasmique (RE) et le dysfonctionnement/apoptose des cellules β. Afin d'identifier les mediateurs moleculaires de la lipotoxicite, nous avons effectue un sequencage-ARN d'ilots humains et une analyse proteomique de cellules INS-1E apres un traitement au palmitate. Materiels et Methodes Six preparations d'ilots humains ont ete exposees au palmitate (0,5mM) durant 48h et l'ARN a ete sequence. Les cellules INS-1E ont ete exposees au palmitate durant 4, 16 ou 24h et le proteome a ete profile par iTRAQ ( n =2). Les analyses des reseaux de regulations ont fait usage des bases de donnees IPA, DAVID et TRANSFAC. L'expression des genes a ete reduite par siRNA dans les cellules β clonales et primaires. La mort cellulaire a ete examinee par coloration nucleaire. Resultats Des analyses comparatives du transcriptome et du proteome des cellules β traitees au palmitate ont identifie 93 genes/proteines regules positivement et 133 regules negativement communs aux 2 analyses. La classification en categories fonctionnelles montre une modification des genes/proteines regulant le metabolisme d'acides gras, le stress du RE, l'apoptose et de plusieurs transporteurs d'acides amines. Nos etudes fonctionnelles ont confirme l'augmentation d'expression des transporteurs d'acides amines Lat1 et Cat1 (>25 %, n =4-5). La diminution de leur expression par siRNA, par contre, ne modifie pas le stress du RE lipotoxique. Un reseau de regulations infere devoile Arnt, FoxO1, APP, JunD et Bach1 comme des regulateurs cles de la lipotoxicite. Les roles de FoxO1, Arnt et App dans la secretion d'insuline, le stress du RE et l'apoptose ont deja ete demontres, accreditant l'hypothese d'un possible role biologique dans le contexte de la lipotoxicite. Conclusions Cette etude est la premiere du genre a fournir un profilage transcriptomique et proteomique de cellules β exposees au palmitate. Nos donnees devoilent de nouveaux mediateurs de lipotoxicite et des reseaux de regulation complexes potentiellement impliques dans la defaillance de la cellule β dans le DT2.

Objectif La scintigraphie n’est plus recommandee dans le bilan d’un nodule thyroidien sauf si le taux de TSH est abaisse. Les nodules chauds sont classiquement consideres comme quasi certainement benins. Par contre, certaines etudes retrospectives recentes rapportent un risque de cancer thyroidien de l’ordre de 3 % au sein d’un nodule chaud [1] . Il s’agit souvent de nodules chauds au sein de thyroides multi-nodulaires rendant parfois difficile la localisation exacte du nodule chaud a l’examen histologique. Le but de l’etude sera d’evaluer la prevalence des cancers thyroidiens parmi les nodules chauds solitaires. Patients et methodes Etude retrospective des donnees histologiques et/ou cytologiques de thyroides de patients presentant un nodule chaud unique avec absence a l’echographie de nodules homolateraux > 1 cm de diametre. Resultats Soixante-huit patients ont ete inclus. Des donnees histologiques etaient disponibles chez 63 patients et cytologiques chez 25 patients. Parmi ces patients, 6 cas de cancers papillaires ont ete demontres a l’histologie : 3 micro-carcinomes papillaires et 1 carcinome papillaire controlateral de 20 mm clairement decouverts de maniere fortuite, 1 micro-carcinome papillaire decrit comme juxta-capsulaire et 1 carcinome papillaire au sein du nodule chez une patiente prealablement traitee par Iode 131. Conclusion Dans notre serie un nodule chaud etait indiscutablement malin, 4 a 5 etaient de decouverte fortuite. La frequence importante des cancers decouverts fortuitement confirme l’importance de localiser avec certitude le nodule chaud a l’examen histologique meme si cela doit diminuer le nombre de patients etudiables.

The deleterious effects of chronically elevated free fatty acid (FFA) levels on glucose homeostasis are referred to as lipotoxicity, and the concurrent exposure to high glucose may cause synergistic glucolipotoxicity. Lipo- and glucolipotoxicity have been studied for over 25 years. Here, we review the current evidence supporting the role of pancreatic β-cell lipo- and glucolipotoxicity in type 2 diabetes (T2D), including lipid-based interventions in humans, prospective epidemiological studies, and human genetic findings. In addition to total FFA quantity, the quality of FFAs (saturation and chain length) is a key determinant of lipotoxicity. We discuss in vitro and in vivo experimental models to investigate lipo- and glucolipotoxicity in β-cells and describe experimental pitfalls. Lipo- and glucolipotoxicity adversely affect many steps of the insulin production and secretion process. The molecular mechanisms underpinning lipo- and glucolipotoxic β-cell dysfunction and death comprise endoplasmic reticulum stress, oxidative stress and mitochondrial dysfunction, impaired autophagy, and inflammation. Crosstalk between these stress pathways exists at multiple levels and may aggravate β-cell lipo- and glucolipotoxicity. Lipo- and glucolipotoxicity are therapeutic targets as several drugs impact the underlying stress responses in β-cells, potentially contributing to their glucose-lowering effects in T2D., SCOPUS: re.j, info:eu-repo/semantics/published

Neonatal diabetes is caused by single gene mutations reducing pancreatic β cell number or impairing β cell function. Understanding the genetic basis of rare diabetes subtypes highlights fundamental biological processes in β cells. We identified 6 patients from 5 families with homozygous mutations in the YIPF5 gene, which is involved in trafficking between the endoplasmic reticulum (ER) and the Golgi. All patients had neonatal/early-onset diabetes, severe microcephaly, and epilepsy. YIPF5 is expressed during human brain development, in adult brain and pancreatic islets. We used 3 human β cell models (YIPF5 silencing in EndoC-βH1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects β cells. Loss of YIPF5 function in stem cell-derived islet cells resulted in proinsulin retention in the ER, marked ER stress, and β cell failure. Partial YIPF5 silencing in EndoC-βH1 cells and a patient mutation in stem cells increased the β cell sensitivity to ER stress-induced apoptosis. We report recessive YIPF5 mutations as the genetic cause of a congenital syndrome of microcephaly, epilepsy, and neonatal/early-onset diabetes, highlighting a critical role of YIPF5 in β cells and neurons. We believe this is the first report of mutations disrupting the ER-to-Golgi trafficking, resulting in diabetes., info:eu-repo/semantics/published