Maturity-onset Diabetes Of Young Research Articles

Clinical and Laboratory Characteristics of MODY (Maturity Onset Diabetes of Young) Cases, Genetic Mutation Spectrum and Phenotype-genotype Relationship.

Maturity-onset diabetes of the young (MODY) occurs due to mutations in genes involved in pancreatic beta cell function and insulin secretion, has heterogeneous clinical and laboratory features, and account for 1-5% of all diabetes cases. The prevalence and distribution of MODY subtypes vary between countries. The aim of this study was to evaluate the clinical and laboratory characteristics, mutation distribution, and phenotype-genotype relationship in a large case series of pediatric Turkish patients genetically diagnosed with MODY. MODY cases from 14 different pediatric endocrinology departments were included. Diagnosis, treatment, follow-up data, and results of genetic analysis were evaluated. A total of 224 patients were included, of whom 101 (45%) were female, and the mean age at diagnosis was 9.4±4.1 years. Gene variant distribution was: 146 (65%) GCK; 43 (19%) HNF1A; 8 (3.6%) HNF4A, 8 (3.6%) KLF11 and 7 (3.1%) HNF1B. The remaining 12 variants were: PDX (n=1), NEUROD1 (n=3), CEL (n=1), INS (n=3), ABCC8 (n=3) and KJNC11 (n=1). Of the cases, 197 (87.9%) were diagnosed with incidental hyperglycemia, 16 with ketosis (7%) and 7 (3%) with diabetic ketoacidosis (DKA), while 30% presented with classical symptoms of diabetes. Two-hundred (89%) had a family history of diabetes. Anti-GAD antibody was detected in 13 cases, anti-islet antibody in eight and anti-insulin antibody in four. Obesity was present in 16. Distribution of therapy was: 158 (71%) diet only; 23 (11%) intensive insulin treatment; 17 (7.6%) sulfonylureas; 10 (4.5%) metformin; and 6 (2.7%) insulin and oral antidiabetic treatment. This was the largest genetically diagnosed series from Turkey. The most common gene variants were GCK and HNF1A with much lower proportions for other MODY types. Hyperglycemia was the most common presenting symptom while 11% of patients had diabetes-associated autoantibodies and 7% were obese. The majority of patients received dietary management only.

MODY6 with NEUROD1 Mutation an Unusual Presentation in Adolescent: A Case Report

MODY( Maturity onset diabetes of young) is a rare monogenic type of diabetes and which comprises 1-5 % of all diabetes cases [1]. It is often misdiagnosed as either type 1 or type 2 diabetes mellitus in children and adolescents due to common clinical signs and symptoms. With the availability of genetic testing, an increasing number of cases of MODY are being reported. We are reporting a case of 15 years old male child who presented with hyperglycemia without metabolic acidosis. He started on standard insulin regimen in view of suspected type1 diabetes. Later he was detected with NEUROD1 mutation, which is associated with MODY6, and the child was put on oral hypoglycemic drug, Metformin. At present the child is not on medication and is euglycemic. NEUROD1 is one of the least reported mutations in MODY6, only 5-6 cases are reported from India, and we report the youngest case.

Identification of appropriate biochemical parameters and cut points to detect Maturity Onset Diabetes of Young (MODY) in Asian Indians in a clinic setting

Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes which is detected by genetic testing. We looked at clinical and biochemcial variables that could help detect possible MODY among Asian Indians with youth-onset diabetes. From the diabetes electronic medical records of a diabetes care centre in Chennai in southern India, demographic, anthropometric, and biochemical details of 34 genetically confirmed MODY participants were extracted. They were compared with patients with type 1 diabetes (T1D) (n = 1011) and type 2 diabetes (T2D) (n = 1605), diagnosed below 30 years of age. Clinical and biochemical variables including body mass index (BMI), glycated hemoglobin, HDL cholesterol, and C-peptide (fasting and stimulated) were analyzed to determine whether cut points could be derived to identify individuals who could be sent for genetic testing to diagnose or rule out MODY in this ethnic group. The age at diagnosis was higher for T2D (26.5 ± 4.0 years) compared to T1D (18.2 ± 6.1 years) and MODY (17.8 ± 6.0 years). Individuals with MODY had BMI, glycated hemoglobin, total cholesterol, triglycerides, HDL cholesterol, and C-peptide levels which were intermediate between T1D and T2D. The identified probable parameters and their cut points to identify cases for MODY genetic screening were BMI 21.2–22.7 kg/m2, glycated hemoglobin 7.2–10%, HDL cholesterol 43–45 mg/dl, fasting C -peptide, 1.2–2.1 ng/ml and stimulated C-peptide, 2.1–4.5 ng/ml. Asian Indians with MODY have clinical features that are intermediate between T1D and T2D and selected biochemical parameters, especially stimulated C peptide cut points were the most useful to diagnose MODY.

ODP166 Autoantibody Positivity and Random C-peptide Profile in Young Ethnic South Indian Population with Diabetes Mellitus

Abstract The islet cell autoantibody and beta-cell reserve profiles of young-onset diabetes patients in India are not only heterogeneous but also differ from those in the rest of the world. We sought to assess 3 standard islet cell autoantibodies and random C-peptide in the young ethnic South Indian population with diabetes mellitus attending the Endocrinology OPD of our tertiary care. A total of 190 young diabetes patients aged between 12-30 years were screened for inclusion in the study. Known cases of gestational diabetes and those on diabetogenic drugs were excluded. Additionally, those with clinical features suggestive of pancreatic diabetes or maturity-onset diabetes of young (MODY), or any diabetes-associated syndromic disorders were also excluded. Finally, 138 eligible young diabetes patients were included in the study. The islet cell autoantibodies against glutamic acid decarboxylase (GAD), insulinoma-associated protein-2 (IA-2), zinc transporter (ZnT8)was measured by sandwich ELISA technique using a human GAD ELISA kit (Euroimmun, Germany), human IA2 ELISA kit (Euroimmun, Germany), human ZnT8 ELISA kit (RSR diagnostics, USA) respectively. Random C-peptide was measured with chemiluminescence immunoassay analyser Advia Centaur XP. Diagnosis of T1DM was based on the requirement of immediate insulin replacement therapy for hyperglycemia with or without acute-onset ketosis with random C-peptide (<0.6 ng/ml) with /without any of islet cell antibodies. Diagnosis of T2DM is based on the history of control of hyperglycemia with oral hypoglycemic agents with documentation of adequate beta-cell reserve (random C-peptide ≥ 0.6 ng/ml) while maintaining euglycemia. Based on the patient characteristics, treatment profile, islet cell antibody status, and beta-cell reserve as assessed by random C-peptide levels, 82 were classified as T1DM, and 48 were classified as T2DM. The rest 8 patients were categorized as unclassified diabetes. GAD antibody was seen in 54(66%) of 82 T1DM patients. Islet cell autoantibody negativity was documented in 21(26%) of T1DM patients. IA-2 and ZnT8 antibodies contributed to an additional 7(8%) to islet cell antibody positivity in T1DM patients. IA-2 antibody positivity was low and random C-peptide was undetectable in many cases of T1DM in our study and is probably due to prolonged duration of diabetes in many T1DM patients. Autoantibody positivity was seen in 4(8%) T2DM patients. These patients need to be followed up for possible evolution of latent autoimmune diabetes in adults.

Diabetic Ketoacidosis (DKA) in Maturity Onset Diabetes of Young (MODY) associated with Sodium-glucose co-transporter-2 inhibitors (SGLT2i)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Unusual late presentation of maturity onset diabetes of young (MODY)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract #1185180: Case of Maturity Onset Diabetes of Young-Type V

Maturity Onset Diabetes of Young (MODY) is a rare cause of diabetes and accounts for 1-5% of cases and has an autosomal dominant mode of inheritance. Diagnostic criteria set forth for MODY include 1. Onset before 25 years of age in one family member 2. Presence of DM in two consecutive generations 3. Absence of β-cell autoantibodies 4. Sustained endogenous insulin secretion.

Abstract 61: Prevalence and clinical profile of maturity onset diabetes of the young among people with diabetes attending a tertiary care institute in North India

Background: Maturity onset diabetes of young (MODY) is considered to be the most underdiagnosed condition and correct diagnosis has a definite bearing on the outcome and clinical course of the disease.Aims and Objectives: To determine the prevalence and clinical profile of MODY among young diabetic patients attending Endocrinology department at SKIMS, India.Methods: This was a cross-sectional study involving 1094 consenting patients with diabetes and age of onset of diabetes (DM) ≤30 years (<25 years in 858 patients). All patients were screened for MODY using clinical criteria and MODY probability calculator (available on diabetesgenes.org). Patients with high clinical probability of MODY and negative anti-GAD65 antibody but fasting serum C-peptide levels >0.6 ng/ml were subjected to the Ala98Val polymorphism (SNP) in HNF1α gene.Results: The prevalence of MODY as per clinical criteria was 7.7%. The patients with MODY were younger (p<0.001), leaner (p<0.001), had younger age at onset of DM (p<0.001) and lower frequency of features of insulin resistance. Among 40patients who were subjected to SNP analysis in HNF1α gene (MODY3), the mutant genotype was seen in 20 (50%) patients.Conclusion: We report a higher prevalence of MODY3 in our young diabetic patients. A high index of suspicion is required to diagnose MODY as misdiagnosis and inappropriate treatment may have a significant impact on quality of life.

Abstract 71: Preserved beta cell function in long standing type 1 diabetes mellitus

Background: Maturity onset diabetes of young (MODY) may be misdiagnosed as type 1 or type 2 diabetes mellitus and there may be an overlap between MODY and type 1 diabetes. The presence of persistent endogenous insulin, after the “honey-moon period” has ended, should lead to evaluation of secondary causes of diabetes including MODY.Aim: To identify subjects with preserved beta cell function; utilizing urinary C-peptide/creatinine ratio (UCPCR) in those, who have been diagnosed and treated as Type 1 diabetes mellitus.Methodology: Hospital based cross sectional study, between February 2019 and February 2021 in 100 Subjects diagnosed as Type 1 DM for more than 3 years.Results: Mean age and duration of DM 14.17 years and 5.3years respectively. Among 18 who had family history of D.M, 7 subjects had 3 generation involvement. GAD antibodies (68%) were more prevalent compared to IA 2 antibodies (56%). 49% had presence of both Anti GAD and IA2 auto antibodies. Mean UCPCR was 0.17. UCPCR >0.2 (suggestive of preserved endogenous insulin secretion) was present in 8 subjects among study population. Among these 8 subjects, 4 subjects had history of DKA episodes, 3 subjects had family history of D.M. 3 subjects did not have either of the auto antibodies. Compared to UCPCR <0.2, subjects with UCPCR >0.2 had statistically significant lower Hba1c (p=0.005), high UCPCR values (p=0.001), high MODY probability scores (p=0.004).Conclusions: UCPCR can be used as a screening tool to identify cases who need further evaluation for secondary causes, including genetic testing for MODY.

Meta-analysis of HNF1A-MODY3 variants among human population.

Previously, numerous case-control studies have highlighted variants responsible for Maturity onset diabetes of young (MODY). However, these studies have been conducted among diverse populations and hence yielded contradictory results. We, therefore, performed a meta-analysis to precisely find the association of SNPs with the disease for the HNF1A gene. Meta-analysis of clinically defined studies deciphering mutations in the HNF1A gene responsible for the development of MODY3 was conducted among various populations to determine associations using statistical approaches. The curation of 505 research articles published between the years 2000-2021 was carried out. Visualization of data-related protocols and statistical-analysis were conducted, which led to the identification of highly prevalent mutations among different populations (majorly Europe). Further comparison between the frequencies of the control (healthy population) and test (diseased population) dataset generated through curation was performed. We identified nine MODY3 mutations (rs587776825, rs1169288, rs1800574, rs2464196, rs137853244, rs137853238, rs587780357, rs137853240 and rs137853243) at the genome-wide significance level ( p < 5.0 × 10-8). The present study confirmed that the data does not follow a normal distribution. Further, the data was confirmed to be a more homogenous type with frequencies having a significant association with the disease. This meta-analysis found significant associations of mutations in HNF1A with MODY3, consistent with previous studies. Our findings should help elucidate the mutations in a compiled form responsible for causing MODY3. The online version contains supplementary material available at 10.1007/s40200-022-00975-8.

Biomarkers: Tools for Discriminating MODY from Other Diabetic Subtypes.

Maturity Onset Diabetes of Young (MODY), characterized by the pancreatic b-cell dysfunction, the autosomal dominant mode of inheritance and early age of onset (often ≤25 years). It differs from normal type 1 and type 2 diabetes in that it occurs at a low rate of 1-5%, three-generational autosomal dominant patterns of inheritance and lacks typical diabetic features such as obesity. MODY patients can be managed by diet alone for many years, and sulfonylureas are also recommended to be very effective for managing glucose levels for more than 30 years. Despite rapid advancements in molecular disease diagnosis methods, MODY cases are frequently misdiagnosed as type 1 or type 2 due to overlapping clinical features, genetic testing expenses, and a lack of disease understanding. A timely and accurate diagnosis method is critical for disease management and its complications. An early diagnosis and differentiation of MODY at the clinical level could reduce the risk of inappropriate insulin or sulfonylurea treatment therapy and its associated side effects. We present a broader review to highlight the role and efficacy of biomarkers in MODY differentiation and patient selection for genetic testing analysis.

Therapeutic Effect of Sunflower Seeds and Flax Seeds on Diabetes.

Diabetes mellitus (DM) is a metabolic syndrome that is spreading like an epidemic throughout the world without any differentiation of races and ethnic groups and has become the cause of death worldwide. It is characterized by high levels of glucose in the blood and has different types classified on the basis of varying pathophysiology. Type 1 diabetes or insulin-dependent diabetes is characterized by insulin insufficiency due to autoimmune dysfunction. Type 2 diabetes or non-insulin-dependent diabetes results from the combination of resistance to insulin action or/and inadequate insulin secretion. Gestational diabetes (GDM) is defined as hyperglycemia due to insulin resistance during pregnancy. Other types include the monogenic type of DM such as neonatal diabetes mellitus (NDM), maturity-onset diabetes of young (MODY), and diabetes in metabolic syndrome. Diabetes is diagnosed by criteria given by American Diabetes Association (ADA) for different tests like fasting plasma glucose test and hemoglobin A1c test. It is characterized by polydipsia, polyphagia, hyperglycemia, and glucosuria. Diabetes mellitus is managed through medications but many studies have proven that consumption of particular foods leads to decreased glucose levels in diabetic patients. Seeds like sunflower and flax seeds have a role in the reduction of glucose levels and can be used to treat type 2 diabetes. The bioactive components in these seeds like chlorogenic acid in sunflower seeds and secoisolariciresinol diglucosoid are involved in the treatment of insulin resistance or insulin production. In different studies, different amounts of these seed extracts were consumed by rats and humans and it resulted in better glycemic control, which provides information that these seeds have anti-diabetic properties.

Ocular surface assessment in maturity-onset diabetes of the young

To examine ocular surface changes in patients with maturity-onset diabetes of young (MODY). Fifty patients with MODY who were transferred to Genetic Diagnosis Department of Diskapi Yildirim Beyazit Training and Research Hospital have been included. All patients were subjected to Ocular Surface Illness Index (OSDI) survey, shirmer test, invasive and non-invasive tear break up time (TBUT), cornea fluorescein, and Lissamine green dye tests. Lastly, meibography measurements have been completed using Sirius Scheimpflug camera (Sirius, CSO, Florence, Italy). All 50 patients had a glucokinase (GCK) mutation. MODY diagnosis time was 5.0 ± 5.5 years (range: 0–20 years) on an average. While the average HBa1c levels were 5.5 (range: 4.8–6.5, reference range: 4–6), none of the patients were diagnosed with diabetic retinopathy in fundus examination. There was no significant difference between MODY and control group in terms of OSDI score, Schirmer 1 test, meibomian gland loss, average BUT, TBUT ((p)0.05). Our work is the first one which specifically evaluates ocular surface in MODY patients. Contrary to the common concept that “dry eye is frequently seen in type 1 and type 2 DM,” we did not come across any significant difference between MODY and control group in ocular surface tests. It might be linked to the fact that not enough time had passed for DR or DES symptoms to be detected. Our patients’ average diabetes diagnosis length might be a short time span for clinical symptoms like DR and DES to show up.

Profiling Extracellular Long RNA Transcriptome in Human Plasma and Extracellular Vesicles for Biomarker Discovery.

SummaryThe recent discovery of extracellular RNAs in blood, including RNAs in extracellular vesicles (EVs), combined with low-input RNA-sequencing advances have enabled scientists to investigate their role in human disease. To date, most studies have been focusing on small RNAs, and methodologies to optimize long RNAs measurement are lacking. We used plasma RNA to assess the performance of six long RNA sequencing methods, at two different sites, and we report their differences in reads (%) mapped to the genome/transcriptome, number of genes detected, long RNA transcript diversity, and reproducibility. Using the best performing method, we further compare the profile of long RNAs in the EV- and no-EV-enriched RNA plasma compartments. These results provide insights on the performance and reproducibility of commercially available kits in assessing the landscape of long RNAs in human plasma and different extracellular RNA carriers that may be exploited for biomarker discovery.

Exceptional diazoxide sensitivity in hyperinsulinaemic hypoglycaemia due to a novel HNF4A mutation.

SummaryDiazoxide is the first-line treatment for patients with hyperinsulinaemic hypoglycaemia (HH). Approximately 50% of patients with HH are diazoxide resistant. However, marked diazoxide sensitivity resulting in severe hyperglycaemia is extremely uncommon and not reported previously in the context of HH due to HNF4A mutation. We report a novel observation of exceptional diazoxide sensitivity in a patient with HH due to HNF4A mutation. A female infant presented with severe persistent neonatal hypoglycaemia and was diagnosed with HH. Standard doses of diazoxide (5 mg/kg/day) resulted in marked hyperglycaemia (maximum blood glucose 21.6 mmol/L) necessitating discontinuation of diazoxide. Lower dose of diazoxide (1.5 mg/kg/day) successfully controlled HH in the proband, which was subsequently confirmed to be due to a novel HNF4A mutation. At 3 years of age, the patient maintains age appropriate fasting tolerance on low dose diazoxide (1.8 mg/kg/day) and has normal development. Diagnosis in proband’s mother and maternal aunt, both of whom carried HNF4A mutation and had been diagnosed with presumed type 1 and type 2 diabetes mellitus, respectively, was revised to maturity-onset diabetes of young (MODY). Proband’s 5-year-old maternal cousin, also carrier of HNF4A mutation, had transient neonatal hypoglycaemia. To conclude, patients with HH due to HNF4A mutation may require lower diazoxide than other group of patients with HH. Educating the families about the risk of marked hyperglycaemia with diazoxide is essential. The clinical phenotype of HNF4A mutation can be extremely variable.Learning points:Awareness of risk of severe hyperglycaemia with diazoxide is important and patients/families should be accordingly educated.Some patients with HH due to HNF4A mutations may require lower than standard doses of diazoxide.The clinical phenotype of HNF4A mutation can be extremely variable.

A rare case of maturity onset diabetes of young (MODY)

A rare case of maturity onset diabetes of young (MODY)

Body mass index and C-peptide are important for the promptly differential diagnosis of maturity-onset diabetes from familial type 2 diabetes in outpatient clinic.

Type 2 diabetic patients are becoming younger and having a tendency to family aggregation, they are easily suspected as maturity-onset diabetes of young (MODY) in the outpatient clinic and send to genetic testing. 9 diabetic families were compared in our outpatient clinic who met the primary diagnosis criteria of MODY. Detailed clinical features and laboratory data including gene sequence were collected and analyzed. The patients met the primary clinical diagnostic criteria of MODY for genetic testing at the first look. However, members of families A1 to A3 had normal Body mass index (BMI) and a lower C-peptide level which indicated impaired pancreatic islet function. In contrast, the members with diabetes of families B1 to B6 had normal or increased C-peptide level which indicated insulin resistance and were overweight with BMI. Genetic testing showed that the mutations in HNF1A, INS, KCNJ11 and so on in families A were consistent with the diagnosis of MODY. No pathogenic mutation was found in the members of families B which were diagnosed with familial T2D. Before the clinical laboratory testing and the further gene test, BMI and the concentration of C-peptide are important for the promptly differential diagnosis of MODY from familial type 2 diabetes and medication instruction in the outpatient clinic which could help to alleviate the burden of genetic testing for them.

COL4A3 Gene Variants and Diabetic Kidney Disease in MODY.

Despite advances in identifying genetic factors of diabetic kidney disease (DKD), much of the heritability remains unexplained. Nine maturity-onset diabetes in young (MODY) probands with kidney biopsy-proven DKD were selected and included in this study. The probands had more severe DKD compared with their parents with MODY, with overt proteinuria or rapid progression to ESKD. We aimed to explore the contribution of the variants in susceptibility genes of DKD to the severity of kidney phenotype between the probands and their parents. Whole-exome sequencing was performed to identify suspected MODY probands and their families. Known DKD susceptibility genes were reviewed. Variants reported to be associated with DKD, or those with minor allele frequency <0.05 and predicted to be pathogenic, were selected and analyzed. Immunofluorescence staining of COL4α3 was performed in kidney specimens of patients with DKD with or without R408H and M1209I of COL4A3 variants. HNF1B-MODY, CEL-MODY, PAX4-MODY, and WFS1-MODY were diagnosed among nine families. We identified 196 selected variants of 25 DKD susceptibility genes among the participants. Analysis of phenotype between probands and parents, gene function, and protein-protein interaction networks revealed that COL4A3 variants were involved in the progression of DKD. Weak granular staining of COL4α3 was observed in the glomerular basement membrane of patients with the R408H and M1209I variants, whereas strong consecutive staining was observed in patients without these variants. Moreover, more number of DKD variants were identified in probands than in their parents with MODY. The genetic effect of more pathogenic variants in various DKD susceptibility genes, especially variants in the COL4A3 gene, partially explained the more severe kidney phenotype in probands with kidney biopsy-proven DKD.

Maturity Onset Diabetes of the Young – An Overview of Common Types. A Review

Abstract Background and aims: Maturity Onset diabetes in Young (MODY) is an autosomal dominant disease and according to an estimate, the MODY cases are 2% of all the diabetic cases. The objective was to review the common types of MODY reported in literature in context to their geographical areas. Material and method: For literature search, PubMed data base was used. The key word was “Maturity onset diabetes of the young”. The articles were reviewed by titles and if found relevant, the abstract and full article (if available) were retrieved. The studies that were published in English, presented original data and describe type of MODY were included. The information related to author, year of publication and type of MODY was extracted in excel sheet. Results: A total of 1135 studies resulted which were reviewed, and 206 articles were finally selected. The studies were grouped according to the regions i.e. Asia, Europe, America, Africa and Australia &amp; Oceania. The MODY 2 was most prevalent in regions i.e. Asia, Europe, America and Australia &amp; Oceania followed by MODY 3. When analysed according to countries, MODY 2 was found prevalent in India, Korea, UK, Italy, Spain, Czech Republic, Canada and Brazil while MODY 3 was common in Japan, China, France Norway and Germany. Conclusion: The MODY 2 was most common. The data from south Asian countries including Pakistan is lacking. As there is a huge burden of diabetes in the country so there is a dire need to do large scale studies on MODY in the country.

A rare case of Diabetic ketoacidosis (DKA) in a patient with genetically confirmed maturity onset diabetes of young (MODY)

A rare case of Diabetic ketoacidosis (DKA) in a patient with genetically confirmed maturity onset diabetes of young (MODY)