Early-onset Diabetes Mellitus Research Articles

The NDDG criteria versus the IADPSG or the ADA criteria for diagnosing early-onset gestational diabetes mellitus or abnormal glucose tolerance.

To analyze the effects of substituting the National Diabetes Data Group (NDDG) criteria with the International Association of Diabetes and Pregnancy Study Groups (IADPSG) or American Diabetes Association (ADA) criteria for the diagnosis of early-onset gestational diabetes mellitus (Early-GDM) or first trimester abnormal glucose tolerance (1t-AGT). A retrospective cohort study was conducted of 3200 women: 400 with Early-GDM, 800 with GDM, and 2000 with Non-GDM, according to the NDDG criteria. Rates of women with missed and new Early-GDM according to the IADPSG or ADA criteria were calculated. Multivariate logistic regression analysis was used to compare perinatal outcomes between groups. Using the IADPSG criteria, 61.6% of women with Early-GDM according to the NDDG were undiagnosed (Missed-Early-GDM group), and 25.9% of women with GDM and 15.7% of women with Non-GDM were diagnosed with Early-GDM (New-Early-GDM groups). Perinatal outcomes were worse in Missed-Early-GDM than in Non-GDM and better in New-Early-GDM groups than in the Early-GDM group. According to the ADA recommendations, only 11.8% of women with Early-GDM according to the NDDG criteria were diagnosed. Replacing the NDDG recommendations for the diagnosis of Early-GDM with the IADPSG or ADA criteria would mean depriving a large number of women with AGT and higher risk of adverse perinatal outcomes from early treatment and treating others with lower risk.

Maternofetal outcomes in early-onset gestational diabetes: does weight gain matter?

Women with early-onset gestational diabetes mellitus (GDM) have overall lower gestational weight gain (GWG) compared to those with later-onset GDM, albeit with usually worse maternofetal outcomes. We intent to investigate the association between inadequate GWG and maternofetal outcomes in pregnant women with early-onset GDM. We performed a retrospective study of women with early-onset GDM based on the National Registry of GDM. Three study groups were defined according to the recommendations of the Institute of Medicine for GWG: excessive GWG (eGWG), adequate (aGWG) or insufficient (iGWG). A total of 8040 pregnant women were included: 27% (n = 2170) eGWG, 31% (n = 2492) aGWG and 42% (n = 3378) iGWG. Preeclampsia (4.3 vs 3 vs 1.6%, p < 0.001), polyhydramnios (3.1 vs 2.3 vs 1.8%, p = 0.008) and cesarean section(37.4 vs 34.1 vs 29.5%, p < 0.001) were significantly more frequent among women with eGWG. Additionally, there was a higher frequency of macrosomia (8.1 vs 3.6 vs 2.4%, p < 0.001), large-for-gestational-age (8.2 vs 3.7 vs 2.6%, p < 0.001) and birth trauma (2.6 vs 1.5 vs 1.1%, p < 0.001) in this group. On the other hand, fetal death (0.2 vs 0.2 vs 0.5%, p = 0.04), small-for-gestational-age (9 vs 10.3 vs 14.9, p < 0.001) and preterm delivery (5.6 vs 7.1 vs 7.5%, p = 0.03) were more frequent in iGWG group. Over two-thirds of pregnant women with early-onset GDM had inappropriate GWG, which was significantly associated with adverse maternofetal outcomes. Weight management must be a focus of special attention in women with early-onset GDM, beyond glycemic control, to achieve healthy pregnancy outcomes.

Low level of serum zinc may be associated with early onset diabetes mellitus

Official Journal of the Endocrine Society of Sri Lanka. The Sri Lanka Journal of Diabetes Endocrinology and Metabolism (SJDEM) publishes original research articles, reviews, and other special features related to diabetes, endocrinology and metabolism in humans and human tissue.

Early-Onset of Gestational Diabetes vs. Late-Onset: Can We Revamp Pregnancy Outcomes?

We assessed risk factors, antenatal and intrapartum complications associated with early-onset Gestational diabetes mellitus (GDM) in comparison with late-onset GDM. This retrospective study included 161 GDM women having singleton pregnancies, without previous medical disorder and delivered at a tertiary care Hospital in Ha'il City, KSA from Dec 2020 till Jun 2021. Women diagnosed at < 24 weeks of pregnancy were grouped as early-onset GDM (n=71) and those diagnosed at ≥ 24 weeks as late-onset GDM (n=90). Both groups were matched for background variables. Chi-square and binary logistic regression analysis were applied with P-value significance at 0.05. Past history of GDM, macrosomia and stillbirth were significant predictors for early-onset GDM (P value 0.000, 0.002 and 0.040 respectively). Regression analysis showed early-onset GDM significantly increases the risk for recurrent urinary tract infections (AOR 2.35), polyhydramnios (AOR 2.81), reduced fetal movements (AOR 2.13), intrauterine fetal demise (AOR 8.06), macrosomia (AOR 2.16), fetal birth trauma (2.58), low APGAR score at birth (AOR 8.06), and neonatal ICU admissions (AOR 2.65). Rate of preterm birth, hypertensive disorders, labor onset (natural vs. induced) and cesarean section and intrapartum maternal complications were same in both groups. Early-onset GDM significantly increases certain maternal (recurrent urinary tract infections, polyhydramnios and reduced fetal movements) and fetal complications (intrauterine fetal demise, macrosomia fetal birth trauma, low APGAR score at birth and neonatal ICU admissions). Most of these adverse pregnancy outcomes can be prevented through early registration and screening, close follow up, growth ultrasounds, and provision of efficient emergency and neonatal care services.

Early Intervention and Lifelong Treatment with GLP1 Receptor Agonist Liraglutide in a Wolfram Syndrome Rat Model with an Emphasis on Visual Neurodegeneration, Sensorineural Hearing Loss and Diabetic Phenotype.

Wolfram syndrome (WS), also known as a DIDMOAD (diabetes insipidus, early-onset diabetes mellitus, optic nerve atrophy and deafness) is a rare autosomal disorder caused by mutations in the Wolframin1 (WFS1) gene. Previous studies have revealed that glucagon-like peptide-1 receptor agonist (GLP1 RA) are effective in delaying and restoring blood glucose control in WS animal models and patients. The GLP1 RA liraglutide has also been shown to have neuroprotective properties in aged WS rats. WS is an early-onset, chronic condition. Therefore, early diagnosis and lifelong pharmacological treatment is the best solution to control disease progression. Hence, the aim of this study was to evaluate the efficacy of the long-term liraglutide treatment on the progression of WS symptoms. For this purpose, 2-month-old WS rats were treated with liraglutide up to the age of 18 months and changes in diabetes markers, visual acuity, and hearing sensitivity were monitored over the course of the treatment period. We found that treatment with liraglutide delayed the onset of diabetes and protected against vision loss in a rat model of WS. Therefore, early diagnosis and prophylactic treatment with the liraglutide may also prove to be a promising treatment option for WS patients by increasing the quality of life.

A mutant wfs1 zebrafish model of Wolfram syndrome manifesting visual dysfunction and developmental delay

Wolfram syndrome (WS) is an ultra-rare progressive neurodegenerative disorder defined by early-onset diabetes mellitus and optic atrophy. The majority of patients harbour recessive mutations in the WFS1 gene, which encodes for Wolframin, a transmembrane endoplasmic reticulum protein. There is limited availability of human ocular and brain tissues, and there are few animal models for WS that replicate the neuropathology and clinical phenotype seen in this disorder. We, therefore, characterised two wfs1 zebrafish knockout models harbouring nonsense wfs1a and wfs1b mutations. Both homozygous mutant wfs1a−/− and wfs1b−/− embryos showed significant morphological abnormalities in early development. The wfs1b−/− zebrafish exhibited a more pronounced neurodegenerative phenotype with delayed neuronal development, progressive loss of retinal ganglion cells and clear evidence of visual dysfunction on functional testing. At 12 months of age, wfs1b−/− zebrafish had a significantly lower RGC density per 100 μm2 (mean ± standard deviation; 19 ± 1.7) compared with wild-type (WT) zebrafish (25 ± 2.3, p < 0.001). The optokinetic response for wfs1b−/− zebrafish was significantly reduced at 8 and 16 rpm testing speeds at both 4 and 12 months of age compared with WT zebrafish. An upregulation of the unfolded protein response was observed in mutant zebrafish indicative of increased endoplasmic reticulum stress. Mutant wfs1b−/− zebrafish exhibit some of the key features seen in patients with WS, providing a versatile and cost-effective in vivo model that can be used to further investigate the underlying pathophysiology of WS and potential therapeutic interventions.

Maximum likelihood estimation for length-biased and interval-censored data with a nonsusceptible fraction.

Left-truncated data are often encountered in epidemiological cohort studies, where individuals are recruited according to a certain cross-sectional sampling criterion. Length-biased data, a special case of left-truncated data, assume that the incidence of the initial event follows a homogeneous Poisson process. In this article, we consider an analysis of length-biased and interval-censored data with a nonsusceptible fraction. We first point out the importance of a well-defined target population, which depends on the prior knowledge for the support of the failure times of susceptible individuals. Given the target population, we proceed with a length-biased sampling and draw valid inferences from a length-biased sample. When there is no covariate, we show that it suffices to consider a discrete version of the survival function for the susceptible individuals with jump points at the left endpoints of the censoring intervals when maximizing the full likelihood function, and propose an EM algorithm to obtain the nonparametric maximum likelihood estimates of nonsusceptible rate and the survival function of the susceptible individuals. We also develop a novel graphical method for assessing the stationarity assumption. When covariates are present, we consider the Cox proportional hazards model for the survival time of the susceptible individuals and the logistic regression model for the probability of being susceptible. We construct the full likelihood function and obtain the nonparametric maximum likelihood estimates of the regression parameters by employing the EM algorithm. The large sample properties of the estimates are established. The performance of the method is assessed by simulations. The proposed model and method are applied to data from an early-onset diabetes mellitus study.

Wolfram syndrome: Portuguese research.

Wolfram syndrome (WFS) is a neurological and endocrinological degenerative disorder, also known as DIDMOAD (Diabetes Insipidus, early-onset Diabetes Mellitus, progressive Optic Atrophy, and Deafness) syndrome. It is an autosomal recessive disorder, mostly involving the Wolfram syndrome 1 gene (WFS1). The phenotypic pleiomorphism, rarity, and molecular complexity complicate the follow-up of these patients. We aimed to describe the clinical characteristics and the follow-up of 11 patients with this disorder. We retrospectively analysed all WFS patients diagnosed between 1990 and 2020 in the Centro Hospitalar São João, a tertiary hospital in Northern Portugal. Eleven patients were included. Four patients had all 4 components of DIDMOAD. The presentation was diabetes mellitus (DM) in 9 patients, optic atrophy (OA) in another patient, and diabetes insipidus (DI) in another one. The median age of DM and OA diagnosis was 6 and 14 years, respectively. Nine patients had diabetes mellitus, and the other 2 patients had impaired glucose tolerance. All patients had OA. Four patients presented DI, all of them diagnosed in adolescence. Four patients had hearing impairment, 5 had urological abnormalities, 5 had neurological disorders, and 8 had psychiatry disorders. Eight patients had a broad spectrum of recessive mutations in WFS1. The information obtained in this study can facilitate further research in an attempt to improve prevention strategies for this devastating disease.

Predictors of severity of retinopathy among subjects with early onset type 2 diabetes mellitus

Purpose: To explore the factors influencing the severity of diabetic retinopathy among early onset type 2 diabetes mellitus. Materials and Methods: A descriptive cross sectional study was undertaken among subjects with early onset type 2 diabetes mellitus diagnosed with retinopathy. Demographic profiles like age, gender, duration of diabetes, co-morbidities and presence of macrovascular or microvascular complications were noted. Retina was evaluated using slit lamp biomicroscopy using 78D lens and Spectral Optical Coherence Tomography (OCT). Results: The study group included 135 subjects. There were 78 NPDR and 57 PDR cases. Those with PDR had higher age, longer duration of diabetes, lower Hb values, higher HbA1C and higher urine micro-albumin. They had a higher triglyceride values and lower HDL values. Conclusion: Higher age, longer duration, anemia, poor glycemic control and subclinical nephropathy were predictive of development of PDR among early onset type 2 DM subjects. Keywords: Early onset diabetes mellitus, NPDR, HbA1C, PDR, Urine micro-albumin.

PERK participates in cardiac valve development via fatty acid oxidation and endocardial-mesenchymal transformation

Protein kinase R-like endoplasmic reticulum kinase (PERK) is one of the endoplasmic reticulum (ER) stress sensors. PERK loss-of-function mutations are known to cause Wolcott–Rallison syndrome. This disease is characterized by early-onset diabetes mellitus, skeletal dysplasia, and cardiac valve malformation. To understand the role of PERK in valve formation in vivo, we used an endothelial-specific PERK conditional knockout mice as well as in vitro PERK inhibition assays. We used ProteoStat dyes to visualize the accumulation of misfolded proteins in the endocardial cushion and valve mesenchymal cells (VMCs). Then, VMCs were isolated from E12.5 fetal mice, by fluorescence assisted cell sorting. Proteomic analysis of PERK-deleted VMCs identified the suppression of proteins related to fatty acid oxidation (FAO), especially carnitine palmitoyltransferase II (CPT2). CPT2 is a critical regulator of endocardial-mesenchymal transformation (EndoMT); however how TGF-β downstream signaling controls CPT2 expression remains unclear. Here, we showed that PERK inhibition suppressed, not only EndoMT but also CPT2 protein expression in human umbilical vein endothelial cells (HUVECs) under TGF-β1 stimulation. As a result, PERK inhibition suppressed mitochondrial metabolic activity. Taken together, these results demonstrate that PERK signaling is required for cardiac valve formation via FAO and EndoMT.

A novel splice-site mutation of the HNF1B gene in a family with maturity onset diabetes of the young type 5 (MODY5).

SummaryMaturity-onset diabetes of the young (MODY) is a form of monogenic diabetes mellitus characterised by early onset and dominant inheritance. Delayed diagnosis or misdiagnosis as type 1 or type 2 diabetes mellitus is common. Definitive genetic diagnosis is essential for appropriate treatment of patients with MODY. The hepatocyte nuclear factor 1-beta (HNF1B) gene is responsible for MODY type 5 (MODY5), which has distinctive clinical features including renal disease. MODY5 should always be considered by clinicians in patients with early onset diabetes and renal anomalies. We report a case of a 30-year-old Japanese male with early-onset diabetes mellitus, renal anomalies and family history of diabetes that was suggestive of MODY5. Renal histology showed no evidence of diabetic nephropathy. Genetic testing revealed a novel heterozygous splice-site mutation of the HNF1B gene in the family members. It was strongly suggested that the mutation could underlie our patient’s MODY5.Learning points:Genetic diagnosis of MODY is relevant for appropriate treatment.Dominantly inherited early-onset diabetes mellitus with renal cysts suggests MODY5.Scanning the non-coding regions is important for not missing a mutation in HNF1B.

Metformin during Pregnancy: Effects on Offspring Development and Metabolic Function.

Maternal obesity during pregnancy and gestational diabetes mellitus (GDM) are both associated with of several postnatal diseases in the offspring, including obesity, early onset hypertension, diabetes mellitus, and reproductive alterations. Metformin is an oral drug that is being evaluated to treat GDM, obesity-associated insulin resistance, and polycystic ovary syndrome (PCOS) during pregnancy. The beneficial effects of metformin on glycemia and pregnancy outcomes place it as a good alternative for its use during pregnancy. In this line of thought, improving the metabolic status of the pregnant mother by using metformin should avoid the consequences of insulin resistance on the offspring's fetal and postnatal development. However, some human and animal studies have shown that metformin during pregnancy could amplify these alterations and be associated with excessive postnatal weight gain and obesity. In this minireview, we discuss not only the clinical and experimental evidence that supports the benefits of using metformin during pregnancy but also the evidence showing a possible negative impact of this drug on the offspring's development.

SUN-679 Early Onset Diabetes Mellitus in a Young Woman with Ring Chromosome 13 Syndrome

Background: Ring chromosome 13 is a rare genetic disorder in which the two ends of chromosome 13 are fused together to form a ring shape. Ring formation subsequently leads to gene deletions on both the long and short arms of the chromosome. Observed phenotypes among these patients are variable due to differences in the number of genetic deletions that occur with fusion. Common clinical features seen in ring chromosome 13 include micro- or anencephaly, severe mental retardation (MR), ambiguous genitalia, growth retardation, and facial dysmorphism. To our knowledge, diabetes mellitus (DM) has only been reported in two published case reports of patients with ring chromosome 13. It has been proposed that development of DM in this syndrome may be due to deletion of the IRS2 gene on the long arm of chromosome 13. This hypothesis is based on evidence from knockout mice studies and genetic comparisons of ring chromosome 13 patients with and without DM. Clinical Case: We present a case of a 23-year-old woman with a known history of mosaic ring chromosome 13 abnormality who was diagnosed with DM at age 21. Diagnosis was made incidentally based on laboratory data obtained at a routine outpatient visit. Hemoglobin A1c at that time was 13.1%. Glutamic acid decarboxylase and insulin antibodies were negative. She has been on a basal-bolus insulin regimen since diagnosis with overall good glycemic control (average hemoglobin A1c 6.5%). She has no known micro- or macrovascular complications of DM. She has no family history of chromosome 13 syndrome or DM. Other notable clinical features associated with her ring chromosome 13 disorder include MR, spastic encephalopathy, delayed puberty (menarche at age 18), scoliosis, facial dysmorphism, and deficiencies in clotting factors 7 and 10. Conclusion: DM is a common disorder that is typically multifactorial in etiology. In rare cases, DM can be the result of monogenic mutations or deletions. We present a case of a young woman with early-onset antibody-negative DM thought to be related to gene deletions resulting from her underlying ring chromosome 13 abnormality. There is some evidence from prior case reports and rodent studies to suggest that DM in patients with this disorder may be the result of IRS2 deletion from the long arm of chromosome 13. Although DM is a rare complication of ring chromosome 13 disorder, early screening should be considered in these patients to prevent development of downstream complications.

A novel splice site indel alteration in the EIF2AK3 gene is responsible for the first cases of Wolcott-Rallison syndrome in Hungary

BackgroundWolcott-Rallison Syndrome (WRS) is a rare autosomal recessive disease that is the most common cause of neonatal diabetes in consanguineous families. WRS is caused by various genetic alterations of the Eukaryotic Translation Initiation Factor 2-Alpha Kinase 3 (EIF2AK3) gene.MethodsGenetic analysis of a consanguineous family where two children were diagnosed with WRS was performed by Sanger sequencing. The altered protein was investigated by in vitro cloning, expression and immunohistochemistry.ResultsThe first cases in Hungary, − two patients in one family, where the parents were fourth-degree cousins - showed the typical clinical features of WRS: early onset diabetes mellitus with hyperglycemia, growth retardation, infection-induced multiple organ failure. The genetic background of the disease was a novel alteration in the EIF2AK3 gene involving the splice site of exon 11– intron 11–12 boundary: g.53051_53062delinsTG. According to cDNA sequencing this created a new splice site and resulted in a frameshift and the development of an early termination codon at amino acid position 633 (p.Pro627AspfsTer7). Based on in vitro cloning and expression studies, the truncated protein was functionally inactive. Immunohistochemistry revealed that the intact protein was absent in the islets of pancreas, furthermore insulin expressing cells were also dramatically diminished. Elevated GRP78 and reduced CHOP protein expression were observed in the liver.ConclusionsThe novel genetic alteration causing the absence of the EIF2AK3 protein resulted in insufficient handling of severe endoplasmic reticulum stress, leading to liver failure and demise of the patients.

Modeling the Effects of Severe Metabolic Disease by Genome Editing of hPSC-Derived Endothelial Cells Reveals an Inflammatory Phenotype

The kinase AKT2 (PKB) is an important mediator of insulin signaling, for which loss-of-function knockout (KO) mutants lead to early onset diabetes mellitus, and dominant active mutations lead to early development of obesity and endothelial cell (EC) dysfunction. To model EC dysfunction, we used edited human pluripotent stem cells (hPSCs) that carried either a homozygous deletion of AKT2 (AKT2 KO) or a dominant active mutation (AKT2 E17K), which, along with the parental wild type (WT), were differentiated into ECs. Profiling of EC lines indicated an increase in proinflammatory and a reduction in anti-inflammatory fatty acids, an increase in inflammatory chemokines in cell supernatants, increased expression of proinflammatory genes, and increased binding to the EC monolayer in a functional leukocyte adhesion assay for both AKT2 KO and AKT2 E17K. Collectively, these findings suggest that vascular endothelial inflammation that results from dysregulated insulin signaling (homeostasis) may contribute to coronary artery disease, and that either downregulation or upregulation of the insulin pathway may lead to inflammation of endothelial cells. This suggests that the standard of care for patients must be expanded from control of metabolic parameters to include control of inflammation, such that endothelial dysfunction and cardiovascular disorders can ultimately be prevented.

Markers for undiagnosed type 2 diabetes mellitus during pregnancy-A population-based retrospective cohort study.

To examine possible markers for undiagnosed type 2 diabetes in early-onset gestational diabetes mellitus (GDM). A population-based retrospective cohort study of women with GDM diagnosed prior to the 24th week, who delivered between 2005 and 2018, was conducted. The results of the 50-g glucose challenge test, 100-g oral glucose tolerance test, and the first available glycosylated hemoglobin (HbA1c) were examined as markers for type 2 diabetes diagnosed 6 to 12 weeks post pregnancy, which is suggestive of pregestational diabetes. This was done by calculating the area under the curve (AUC) of the receiver operating characteristic (ROC) curve for each marker. These markers and additional ones were evaluated for independency by stepwise multivariate logistic regression. Of 69 417 pregnancies, 3321 (5%) pregnancies were with GDM. Of them, in 261 (8%) women GDM was diagnosed prior to the 24th week, and 219 (84%) women had available data for analysis. Among them, 11 (5%) women had type 2 diabetes post pregnancy. Elevated HbA1c was the most accurate marker for undiagnosed type 2 diabetes (AUC 91% with 95% CI [81%-100%]) and the only independent marker for undiagnosed type 2 diabetes in multivariate analysis (odds ratio [OR] 19; 95% CI [3.2-109], C statistic = 88%). Using the ROC curve, a cutoff of 5.8% predicted type 2 diabetes with 89% sensitivity, 86% specificity, 99.4% negative predictive value, and 23% positive predictive value. Early-onset GDM with HbA1c ≥ 5.8% should be managed as type 2 diabetes. Definitive diagnosis should be done after delivery.

2164-P: Paired Box 6 Modulates Pancreatic Beta-Cell Insulin Secretion through Regulation of Munc18-1/2 Expression: Involvement of CREB Signaling

The Paired box 6 (PAX6) transcription factor is crucial for normal pancreatic islet development and function. Heterozygous mutations of PAX6 are associated with impaired insulin secretion and early-onset diabetes mellitus in human. Previous studies demonstrated that PAX6 plays critical roles in insulin biosynthesis, glucose-sensing and glucose-induced ATP synthesis (the proximal signaling of insulin secretion). Yet the molecular mechanism of PAX6 in controlling beta-cell insulin secretion, especially the involvement of distal signaling, remains ambiguous. This study investigated the regulatory role of PAX6 in exocytotic proteins, the core components of distal signaling of insulin secretion, by using human pancreatic beta-cell line EndoC-bH1. The correlation between PAX6 and type 2 diabetes mellitus (T2DM)-associated beta-cell dysfunction was also assessed. Loss-of-function and gain-of-function studies showed that PAX6 positively regulated the expression of exocytotic proteins Munc18-1 and Munc18-2 in beta-cells by modulating the activity of cAMP response element-binding protein (CREB). The PAX6/CREB/Munc18-1/2 axis in turn controlled glucose-stimulated insulin secretion. On the other hand, EndoC-bH1 cells under diabetic condition displayed diminished PAX6 expression, blunted CREB phosphorylation and Munc18-1/2 down-regulation which were rescued by PAX6 overexpression. We conclude that PAX6 regulates distal signaling of insulin secretion through CREB/Munc18-1/2 axis; while maintenance of normal PAX6 expression or activity in human beta-cells may serve as a promising strategy in preserving beta-cell function and delaying the onset of T2DM. Disclosure W. So: None. W. Han: None. Funding National Medical Research Council of Australia

328-LB: Characteristic Features in the Intraislet Ductal Cells of Diabetic C414A-CRY1 Transgenic Mice

The transgenic mice ubiquitously expressing the zinc-binding site-mutant CRY1 (C414A-CRY1) show early onset diabetes mellitus similar to human MODY characterized by β-cell dysfunction. In the Tg mice with age, atypical ductal structures emerged inside islets, suggesting that islet cells can transdifferentiate to duct-like cells as we have reported at ADA Scientific Sessions in 2017 and 2018. To explore further molecular features of intra-islets ducts, we conducted staining experiments for Dolichos biflorus agglutinin (DBA) lectin in the pancreatic sections of well-matured mice. The results showed that high levels of staining for DBA lectin were observed in normal ducts of both wild type and Tg mice. In contrast, majority of intra-islet ductal structures especially still not fully developed small ones were weakly positive for DBA lectin, suggesting immaturity for ductal functions of the intra-islet ductal cells. Furthermore, the variation of the staining levels for DBA lectin in intra-islet ductal cells was evidently larger than that in other ductal cells, indicating heterogeneity in the cell functions among intra-islet ductal cells. We also found that remarkably high accumulation of FAM98A, an RNA-binding protein whose functions are still not decisive, was observed in the intra-islet ducts in the Tg mice. In normal ducts, moderate staining of FAM98A was observed. As for pancreatic endocrine cells, although as a whole the immunostaining levels were much weaker than those of acini and ductal cells, discernable staining of FAM98A is detected in both α and β cells of islets. Taken together, our results indicate that intra-islet ductal cells have unique feature distinct from normal ductal cells, and suggest that FAM98A may play important roles in the generation of atypical ductal cells from non-ductal cells in the islet. Disclosure S. Okano: None. A. Yasui: None. S. Kanno: None. K. Satoh: None. M. Igarashi: None. O. Nakajima: None. Funding Japan Society for the Promotion of Science; Tohoku University

EIF2AK3 novel mutation in a child with early-onset diabetes mellitus, a case report

BackgroundWolcott-Rallison syndrome (WRS) is caused by a biallelic mutation in the gene encoding eukaryotic translation initiation factor 2-alpha kinase 3 (EIF2AK3) on chromosome 2p11.2. This condition is characterized by permanent early-onset diabetes mellitus, epiphyseal dysplasia, and hepatic dysfunction. We report a patient with WRS born to a consanguineous marriage due to a novel biallelic frameshift mutation in the EIF2AK3 gene.Case presentationOur patient was a 2-year-and-6-month-old Yemeni girl born to consanguineous parents who was diagnosed with neonatal diabetes at 20 days of age. She presented with chronic diarrhea and liver dysfunction. The child was normocephalic and exhibited failure to thrive and hepatomegaly with no skeletal deformities. Further investigations revealed microcytic anemia, liver impairment and primary hypothyroidism. Genetic testing confirmed the diagnosis of WRS via identification of a novel biallelic frameshift mutation in the EIF2AK3 gene. During her hospital stay, she went into septic shock and developed multi-organ failure, including fulminant hepatic failure. She unfortunately died within 2 weeks of her hospital stay.ConclusionsWolcott-Rallison syndrome is recognized as the most common cause of early-onset diabetes in infants born to consanguineous marriages. Screening for genetic mutations in EIF2AK3 is recommended for establishing early diagnosis, providing genetic counselling, and predicting the development of additional clinical features, most importantly hepatic failure. Hence, this screening is important for guiding optimal management and improving patient outcome.

Urinary proteome signature of Renal Cysts and Diabetes syndrome in children

Renal Cysts and Diabetes Syndrome (RCAD) is an autosomal dominant disorder caused by mutations in the HNF1B gene encoding for the transcriptional factor hepatocyte nuclear factor-1B. RCAD is characterized as a multi-organ disease, with a broad spectrum of symptoms including kidney abnormalities (renal cysts, renal hypodysplasia, single kidney, horseshoe kidneys, hydronephrosis), early-onset diabetes mellitus, abnormal liver function, pancreatic hypoplasia and genital tract malformations. In the present study, using capillary electrophoresis coupled to mass spectrometry (CE-MS), we investigated the urinary proteome of a pediatric cohort of RCAD patients and different controls to identify peptide biomarkers and obtain further insights into the pathophysiology of this disorder. As a result, 146 peptides were found to be associated with RCAD in 22 pediatric patients when compared to 22 healthy age-matched controls. A classifier based on these peptides was generated and further tested on an independent cohort, clearly discriminating RCAD patients from different groups of controls. This study demonstrates that the urinary proteome of pediatric RCAD patients differs from autosomal dominant polycystic kidney disease (PKD1, PKD2), congenital nephrotic syndrome (NPHS1, NPHS2, NPHS4, NPHS9) as well as from chronic kidney disease conditions, suggesting differences between the pathophysiology behind these disorders.