Early-onset Diabetes Research Articles

Exon Sequencing of HNF1β in Chinese Patients with Early-Onset Diabetes.

Maturity-onset diabetes of the young (MODY) due to variants of hepatocyte nuclear factor 1-beta (HNF1β) (MODY5) has not been well studied in the Chinese population. This study aimed to estimate its prevalence and evaluate the application of a clinical screening method (Faguer score) in Chinese early-onset diabetes (EOD) patients. Among 679 EOD patients clinically diagnosed with type 2 diabetes mellitus (age at diagnosis ??0 years), the exons of HNF1β were sequenced. Functional impact of rare variants was evaluated using a dual-luciferase reporter system. Faguer scores ?? prompted multiplex ligation-dependent probe amplification (MLPA) for large deletions. Pathogenicity of HNF1β variants was assessed following the American College of Medical Genetics and Genomics (ACMG) guidelines. Two rare HNF1β missense mutations (E105K and G454R) were identified by sequencing in five patients, showing functional impact in vitro. Another patient was found to have a whole-gene deletion by MLPA in 22 patients with the Faguer score above 8. Following ACMG guidelines, six patients carrying pathogenic or likely pathogenic variant were diagnosed with MODY5. The estimated prevalence of MODY5 in Chinese EOD patients was approximately 0.9% or higher. MODY5 is not uncommon in China. The Faguer score is helpful in deciding whether to perform MLPA analysis on patients with negative sequencing results.

New Insights Into TRMT10A Syndrome: Case Report and Literature Review.

TRMT10A is related to a syndrome characterized by early-onset diabetes mellitus, microcephaly, epilepsy, and intellectual disability. We report a case of a patient showing spastic-ataxic paraparesis and Dandy-Walker variant associated with a causative homozygous c.421-1G > A variant in the TRMT10A gene, affecting a canonical splicing site. This mutation disrupts the "SAM-dependent methyltransferase TRM10-type domain", which is implicated in methylation and S-adenosylmethionine metabolic biological processes, crucial for mitochondrial and glucose metabolism. The prominent neurological involvement of our patient enhances the implication of TRMT10A in the brain development, suggesting a potential association between TRMT10A variants and dominant neurological phenotypes. This case expands the clinical spectrum of TRMT10A syndrome highlighting the importance of considering this gene in the evaluation of patients with brain/cerebellar malformations and spastic-ataxic paraparesis. Further research is warranted to elucidate the underlying pathogenic mechanisms and potential therapeutic implications.

The Relationship Between Age at Diabetes Onset and Clinical Outcomes in Newly Diagnosed Type 2 Diabetes: A Real-World Two-Center Study.

This study was developed with the goal of clarifying whether there is any relationship between type 2 diabetes mellitus (T2DM) age of onset and clinical outcomes for patients in National Metabolic Management Centers (MMC). From September 2017 - June 2022, 864 total T2DM patients were recruited in MMC and assigned to those with early-onset and late-onset diabetes (EOD and LOD) based on whether their age at disease onset was ≤ 40 or > 40 years. All patients received standardized management. Baseline and 1-year follow-up data from these two groups of patients were assessed. Associations between onset age and other factors were evaluated with a multivariate linear regression approach, adjusting for appropriate covariates. Outcomes in particular subgroups were also assessed in stratified analyses. Markers of dysregulated glucose metabolism and BMI values were significantly higher among EOD patients as compared to LOD patients. Subjects in both groups exhibited significant improvements in several disease-related parameters on 1-year follow-up after undergoing metabolic management. EOD patients exhibited significantly greater percentage reductions in HbA1c levels (-28.49 (-44.26, -6.45)% vs -13.70 (-30.15,-1.60)%, P =0.017) relative to LOD patients following adjustment for confounders. Significant differences were also detected between these groups when focused on subgroups of patients who were male, exhibited a BMI ≥ 25, an HbA1c ≥ 9, or had a follow-up frequency < 2. Data from a 1-year follow-up time point suggest that a standardized metabolic disease management model can promote effective metabolic control in newly diagnosed T2DM patients, particularly among individuals with EOD.

Monogenic Defects of Beta Cell Function: From Clinical Suspicion to Genetic Diagnosis and Management of Rare Types of Diabetes

Monogenic defects of beta cell function refer to a group of rare disorders that are characterized by early-onset diabetes mellitus due to a single gene mutation affecting insulin secretion. It accounts for up to 5% of all pediatric diabetes cases and includes transient or permanent neonatal diabetes, maturity-onset diabetes of the young (MODY), and various syndromes associated with diabetes. Causative mutations have been identified in genes regulating the development or function of the pancreatic beta cells responsible for normal insulin production and/or release. To date, more than 40 monogenic diabetes subtypes have been described, with those caused by mutations in HNF1A and GCK genes being the most prevalent. Despite being caused by a single gene mutation, each type of monogenic diabetes, especially MODY, can appear with various clinical phenotypes, even among members of the same family. This clinical heterogeneity, its rarity, and the fact that it shares some features with more common types of diabetes, can make the clinical diagnosis of monogenic diabetes rather challenging. Indeed, several cases of MODY or syndromic diabetes are accurately diagnosed in adulthood, after having been mislabeled as type 1 or type 2 diabetes. The recent widespread use of more reliable sequencing techniques has improved monogenic diabetes diagnosis, which is important to guide appropriate treatment and genetic counselling. The current review aims to summarize the latest knowledge on the clinical presentation, genetic confirmation, and therapeutic approach of the various forms of monogenic defects of beta cell function, using three imaginary clinical scenarios and highlighting clinical and laboratory features that can guide the clinician in reaching the correct diagnosis.

Insights from a Wolfram syndrome cohort: clinical and molecular findings from a specialized diabetes reference center.

Considering the rarity and clinical and molecular diversity of Wolfram syndrome (WS), the objective of this study was to identify patients with a clinical presentation suggestive of WS following up at a single Brazilian diabetes service and analyze their clinical and molecular characteristics. The study included all patients with a clinical presentation of WS following up between 1991 and 2022 with early-onset diabetes mellitus and other WS signs and symptoms. A retrospective analysis was conducted, including patients' age, sex, consanguinity, age at symptom onset, diagnosis of diabetes mellitus, optic atrophy, diabetes insipidus, neurological and psychiatric disorders, hearing loss, urinary disorders, hypogonadism, and WFS1 molecular analysis. Eight patients were identified, all of whom were diagnosed with diabetes mellitus at an average age of 3.7 years. Optic atrophy, diabetes insipidus, and hearing loss were common, while psychiatric and neurological alterations were observed in some cases. Genetic analysis revealed pathogenic variants in homozygosity or compound heterozygosity. The most frequent variant was p. Val412Serfs29, present in five of the seven families. This study represents the second-largest Brazilian sample of WS and is the first cohort from a single center in Southeast Brazil. The patients had an early, severe, and complete clinical presentation. The genetic variants identified were consistent with previous literature descriptions. The variant p. Val412Serfs29 was particularly common in this cohort, highlighting its relevance in the region.

Diverse Clinical and Immunological Profiles in Patients with IPEX Syndrome: a Multicenter Analysis from Turkey.

Immunodysregulation, Polyendocrinopathy, Enteropathy, and X-linked syndrome (IPEX), caused by pathogenic FOXP3 variants, is a rare autoimmune disorder with diverse clinical features, including early-onset diabetes, eczema, and enteropathy. Atypical cases show milder symptoms and unique signs, requiring different treatments. Therefore, there are ambiguities in the accurate diagnosis and management of IPEX. We sought to present clinical, genetic, and immunological assessments of 12 IPEX patients with long-term follow-up to facilitate the diagnosis and management of the disease. Clinical findings and treatment options of the patients were collected over time. Lymphocyte subpopulations, protein expressions, regulatory T (Treg) and circulating T follicular helper (cTFH) cells, and T-cell proliferation were analyzed. Predominant presentations included autoimmunity (91.6%), failure to thrive (66.7%), and eczema (58.3%). There were four classical and eight atypical IPEX individuals. Allergic manifestations were more common in atypical patients. Notably, chronic diarrhea demonstrated heightened severity compared to other manifestations. Four patients (33.3%) demonstrated eosinophilia, and nine (75%) showed high serum IgE levels. Most patients exhibited normal percentages of Treg cells with reduced CD25, FOXP3, and CTLA-4 expressions, corrected after hematopoietic stem cell transplantation (HSCT). Compared to healthy controls, the TH2-like skewing accompanied by reduced TH17-like responses was observed in cTFH and Treg cells of patients. Overall, nine patients (75%) received immunosuppressants (ISs), and six (50%) underwent HSCT, which was the only treatment revealing sustained control. Sirolimus was used in six patients and showed better control than other ISs. The first cohort from Turkey with long-term follow-up results, comparing typical and atypical cases, provides insights into the outcomes of different therapeutic modalities and T- cell subtype changes in IPEX syndrome.

Discovery of a TRMT10A mutation in a case of atypical diabetes: Case report

It is notable that monogenic forms of diabetes are exceedingly uncommon, with only 28 genes thus far identified. Such conditions frequently result in the dysfunction of pancreatic cells responsible for insulin production. Mutation in the TRMT10A gene leads to a rare genetic disease that is associated with endocrine and metabolic disorders, including diabetes and short stature. This article presents a review of the existing literature on the subject, describing the association between TRMT10A gene mutation and diabetes. It also presents the clinical case of a young girl with type 1 diabetes and facial dysmorphia. TRMT10A gene mutation has been linked to syndromic juvenile diabetes in a manner analogous to Wolfram's syndrome. This form of diabetes, which manifests in early childhood and is associated with microcephaly, epilepsy and intellectual disability, is caused by mutations in the gene for homolog A of tRNA methyltransferase 10 (TRMT10A). This emphasizes the importance of using a targeted panel to recognize previously unidentified monogenic diabetes among early-onset non-insulin-dependent diabetes in the absence of obesity and autoimmunity. In view of the aforementioned data, it is recommended that TRMT10A sequencing be considered in children or adults with early-onset diabetes and a history of intellectual disability, microcephaly and epilepsy.

The Impact of Genetic History on the Risk of Developing Type II Diabetes

Type II Diabetes Mellitus (T2DM) is a global health issue with a growing prevalence due to both environmental and genetic factors. Genetic predisposition is a critical determinant of risk, with heritability studies revealing that 40-80% of T2DM risk can be attributed to genetic factors. Key genetic variants, such as those in TCF7L2, PPARG, KCNJ11, and FTO, have been associated with increased risk, impacting pathways related to insulin secretion and resistance. Monogenic forms of diabetes like Maturity-Onset Diabetes of the Young (MODY) highlight the role of single-gene mutations in early-onset diabetes. Familial aggregation studies highlight the significant role of genetic predisposition, with individuals having a family history of T2DM at a markedly higher risk. Epigenetic mechanisms further complicate this risk by introducing heritable changes in gene expression influenced by environmental factors. Genetic testing, including Polygenic Risk Scores (PRS), aids in identifying individuals at increased risk, but their predictive power is limited by the polygenic nature of T2DM. Personalized prevention and management strategies are crucial, utilizing genetic information to tailor interventions and pharmacogenomics to optimize treatment. Culturally sensitive support and education are also essential for managing T2DM. Future research directions include leveraging advanced genomic technologies to further elucidate T2DM’s genetic basis and improve personalized medicine approaches. Keywords: Genetic History, Risk, Type II Diabetes Mellitus.

Phenotypic features, prevalence of KCNJ11-MODY in Chinese patients with early-onset diabetes and a literature review.

Gain-of-function (GOF) variants of KCNJ11 cause neonate diabetes and maturity-onset diabetes of the young (KCNJ11-MODY), while loss-of-function (LOF) variants lead to hyperinsulinemia hypoglycemia and subsequent diabetes. Given the limited research of KCNJ11-MODY, we aimed to analyse its phenotypic features and prevalence in Chinese patients with early-onset type 2 diabetes (EOD). We performed next-generation sequencing on 679 Chinese EOD patients to screen for KCNJ11 exons variants. Bioinformatics prediction and the American College of Medical Genetics and Genomics guidelines was used to determine the pathogenicity and diagnosed KCNJ11-MODY. A literature review was conducted to investigate the phenotypic features of KCNJ11-MODY. We identified six predicted deleterious rare variants in six EOD patients (0.88%). They were classified as uncertain significance (variant of uncertain significance [VUS]), but more common in this EOD cohort than a general Chinese population database, however, without significant difference (53/10,588, 0.50%) (p = .268). Among 80 previously reported patients with KCNJ11-MODY, 23.8% (19/80) carried 9 (32.1%) LOF variants, who had significantly older age at diagnosis, higher birthweight and higher fasting C-peptide compared to patients with GOF variants. Many patients carrying VUS were not correctly diagnosed. Some rare variants of KCNJ11 might contribute to the development of Chinese EOD, although available evidence has not enough power to support them as cause of KCNJ11-MODY. The clinical features of LOF variants were different from GOF variants in KCNJ11-MODY patients. It is necessary to evaluate the pathogenicity of VUS through function experiments.

Microvascular disease and early diabetes onset are associated with deficits in femoral neck bone density and structure among older adults with longstanding type 1 diabetes.

Adults with type 1 diabetes (T1D) have increased hip fracture risk, yet no studies have assessed volumetric bone density or structure at the hip in older adults with T1D. Here, we used previously collected 3D CT scans of the proximal femur from older adults with longstanding T1D and non-diabetic controls to identify bone deficits that may contribute to hip fracture in T1D. In this retrospective cohort study, we identified 101 adults with T1D and 181 age-, sex-, and race-matched non-diabetic controls (CON) who received abdominal or pelvis CT exams from 2010 to 2020. Among adults with T1D, 33 (33%) had mild-to-moderate nephropathy, 61 (60%) had neuropathy, and 71 (70%) had retinopathy. Within the whole cohort, adults with T1D tended to have lower FN density, though differences did not reach statistical significance. The subset of the T1D group who were diagnosed before age 15 had lower total BMC (-14%, TtBMC), cortical BMC (-19.5%, CtBMC), and smaller Ct cross-sectional area (-12.6, CtCSA) than their matched controls (p<.05 for all). Individuals with T1D who were diagnosed at a later age did not differ from controls in any bone outcome (p>.21). Furthermore, adults with T1D and nephropathy had lower FN aBMD (-10.6%), TtBMC (-17%), CtBMC (-24%), and smaller CtCSA (-15.4%) compared to matched controls (p<.05 for all). Adults with T1D and neuropathy had cortical bone deficits (8.4%-12%, p<.04). In summary, among older adults with T1D, those who were diagnosed before the age of 15yr, as well as those with nephropathy and neuropathy had unfavorable bone outcomes at the FN, which may contribute to the high risk of hip fractures among patients with T1D. These novel observations highlight the longstanding detrimental impact of T1D when present during bone accrual and skeletal fragility as an additional complication of microvascular disease in individuals with T1D.

Early Onset of Type 1 Diabetes in Kuwait: Distinct Clinical, Metabolic, and Immunological Characteristics.

Exploring early-onset diabetes in terms of describing characteristics at time of diagnosis might aid in a better understanding of etiology and may have implications on management and prevention. The aim of this study was to investigate the prevalence of early-onset type 1 diabetes (T1D) in Kuwait as well as describe their baseline clinical, biochemical, and immunological characteristics. Medical records of children newly diagnosed with T1D and registered in the Childhood-Onset Diabetes electronic Registry (CODeR) in Kuwait between 2017 and 2022 were reviewed. Early-onset T1D was defined as diagnosis at age younger than 6 years. 2,051 children were registered with new-onset T1D between 2017 and 2022, of which 657 (32.0%) were diagnosed at early onset. There has been a trend of slight increase in the percentage of early-onset T1D after 2020 (15.2%) with a prevalence of 18.4% and 20.2% in 2021 and 2022, respectively (p = 0.056). Age at onset was inversely related to admission to the pediatric intensive care unit (OR = 0.90, 95% CI: 0.85, 0.95, p &lt; 0.0001) and was directly related to positive celiac autoimmunity (p = 0.022), higher hemoglobin A1C (p &lt; 0.0001), and C-peptide levels (p &lt; 0.0001). However, age at onset of T1D was inversely related to the higher vitamin D levels (p &lt; 0.0001). These findings reinforce the need for increased attention to be given to study the development of T1D in children of younger age. This in turn will support special management and prevention measures targeted toward this vulnerable age group.

Wolfram Syndrome 1: A Neuropsychiatric Perspective on a Rare Disease.

Wolfram syndrome 1 (WS1) is an uncommon autosomal recessive neurological disorder that is characterized by diabetes insipidus, early-onset non-autoimmune diabetes mellitus, optic atrophy, and deafness (DIDMOAD). Other clinical manifestations are neuropsychiatric symptoms, urinary tract alterations, and endocrinological disorders. The rapid clinical course of WS1 results in death by the age of 30. Severe brain atrophy leads to central respiratory failure, which is the main cause of death in WS1 patients. Mutations in the WFS1 gene, located on chromosome 4p16, account for approximately 90% of WS1 cases. The gene produces wolframin, a transmembrane glycoprotein widely distributed and highly expressed in retinal, neural, and muscular tissues. Wolframin plays a crucial role in the regulation of apoptosis, insulin signaling, and ER calcium homeostasis, as well as the ER stress response. WS1 has been designated as a neurodegenerative and neurodevelopmental disorder due to the numerous abnormalities in the ER stress-mediated system. WS1 is a devastating neurodegenerative disease that affects patients and their families. Early diagnosis and recognition of the initial clinical signs may slow the disease's progression and improve symptomatology. Moreover, genetic counseling should be provided to the patient's relatives to extend multidisciplinary care to their first-degree family members. Regrettably, there are currently no specific drugs for the therapy of this fatal disease. A better understanding of the etiology of WS1 will make possible the development of new therapeutic approaches that may enhance the life expectancy of patients. This review will examine the pathogenetic mechanisms, development, and progression of neuropsychiatric symptoms commonly associated with WS1. A thorough understanding of WS1's neurophysiopathology is critical for achieving the goal of improving patients' quality of life and life expectancy.

Positive parental history of diabetes is associated with early diagnosis, better dietary compliance, and glycemic control among type 2 diabetes patients in southern Sri Lanka

BackgroundParental history of diabetes is an established risk factor for type 2 diabetes mellitus (T2DM). There is limited data on the association of parental history with the prevalence of T2DM in Sri Lanka. The study aims to examine the prevalence and correlation of parental history and factors such as the onset age, glycaemic control, and self-reported dietary compliance among T2DM patients. With a rising incidence of T2DM in Sri Lanka, understanding the impact of parental history on age at diagnosis and glycemic control can aid in targeted screening and interventions.MethodsA cross-sectional study was carried out on 500 T2DM patients attending a diabetes clinic in Galle, the capital of Southern Sri Lanka with a multiethnic population. Convenient sampling strategy was followed in the recruitment process and a questionnaire-based method was used to collect the data. All the collected data was analysed using SPSS V 25.0.Results51.2% had a parental history of T2DM, and those with a positive parental history were diagnosed six years earlier than those with a negative parental history (p < 0.001). A significant correlation between parental history and gestational diabetes mellitus (GDM) was observed (p < 0.001). Patients with a parental history reported better dietary adherence (p < 0.001). Binary logistic regression analysis revealed patients with positive parental history had significantly lower HbA1C (p = 0.003, OR = 0.748).ConclusionT2DM patients with a parental history showed significant association with early diabetes onset, GDM, better glycemic control, and dietary adherence.

Early-onset and uncontrolled diabetes mellitus factors correlate with complications of Peyronie's disease.

Peyronie's disease (PD) is a connective tissue disorder that affects the penis and is characterized by abnormal collagen structure in the penile tunica albuginea, resulting in plaque formation and penile deformity. PD's overall prevalence is estimated at 3.2% to 8.9%, with rates as high as 20.3% among men with type 2 diabetes mellitus (DM). However, the characteristics of DM associated with PD complications remain unclear. To explore clinical associations between DM characteristics and PD complications. We conducted a retrospective analysis of patients with DM and PD who presented at our institution between 2007 and 2022. We examined patients' clinical histories, DM- and PD-related clinical parameters, and complications. Penile deformities were assessed through physical examination, photographs, and penile Doppler ultrasound. Patients were categorized into subgroups based on age of DM onset: early (<45years), average (45-65years), and late (>65years). Outcomes included effects of DM characteristics on PD development, progression, and severity. In total, 197 patients were included in the evaluation. Early-onset diabetes and elevated hemoglobin A1c (HbA1c) levels exhibited significant correlations with the early development of PD (ρ = 0.66, P < .001, and ρ = -0.24, P < .001, respectively). Furthermore, having DM at an early age was associated with the occurrence of penile plaque (ρ = -0.18, P = .03), and there were no significant differences in plaque dimensions (ρ = -0.29, P = .053). A rise in HbA1c levels after the initial PD diagnosis displayed positive correlations with the formation of penile plaque (ρ = 0.22, P < .006). These findings emphasize the need for comprehensive assessments and personalized treatment strategies for individuals with DM and PD. Enhanced management approaches can improve outcomes for those facing both challenges. Limitations include the single-site retrospective design with potential selection bias, inaccuracies in medical record data, and challenges in controlling confounding variables. This study highlights that early-onset diabetes and poor diabetes control, as indicated by a subsequent rise in HbA1c levels following PD diagnosis, are significantly correlated with the onset and severity of PD. Revealing the mechanisms behind these findings will help us develop better management strategies for individuals with DM and PD.

Coinheritance of HNF1A and glucokinase variants in maturity-onset diabetes of the young.

Maturity-onset diabetes of the young (MODY) is a group of monogenic forms of diabetes mellitus characterized by early-onset diabetes with dominant inheritance of beta-cell dysfunction. There are few reports of the coinheritance of glucokinase (GCK) and hepatocyte nuclear factor 1 alpha gene (HNF1A) variants underlying MODY in patients. Herein, we describe a case involving combinations of monoallelic GCK and HNF1A variants associated with MODY. A 10-year-old Japanese girl with a three-generation family history of diabetes without obesity showed high levels of urinary glucose during a school screening test. Her glucose metabolism profile revealed 124 mg/dL of fasting glucose, 6.9% glycated hemoglobin (HbA1c), and 2.78 ng/mL of C-peptide immunoreactivity levels. In a 75-g oral glucose tolerance test, her base glucose, peak glucose, insulin resistance, and homeostasis model assessment of beta cell function levels were 124 mg/dL, 210 mg/dL (120 min), 1.71, and 33%, respectively. Based on the clinical phenotype of GCK-MODY, alimentary and exercise therapy without oral hypoglycemic agents were used to maintain her fasting glucose and HbA1c levels. We explored the coinheritance of MODY with GCK and HNF1A variants in this and past cases and found that careful clinical follow-up is required to firmly establish phenotypic features. Moreover, the accumulation of data on genetically confirmed MODY associated with the coinheritance of GCK and HNF1A variants will be useful for understanding genotype-phenotype correlations. MODY is a group of monogenic forms of diabetes mellitus characterized by early-onset diabetes with the dominant inheritance of beta-cell dysfunction. MODY2 and MODY3 caused by heterozygous loss-of-function variants in the glucokinase (GCK) and hepatocyte nuclear factor 1 alpha (HNF1A) genes, respectively, are the most common forms of the disease. Few cases of MODY have previously been reported as being associated with the coinheritance of GCK and HNF1A variants. Careful clinical follow-up is required to firmly establish phenotypic features in the coinheritance of MODY with GCK and HNF1A variants. The accumulation of data on genetically confirmed MODY associated with the coinheritance of GCK and HNF1A variants will be useful for understanding genotype-phenotype correlations.

Lower achievement of guideline recommended care in Canadian adults with early-onset diabetes: A population-based cohort study

AimsAdults with early-onset diabetes (age < 40 years) have an increased risk of complications, and it is unclear whether they are receiving guideline recommended care. We compared the frequency and results of haemoglobin A1c (HbA1c) testing in adults with early-onset and usual-onset diabetes and assessed factors related to guideline concordance. MethodsPopulation-level databases from Alberta, Canada (∼4.5 million) were used to identify adults with incident diabetes. The cohort was stratified by age at diagnosis (< 40 vs. ≥ 40 years) and then followed for 365 days for HbA1c testing. Adjusted multivariable analyses were used to identify clinical and sociodemographic factors associated with guideline concordance. ResultsAmong 23,643 adults with incident diabetes (mean age 54.1 ± 15.4 years; 42.1 % female), 18.9 % had early-onset diabetes. Early-onset diabetes was associated with lower frequency of testing (adjusted odds ratio (aOR), 0.80; 95 % CI 0.70–0.90) and above target glycaemic levels compared to usual-onset diabetes (aOR, 1.45; 95 % CI 1.29–1.64). Factors associated with guideline concordant frequency of HbA1c testing were rural residence and insulin use. ConclusionsIn our universal care setting with premium-free health care, early-onset diabetes was associated with lower rates of HbA1c testing and sub-optimal glycaemic control compared to those with usual-onset diabetes.

352-OR: Selective Loss of the Spliced Form of Xbp1 Causes Early-Onset Diabetes in Male but Not Female Mice

352-OR: Selective Loss of the Spliced Form of Xbp1 Causes Early-Onset Diabetes in Male but Not Female Mice

Familial Mediterranean fever gene variations could trigger VPS16-associated early-onset dystonia and diabetes mellitus: clinical identification of a family with MEFV and VPS16 genetic variation association.

We describe the clinical pictures of an index case with dystonia and his family resulting from VPS16 and MEFV genetic variations based on previously published data and discuss the mechanisms that may have brought out the clinical findings. A 17-year-old male had generalized dystonia that started at age 6 years, non-febrile abdominal pain attacks and was diagnosed with type 1 diabetes at age 14 years. Meanwhile, his 13-year-old sister had the same clinical presentation. His father was diabetic and his mother was asymptomatic. There was no consanguinity between the parents. Genetic variations were detected with whole exome sequencing. VPS16 c.1513C>T/p.Arg505* (likely pathogenic), MEFV c.2080A>G p.Met694val (pathogenic) and MEFV c.1772T>C p.Ile591Thr (unknown significance) heterozygous variants were detected in his siblings. The father had VPS16 c.1513C>T/p.Arg505* and MEFV c.2080A>G p Met694val variations and the mother had MEFV c.1772T>C p.Ile591Thr variations. The occurrence of these diseases in siblings but their absence in the parents suggests the idea that the coexistence of two separate variations in the VPS16 and MEFV genes determines the phenotype. In addition, the increase in MEFV variation load in this family and the fact that DM occurs at an earlier age suggest that inflammation may cause an early diabetic clinical presentation.

Discovery and validation of a novel inhibitor of HYPE-mediated AMPylation.

Adenosyl monophosphate (AMP)ylation (the covalent transfer of an AMP from Adenosine Triphosphate (ATP) onto a target protein) is catalyzed by the human enzyme Huntingtin Yeast Interacting Partner E (HYPE)/FicD to regulate its substrate, the heat shock chaperone binding immunoglobulin protein (BiP). HYPE-mediated AMPylation of BiP is critical for maintaining proteostasis in the endoplasmic reticulum and mounting a unfolded protein response in times of proteostatic imbalance. Thus, manipulating HYPE's enzymatic activity is a key therapeutic strategy towardthe treatment of various protein misfolding diseases, including neuropathy and early-onset diabetes associated with two recently identified clinical mutations of HYPE. Herein, we present an optimized, fluorescence polarization-based, high-throughput screening (HTS) assay to discover activators and inhibitors of HYPE-mediated AMPylation. After challenging our HTS assay with over 30,000 compounds, we discovered a novel AMPylase inhibitor, I2.10. We also determined a low micromolar IC50 for I2.10 and employed biorthogonal counter-screens to validate its efficacy against HYPE's AMPylation of BiP. Further, we report low cytotoxicity of I2.10 on human cell lines. We thus established an optimized, high-quality HTS assay amenable to tracking HYPE's enzymatic activity at scale, and provided the first novel small-molecule inhibitor capable of perturbing HYPE-directed AMPylation of BiP in vitro. Our HTS assay and I2.10 compound serve as a platform for further development of HYPE-specific small-molecule therapeutics.

Etiologies underlying subtypes of long-standing type 2 diabetes.

Attempts to subtype, type 2 diabetes (T2D) have mostly focused on newly diagnosed European patients. In this study, our aim was to subtype T2D in a non-white Emirati ethnic population with long-standing disease, using unsupervised soft clustering, based on etiological determinants. The Auto Cluster model in the IBM SPSS Modeler was used to cluster data from 348 Emirati patients with long-standing T2D. Five predictor variables (fasting blood glucose (FBG), fasting serum insulin (FSI), body mass index (BMI), hemoglobin A1c (HbA1c) and age at diagnosis) were used to determine the appropriate number of clusters and their clinical characteristics. Multinomial logistic regression was used to validate clustering results. Five clusters were identified; the first four matched Ahlqvist et al subgroups: severe insulin-resistant diabetes (SIRD), severe insulin-deficient diabetes (SIDD), mild age-related diabetes (MARD), mild obesity-related diabetes (MOD), and a fifth new subtype of mild early onset diabetes (MEOD). The Modeler algorithm allows for soft assignments, in which a data point can be assigned to multiple clusters with different probabilities. There were 151 patients (43%) with membership in cluster peaks with no overlap. The remaining 197 patients (57%) showed extensive overlap between clusters at the base of distributions. Despite the complex picture of long-standing T2D with comorbidities and complications, our study demonstrates the feasibility of identifying subtypes and their underlying causes. While clustering provides valuable insights into the architecture of T2D subtypes, its application to individual patient management would remain limited due to overlapping characteristics. Therefore, integrating simplified, personalized metabolic profiles with clustering holds greater promise for guiding clinical decisions than subtyping alone.