Screening for monogenic subtypes of gestational diabetes in a high prevalence island population - A whole exome sequencing study.

AIMS: The reported frequency of monogenic defects of beta cell function in gestational diabetes (GDM) varies extensively. This study aimed to evaluate the frequency and molecular spectrum of variants in genes associated with monogenic/atypical diabetes in non-obese females of Maltese ethnicity with GDM. METHODS: 50 non-obese females who met the International Association of the Diabetes and Pregnancy Study Groups (IADPSG) criteria for diagnosis of GDM and with a first-degree relative with non-autoimmune diabetes were included in this study. Whole exome capture and high throughput sequencing was carried out. Rare sequence variants were filtered, annotated, and prioritised according to the American College for Medical Genetics guidelines. For selected missense variants we explored effects on protein stability and structure through in-silico tools. RESULTS: We identified three pathogenic variants in GCK, ABCC8 and HNF1A and several variants of uncertain significance in the cohort. Genotype-phenotype correlations and post-pregnancy follow-up data are described. CONCLUSIONS: This study provides the first insight into an underlying monogenic aetiology in non-obese females with GDM from an island population having a high prevalence of diabetes. It suggests that monogenic variants constitute an underestimated cause of diabetes detected in pregnancy, and that careful evaluation of GDM probands to identify monogenic disease subtypes is indicated.

Case Report: Identification of an HNF1B p.Arg527Gln mutation in a Maltese patient with atypical early onset diabetes and diabetic nephropathy.

BACKGROUND: The diagnosis of atypical non-autoimmune forms of diabetes mellitus, such as maturity onset diabetes of the young (MODY) presents several challenges, in view of the extensive clinical and genetic heterogeneity of the disease. In this report we describe a case of atypical non autoimmune diabetes associated with a damaging HNF1ß mutation. This is distinguished by a number of uncharacteristic clinical features, including early-onset obesity, the absence of renal cysts and diabetic nephropathy. HNF1ß-MODY (MODY5) is an uncommon form of monogenic diabetes that is often complicated by a wide array of congenital morphological anomalies of the urinary tract, including renal cysts. This report expands on the clinical phenotypes that have been described in the context of HNF1ß mutations, and is relevant as only isolated cases of diabetic nephropathy in the setting of MODY5 have been reported. CASE PRESENTATION: An obese Maltese female with non-autoimmune diabetes, microalbuminuria, glomerular hyperfiltration, fatty liver and no renal cysts was studied by whole exome sequencing to investigate potential genes responsible for the proband's phenotype. A rare missense mutation at a highly conserved site in exon 8 of HNF1ß was identified (c.1580G > A, NM_000458.3, p.Arg527Gln), with multiple in-silico predictions consistent with pathogenicity. This mutation has not been previously characterised. Additionally, several common susceptibility variants associated with early-onset obesity, polygenic type 2 diabetes and nephropathy were identified in the proband that could impose additional effects on the phenotype, its severity or its clinical course. CONCLUSION: This report highlights several atypical features in a proband with atypical diabetes associated with an HNF1ß missense mutation. It also reinforces the concept that monogenic causes of diabetes could be significant contributors to disease burden in obese individuals with atypical diabetes.

Expression of cell cycle regulators and biomarkers of proliferation and regrowth in human pituitary adenomas.

PURPOSE: The pathogenesis of pituitary adenomas (PA) is complex. Ki-67, pituitary tumour transforming gene (PTTG), vascular endothelial growth factor (VEGF), cyclin D1, c-MYC and pituitary adenylate cyclase-activating peptide (PACAP) protein expression were analysed and correlated with tumour and patient characteristics. METHODS: 74 pituitary tumour samples (48 non-functional PA, 26 functional PAs); Immunohistochemical analysis of protein expression, retrospective analysis of MR images and in vitro analysis of octreotide treatment was carried out on GH3 cells. RESULTS: PTTG expression was negatively associated with age and positively with PA size, regrowth and Ki-67 index. Cyclin D1 correlated with Ki-67 and tumour size. c-MYC negatively correlated with size of tumour and age; and correlated with PTTG expression. Somatostatin analogue treatment was associated with lower Ki-67, PTTG and Cyclin D1 expression while T2 hypointense PAs were associated with lower PTTG, cyclin D1, c-MYC and Ki-67. In vitro analyses confirmed the effect of somatostatin analogue treatment on Pttg and Cyclin D1 expression. CONCLUSIONS: Interesting and novel observations on the differences in expression of tumour markers studied are reported. Correlation between Ki-67 expression, PTTG nuclear expression and recurrence/regrowth of PAs, emphasizes the role that Ki-67 and PTTG expression have as markers of increased proliferation. c-MYC and PTTG nuclear expression levels were correlated providing evidence that PTTG induces c-MYC expression in PAs and we propose that c-MYC might principally have a role in early pituitary tumorigenesis. Evidence is shown that the anti-proliferative effect of somatostatin analogue treatment in vivo occurs through regulation of the cell cycle.

Epidemiology and radiological geometric assessment of pituitary macroadenomas: population-based study.

CONTEXT: Pituitary adenomas are relatively common tumours with diverse clinical features. Epidemiological data are important to help quantify health burden. OBJECTIVE: To provide in-depth epidemiological data on macroadenomas and radiologically characterize macroadenomas. DESIGN: Population-based retrospective analysis, Prevalence as at 2014; Incidence based on data from 2000 to 2014, Retrospective analysis of baseline MRI. SETTING: The Maltese islands. PATIENTS: 173/136 patients with macroadenomas for prevalence/incidence estimates respectively, 122 baseline MRI for radiological characterization. MAIN OUTCOME MEASURES: Prevalence rates, Standardized Incidence rates (SIR), MRI findings. RESULTS: The prevalence for macroadenomas was 40·67/100 000 people and the SIR was 1·90/100 000/year. Giant pituitary adenomas (>40 mm) constituted 4·8% of the whole cohort of PAs and the SIR was 0·18/100 000/year. Giant prolactinomas constituted 4·7% of all the prolactinomas and the SIR was 0·07/100 000/year, while giant NFPA constituted 6·0% of all NFPA and the SIR was 0·12/100 000/year. There was a statistically significant difference in the degree of suprasellar extension (P < 0·001) and infrasellar extension (P = 0·028) between the different macroadenoma subtypes and in the vertical extension indices (median vertical extension index NFPA 3·0 mm; PRLoma -7·7 mm; GH-secreting PA -1·7 mm; P < 0·001). Pituitary macroadenomas with cavernous sinus invasion were statistically significantly larger than those without cavernous sinus invasion (P < 0·001). NFPA had predominantly a superior extension into the cavernous sinus (63·6%) compared to the functional PAs which had predominantly an inferior extension into the cavernous sinus (59·1%) (P = 0·032). CONCLUSIONS: The various macroadenoma subtypes' epidemiological data are presented and differences between growth patterns among the various subtypes are highlighted.

Biological and biochemical characteristics of a Mediterranean population with Gestational Diabetes Mellitus.

The interplay of various nutrients provided to the developing foetus determines the growth potential of the conceptus. This study assessed the inter-relationship between these nutrients in a Mediterranean population including 1062 pregnant, previously non-diabetic women. These underwent an oral glucose tolerance test (oGTT) and were accordingly classified into gestational hyperglycaemic and normoglycaemic groups. Fasting insulin, HbA1c, and lipid profiles were further assessed, and the anthropomorphic characteristics of the mother and child at birth were measured. Lipid profiles were compared between the two groups and related to the biological characteristics of the mother and child at birth. Gestational hyperglycaemia was significantly associated with elevated triglycerides (P<0.0001) and decreased low density lipoprotein cholesterol (LDL-C) (P=0.02). There were no significant changes in total cholesterol and high density lipoprotein cholesterol (HDL-C) levels. Maternal BMI correlated positively with the various glycaemic indices (P<0.0001) and triglycerides (P<0.0001), but inversely with cholesterol (P<0.0001), HDL-C (P<0.0001) and LDL-C (P<0.0001). The infant birth weight correlated positively with maternal body weight (P<0.0001), LDL-C (P<0.0001) and the glycaemic indices (P<0.0001), but negatively with cholesterol (P<0.0001), triglycerides (P<0.0001), HDL-C (P<0.0001) and FBG (P<0.0001). This study confirms that the maternal body mass index (BMI), insulin resistance, and LDL-C levels positively contribute towards foetal growth, whereas a negative correlation was noted with cholesterol, triglycerides, and HDL-C.

Association between a polygenic lipodystrophy genetic risk score and diabetes risk in the high prevalence Maltese population.

BACKGROUND: Type 2 diabetes (T2DM) is genetically heterogenous, driven by beta cell dysfunction and insulin resistance. Insulin resistance drives the development of cardiometabolic complications and is typically associated with obesity. A group of common variants at eleven loci are associated with insulin resistance and risk of both type 2 diabetes and coronary artery disease. These variants describe a polygenic correlate of lipodystrophy, with a high metabolic disease risk despite a low BMI. OBJECTIVES: In this cross-sectional study, we sought to investigate the association of a polygenic risk score composed of eleven lipodystrophy variants with anthropometric, glycaemic and metabolic traits in an island population characterised by a high prevalence of both obesity and type 2 diabetes. METHODS: 814 unrelated adults (n = 477 controls and n = 337 T2DM cases) of Maltese-Caucasian ethnicity were genotyped and associations with phenotypes explored. RESULTS: A higher polygenic lipodystrophy risk score was correlated with lower adiposity indices (lower waist circumference and body mass index measurements) and higher HOMA-IR, atherogenic dyslipidaemia and visceral fat dysfunction as assessed by the visceral adiposity index in the DM group. In crude and covariate-adjusted models, individuals in the top quartile of polygenic risk had a higher T2DM risk relative to individuals in the first quartile of the risk score distribution. CONCLUSION: This study consolidates the association between polygenic lipodystrophy risk alleles, metabolic syndrome parameters and T2DM risk particularly in normal-weight individuals. Our findings demonstrate that polygenic lipodystrophy risk alleles drive insulin resistance and diabetes risk independent of an increased BMI.

High Population Frequency of GNRHR p.Q106R in Malta: An Evaluation of Fertility and Hormone Profiles in Heterozygotes.

Context: The gonadotropin-releasing hormone receptor variant GNRHR p.Q106R (rs104893836) in homozygosity, compound heterozygosity, or single heterozygosity is often reported as the causative variant in idiopathic hypogonadotropic hypogonadism (IHH) patients with GnRH deficiency. Genotyping of a Maltese newborn cord-blood collection yielded a minor allele frequency (MAF) 10 times higher (MAF = 0.029; n = 493) than that of the global population (MAF = 0.003). Objective: To determine whether GNRHR p.Q106R in heterozygosity influences profiles of endogenous hormones belonging to the hypothalamic-pituitary axis and the onset of puberty and fertility in adult men (n = 739) and women (n = 239). Design Setting and Participants: Analysis of questionnaire data relating to puberty and fertility, genotyping of the GNRHR p.Q106R variant, and hormone profiling of a highly phenotyped Maltese adult cohort from the Maltese Acute Myocardial Infarction Study. Main Outcome and Results: Out of 978 adults, 43 GNRHR p.Q106R heterozygotes (26 men and 17 women) were identified. Hormone levels and fertility for all heterozygotes are within normal parameters except for TSH, which was lower in men 50 years or older. Conclusion: Hormone data and baseline fertility characteristics of GNRHR p.Q106R heterozygotes are comparable to those of homozygous wild-type individuals who have no reproductive problems. The heterozygous genotype alone does not impair the levels of investigated gonadotropins and sex steroid hormones or affect fertility. GNRHR p.Q106R heterozygotes who exhibit IHH characteristics must have at least another variant, probably in a different IHH gene, that drives pathogenicity. We also conclude that GNRHR p.Q106R is likely a founder variant due to its overrepresentation and prevalence in the island population of Malta.

Prevalence and incidence of pituitary adenomas: a population based study in Malta.

Epidemiological data is important to correctly quantify the extent of disease and needed health care resources. The aim of the study was to establish the prevalence and incidence of pituitary adenomas (PAs) in the same well defined population, with in-depth analysis of the various subtypes. The design involved a retrospective cross-sectional analysis of PA patients diagnosed prior to 31 July 2011 for prevalence estimates and those diagnosed between July 2000 and July 2011 for incidence estimation. A thorough search for patients with PAs was carried out in central hospital registries including outpatients departments, surgical registries, radiological department and specialty clinic databases. Prevalence rates/100,000 and Standardised incidence ratios (SIR)/100,000/year were worked out. The respective prevalence rates and SIR for PAs overall were 75.7/100,000, and 4.27/100,000/year, for Prolactinomas 35.0/100,000 and 2.05/100,000/year, for nonfunctioning PA 25.9/100,000 and 1.79/100,000/year and for GH-secreting PAs 12.5/100,000 and 0.31/100,000/year. The overall prevalence for macroadenomas was 32.8/100,000 and SIR was 1.49/100,000/year. The prevalence rate in males for PAs overall was 46.3/100,000 and SIR was 2.08/100,000/year and in females 104.8/100,000 and SIR was 6.58/100,000/year. Females had a lower proportion of macroadenomas than males (29.5 vs. 75.0%; P < 0.001) and macroadenomas tended to present at a later age compared to microadenomas (48 vs. 34.5; P < 0.001). The highest SIR was reached in the 30-39 age group at 7.42/100,000/year. Our data confirm the considerable disease burden that PAs bear on health care resources. Males and females have similar prevalence and SIR rates for macroadenomas but there is a significant increase in SIR in females of child bearing age compared to males. These observations may have important implications in terms of the economic burden and need for early intervention.

An unusual site for calciphylaxis: a case report.

BACKGROUND: Calciphylaxis is a rare condition characterized by calcification of the tunica media of small arteries with or without endovascular fibrosis, extravascular calcification and vascular thrombosis, leading to tissue ischemia and hence necrosis of tissues supplied by respective vessel. CASE REPORT: An 83-year-old lady presented with a 2-week history of rapidly progressing painful necrotic vulval lesion. This patient was being treated medically with bisphosphonates for mild hypercalcaemia secondary to a parathyroid adenoma. The diagnosis of calciphylaxis was made by biopsy of lesion, revealing extensive necrotic areas and multiple abscesses with numerous thrombosed and calcified blood vessels. CONCLUSIONS: This case shows an unusual presentation of calciphylaxis, in a patient with primary hyperparathyroidism, in the absence of end stage renal failure. The pathogenesis of the condition is still relatively unknown. Particularly of note in this case is the presentation of the lesion 9 months after the start of treatment with bisphosphonate after the relative decrease of serum parathyroid levels and serum calcium levels. This leads to the question of initiation of the pathology - did the bisphosphonate treatment have an input in initiation of the lesion? The case under review adds a new differential diagnosis to necrotic vulval lesions, other than malignancy.

Epidemiology and blood parameter changes in Cushing's syndrome - a population-based study.

PURPOSE: To provide complete epidemiological data on Cushing's syndrome (CS) with analysis and differentiation of biochemical parameters, including blood count indices and serum inflammation-based scores. METHODS: Clinical records of 35 patients diagnosed with CS between 2008 and 2020 at Malta's only central National Health Service hospital were retrospectively analyzed. Detailed clinical and biochemical data were obtained for each patient. Correlation and receiver operator characteristics (ROC) curve analyses were used to establish a threshold value for different variables to predict malignant CS. RESULTS: Standardized incidence rate (SIR) (/million/year) of CS was 4.5, and SIR of Cushing's disease (CD) was 2.3, 0.5 for ectopic CS, 1.5 for cortisol secreting adrenal adenoma, and 0.3 cases for cortisol-producing ACC. Malignant cause of CS had statistically significantly higher cortisol levels and size of tumor and lower potassium at diagnosis (P < 0.001). Additionally, malignant causes had a higher neutrophil-to-lymphocyte ratio (NLR) (P = 0.001) and systemic immune inflammation index (P = 0.005) and a lower lymphocyte-to-monocyte ratio (P < 0.001). Using ROC curve analysis to predict malignant cause of CS, a potassium level of < 3.05 was 75% sensitive and 100% specific (ROC-AUC 0.907, P = 0.001), a post-ODST cortisol level of > 841 nmol/L was 100% sensitive and 91% specific (ROC-AUC 0.981, P < 0.001), while a NLR ratio > 3.9 was 100% sensitive and 57.7% specific (ROC-AUC 0.885, P = 0.001). CONCLUSION: Biochemical and blood count indices and serum inflammatory-based scores differ remarkably between benign and malignant causes of endogenous CS. Such indices can help predict the severity of disease and prognosis.

Whole Genome Sequencing Unravels New Genetic Determinants of Early-Onset Familial Osteoporosis and Low BMD in Malta.

BACKGROUND: Osteoporosis is a skeletal disease with a strong genetic background. The study aimed to identify the genetic determinants of early-onset familial osteoporosis and low bone mineral density (BMD) in a two-generation Maltese family. METHODS: Fifteen relatives aged between 28-74 years were recruited. Whole genome sequencing was conducted on 12 relatives and shortlisted variants were genotyped in the Malta Osteoporotic Fracture Study (MOFS) for replication. RESULTS: Sequential variant filtering following a dominant inheritance pattern identified rare missense variants within SELP, TGF-ß2 and ADAMTS20, all of which were predicted to be likely pathogenic and participate in osteoimmunology. TGF-ß2 c.1136C>T was identified in five individuals from the MOFS in heterozygosity, four of whom had osteopenia/osteoporosis at the lumbar spine and hip, and/or had sustained a low-trauma fracture. Heterozygosity for the ADAMTS20 c.4090A>T was accompanied by lower total hip BMD (p = 0.018) and lower total serum calcium levels in MOFS (p < 0.01), recapitulating the findings from the family. Women carrying at least one copy of the alternative allele (TC/CC) for SELP c.2177T>C exhibited a tendency for lower lumbar spine BMD and/or wrist fracture history relative to women with TT genotype. CONCLUSIONS: Our findings suggest that the identified variants, alone or in combination, could be causal factors of familial osteoporosis and low BMD, requiring replication in larger collections.

Frequency and spectrum of glucokinase mutations in an adult Maltese population.

AIM: To investigate the frequency and spectrum of glucokinase (GCK) mutations in a cohort of adults from an island population having a high prevalence of diabetes mellitus (DM). METHODS: A single-centre cohort study was conducted, including 145 non-obese adults of Maltese-Caucasian ethnicity with impaired fasting glycaemia (IFG) or non-autoimmune diabetes diagnosed before the age of 40 years. Bidirectional sequencing of the GCK coding regions was performed. Genotype-phenotype associations and familial segregation were explored and the effects of missense variants on protein structure were evaluated using computational analysis. RESULTS: Three probands with pathogenic/likely pathogenic GCK variants in the heterozygous state having clinical features consistent with GCK-diabetes were detected. The missense variants have structurally destabilising effects on protein structure. GCK variant carriers exhibited a significantly lower body mass index and serum triglyceride levels when compared to GCK variant non-carriers. CONCLUSIONS: The frequency of GCK-diabetes is approximately 2% in non-obese Maltese adults with diabetes or prediabetes. This study broadens the mutational spectrum of GCK and highlights clinical features that could be useful in discriminating GCK-DM from type 2 DM or prediabetes. It reinforces the need for increased molecular testing in young adults with diabetes having a suspected monogenic aetiology.

Predictors of vibration perception threshold in type 2 diabetic patients with proliferative retinopathy.

PURPOSE OF THE STUDY: Distal peripheral neuropathy (DPN) is a troublesome complication of diabetes mellitus (DM). The factors associated with the disease are still incompletely understood. The purpose of this study was to investigate factors associated with vibration perception threshold (VPT) as a marker of DPN in a type 2 diabetic population with advanced microvascular disease. METHODS: The study included 203 diabetic patients (117 male, 86 female) with proliferative diabetic retinopathy. Subjects were investigated by questionnaires, clinical examinations, blood and urine sampling, and review of medical records in the period from November 2008 through April 2009. Presence of DPN was defined as VPT ≥25 V. RESULTS: The mean (±SD) age was 65.2 (±9.9) years and median (IQR) diabetes duration was 18 (10-25) years. Forty-six per cent of subjects were found to have DPN, defined as a VPT ≥25 V by neurothesiometer testing. Prevalence of DPN was found to be associated with age (p=0.038), male gender (p=0.046), low haemoglobin (p<0.001), high erythrocyte sedimentation rate (p=0.03), uric acid values (p=0.034), and peripheral vascular disease (PVD) (p=0.003) in univariate analysis. Multivariate logistic regression analysis revealed male gender (OR 5.52; p<0.001) and low haemoglobin values (B=-0.58; p<0.001) to be independent predictors of VPT ≥25 V in subjects with proliferative retinopathy, while linear regression analysis revealed male gender (p<0.001), haemoglobin (p=0.001), age (p=0.04), and PVD (p=0.001) to be significant predictors of VPT. CONCLUSIONS: This study reports a novel independent association of DPN with low haemoglobin values. In the study population with type 2 DM and proliferative retinopathy, DPN was also independently associated with male gender, age, and PVD. Further studies are needed to confirm the association with low haemoglobin and identify the underlying mechanism.

Association Between Neutrophil-Lymphocyte Ratio and Gestational Diabetes-A Systematic Review and Meta-Analysis.

A growing body of evidence shows that the neutrophil-lymphocyte ratio (NLR) is a surrogate index of systemic inflammation in several chronic diseases. Conflicting associations between NLR and gestational diabetes mellitus (GDM) have been reported in individual studies. This meta-analysis sought to investigate the association between NLR and GDM. The PubMed, EMBASE, and Google Scholar databases were searched to identify relevant articles. The pooled standardized mean difference with 95% CI was calculated using a random-effects model. Subgroup and meta-regression analysis were carried out to control for the effects of GDM diagnostic criteria, ethnicity, body mass index (BMI), and age. Eleven eligible articles were included, containing 1271 participants with GDM and 1504 controls. Pooled outcomes indicated a higher NLR in GDM pregnancies than in normoglycemic controls (SMD = 0.584; 95% CI, 0.339-0.830; P < .001), although extensive heterogeneity between studies was noted. Subgroup analysis revealed that the higher pooled estimate in GDM was not affected by diagnostic criteria, ethnicity, or BMI, although matching for BMI reduced heterogeneity between studies. This meta-analysis supports the higher NLR in GDM described by some individual studies.

Gestational diabetes, environmental temperature and climate factors - From epidemiological evidence to physiological mechanisms.

Gestational diabetes (GDM) is a common metabolic complication of pregnancy that is generally asymptomatic in its clinical course, although it is potentially associated with a wide range of both maternal and foetal complications. The population prevalence of GDM varies widely, depending on the clinical diagnostic criteria, ethnicity, demographics and background prevalence of type 2 diabetes. Climate variability and environmental temperature have recently come to the forefront as potential direct or indirect determinants of human health. The association between GDM and environmental temperature is complex, and studies have often reported conflicting findings. Epidemiologic studies have shown a direct relation between rising environmental temperature and the risk of both GDM and impaired beta cell function. Seasonal trends in the prevalence of GDM have been reported in several populations, with a higher prevalence in summer months. Multiple mechanisms have been proposed to explain the GDM-temperature correlation. A growing body of evidence supports a link between temperature, energy expenditure and adipose tissue metabolism. Brown adipose tissue thermogenesis, induced by cold temperatures, improves insulin sensitivity. Further biological explanations for the GDM-temperature correlation lie in potential association with low vitamin D levels, which varies according to sunshine exposure. Observational studies are also complicated by lifestyle factors, such as diet and physical activity, that could exhibit seasonal variation. In this review article, we provide a systematic overview of available epidemiological evidence linking environmental temperature and gestational diabetes. Furthermore, the physiological mechanisms that give biological plausibility to association between GDM and temperature are explored. As future climate patterns could drive global changes in GDM prevalence, this knowledge has important implications for both clinicians and researchers.

Bisphenol A and Type 2 Diabetes Mellitus: A Review of Epidemiologic, Functional, and Early Life Factors.

Type 2 diabetes mellitus (T2DM) is characterised by insulin resistance and eventual pancreatic ß-cell dysfunction, resulting in persistent high blood glucose levels. Endocrine disrupting chemicals (EDCs) such as bisphenol A (BPA) are currently under scrutiny as they are implicated in the development of metabolic diseases, including T2DM. BPA is a pervasive EDC, being the main constituent of polycarbonate plastics. It can enter the human body by ingestion, through the skin, and cross from mother to offspring via the placenta or breast milk. BPA is a xenoestrogen that alters various aspects of beta cell metabolism via the modulation of oestrogen receptor signalling. In vivo and in vitro models reveal that varying concentrations of BPA disrupt glucose homeostasis and pancreatic ß-cell function by altering gene expression and mitochondrial morphology. BPA also plays a role in the development of insulin resistance and has been linked to long-term adverse metabolic effects following foetal and perinatal exposure. Several epidemiological studies reveal a significant association between BPA and the development of insulin resistance and impaired glucose homeostasis, although conflicting findings driven by multiple confounding factors have been reported. In this review, the main findings of epidemiological and functional studies are summarised and compared, and their respective strengths and limitations are discussed. Further research is essential for understanding the exact mechanism of BPA action in various tissues and the extent of its effects on humans at environmentally relevant doses.

Monogenic diabetes characteristics in a transnational multicenter study from Mediterranean countries.

BACKGROUND: Diagnosis of monogenic diabetes has important clinical implications for treatment and health expenditure. However, its prevalence remains to be specified in many countries, particularly from South Europe, North Africa and Middle-East, where non-autoimmune diabetes in young adults is increasing dramatically. AIMS: To identify cases of monogenic diabetes in young adults from Mediterranean countries and assess the specificities between countries. METHODS: We conducted a transnational multicenter study based on exome sequencing in 204 unrelated patients with diabetes (age-at-diagnosis: 26.1 ± 9.1 years). Rare coding variants in 35 targeted genes were evaluated for pathogenicity. Data were analyzed using one-way ANOVA, chi-squared test and factor analysis of mixed data. RESULTS: Forty pathogenic or likely pathogenic variants, 14 of which novel, were identified in 36 patients yielding a genetic diagnosis rate of 17.6%. The majority of cases were due to GCK, HNF1A, ABCC8 and HNF4A variants. We observed highly variable diagnosis rates according to countries, with association to genetic ancestry. Lower body mass index and HbA1c at study inclusion, and less frequent insulin treatment were hallmarks of pathogenic variant carriers. Treatment changes following genetic diagnosis have been made in several patients. CONCLUSIONS: Our data from patients in several Mediterranean countries highlight a broad clinical and genetic spectrum of diabetes, showing the relevance of wide genetic testing for personalized care of early-onset diabetes.

Pre-eclampsia complicated by severe hyponatraemia.

A 41-year-old woman was diagnosed with pre-eclampsia at 35 weeks gestation. She was treated with antihypertensives but, unfortunately, her condition became complicated by severe hyponatraemia. Her sodium levels rapidly dropped to 125 mmol/L. The cause for the hyponatraemia was the syndrome of inappropriate antidiuretic hormone secretion. She was initially managed with fluid restriction, but an emergency caesarean section was necessary in view of fetal distress. Her sodium levels returned to normal within 48 hours of delivery.Pre-eclampsia is rarely associated with hyponatraemia. A low maternal sodium level further increases the mother's risk for seizures during this state. Additionally, the fetal sodium rapidly equilibrates to the mother's and may result in fetal tachycardia, jaundice and polyhdraminios. All these factors may necessitate an emergency fetal delivery.

Screening for monogenic diabetes in primary care.

AIMS: Updates on the latest diagnostic methods and features of MODY (Maturity Onset Diabetes of the Young) and promotion of education and awareness on the subject are discussed. METHOD: Previous recommendations were identified using PubMed and using combinations of terms including "MODY" "monogenic diabetes" "mature onset diabetes" "MODY case review". The diabetesgenes.org website and the US Monogenic Diabetes Registry (University of Colorado) were directly referenced. The remaining referenced papers were taken from peer-reviewed journals. The initial literature search occurred in January 2017 and the final search occurred in September 2018. RESULTS: A diagnosis of MODY has implications for treatment, quality of life, management in pregnancy and research. The threshold for referral and testing varies among different ethnic groups, and depends on body mass index, family history of diabetes and associated syndromes. Novel causative genetic variations are still being discovered however testing is currently limited by low referral rates. Educational material is currently being promoted in the UK in an effort to raise awareness. CONCLUSIONS: The benefits and implications of life altering treatment such as termination of insulin administration are significant but little can be done without appropriate identification and referral.

Healthcare Professionals' Perceptions of Type 2 Diabetes Mellitus Care in the Mediterranean Region.

INTRODUCTION: This study aimed to assess the adherence to guidelines by practitioners working in the Mediterranean region and to identify the reasons for non-compliance. METHODS: A opportunistic self-administered questionnaire was circulated among members of the Mediterranean Group for the Study of Diabetes (MGSD) and regional diabetic associations. The study was limited to the Mediterranean region; 2841 medical practitioners participated in the study. Intervention involved a self-administered questionnaire enabling demographic and personal details to be correlated to relevant information related to practice and continuing health professional education (CHPE) attitudes, perceptions related to diabetes and healthcare systems in the community, and physicians' attitudes to healthcare practices and target goals relevant to type 2 diabetes mellitus (T2DM). The main outcome measure was adherence to evidence-based guidelines. RESULTS: While the majority of respondents (69.9%) reported being confident in managing these patients, and 79.2% reported being aware of the availability of local guidelines; only a fifth opted to manage patients by strictly targeting an HbA1c value below 6.5%, while 3.3% were happy to maintain an HbA1c value of up to 8.0%. These goals appeared to be tempered by fear of eliciting hypoglycaemia in the belief that patients and their families do not have the skills to manage the complication. Endocrinologists/internists preferred more rigid control. CONCLUSION: It is clear that the promulgation of evidence-based guidelines cannot assume automatic adoption in clinical practice since adoption is tempered by on-the-ground practice circumstances that make the practitioner reluctant to fully endorse and adopt the targets defined by the guidelines. The evidence-based guidelines need to be modified for local or regional circumstances. FUNDING: This study and the Rapid Service Fee were supported by a financial grant from the Mediterranean Group for the Study of Diabetes which is supported by an unrestricted educational grant from Servier.