1,390 results on '"mody"'
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2. MODY calculator applied in patients with clinical diagnosis of type 1 diabetes mellitus: Is a higher cutoff needed?
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Peghinelli, Vinícius Vigliazzi, De Sibio, Maria Teresa, Depra, Igor de Carvalho, Teles Bezerra, Milena Gurgel, Sakalem, Marna Eliana, Júnior, Adriano Francisco De Marchi, da Rocha, Paula Barreto, Tilli, Helena Paim, Gonçalves, Bianca Mariani, Vieira, Ester Mariane, Lourenço, Mariana Menezes, and Nogueira, Célia Regina more...
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- 2024
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3. Novel Treatment Options in Patients with Maturity-Onset Diabetes of the Young.
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Müssig, Karsten
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MATURITY onset diabetes of the young , *PANCREATIC beta cells , *INSULIN therapy , *HYPOGLYCEMIA , *BETA functions - Abstract
Maturity-onset diabetes of the young (MODY) is the most common monogenetic form of diabetes with an autosomal dominant inheritance pattern. MODY is caused by mutations in genes important for the development and function of pancreatic beta cells, resulting in impaired insulin secretion capacity. To date, 14 different types have been described. While glucokinase (GCK)-MODY (formerly MODY-2) generally requires no drug therapy, other forms of MODY, such as hepatocyte nuclear factor-1-alpha (HNF1A)-MODY (formerly MODY-3) and HNF4A (formerly MODY-1), usually respond very well to sulfonylurea therapy. However, these MODY forms are characterised by a progressive course, meaning that insulin therapy is often required as the disease progresses. Both sulfonylurea therapy and insulin therapy are associated with an increased risk of hypoglycaemia and frequent weight gain. Newer blood glucose-lowering therapies, such as SGLT2 inhibitors (SGLT2i), DPP-4 inhibitors (DPP4i) and GLP-1 receptor agonists (GLP-1RA), have a much lower risk of hypoglycaemia and usually have a favourable effect on body weight. This review aims to provide an overview of the treatment of MODY patients with SGLT2i, DPP4i and GLP-1RA on the basis of previously published clinical studies, case series and case reports. [ABSTRACT FROM AUTHOR] more...
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- 2025
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4. Recognition of GCK Homozygote missense (His424Tyr) variant in a female patient with neonatal hyperglycemia.
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Pashapour Yeganeh, Amirreza, Rahimi Farahani, Marjan, Panahi, Nekoo, Mohammad Amoli, Mahsa, Nickhah Klashami, Zeynab, Aghaei Meybodi, Hamid Reza, and Soltani, Akbar
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TYPE 1 diabetes , *ETIOLOGY of diabetes , *MATURITY onset diabetes of the young , *GENETIC testing , *LASER photocoagulation , *GESTATIONAL diabetes - Abstract
Introduction: Heterozygous mutations in the GCK gene result in mildly elevated glucose levels from birth, and the homozygous loss-of-function mutations leads to permanent neonatal diabetes. In the present study we aim to investigate the cause of diabetes in an adult female patient with unusual course of diabetes. Case presentation: We evaluate a female patient who previously encountered significant hyperglycemia during the infancy and subsequently experienced a relatively uneventful childhood. In later years, she faced significant hyperglycemia and retinopathy that required laser photocoagulation. Her treatment history included periods of oral hypoglycemic agents or insulin, which occasionally led to hypoglycemia, as well as extended intervals without treatment. However, she never required hospitalization for diabetic ketoacidosis. The patient's family history was significant, with her parents being cousins and having a history of prediabetes and gestational diabetes in several family members. Autoantibody tests for type 1 diabetes were negative. Next-generation sequencing analysis of the coding regions and conserved splice sites of several genes identified a homozygous GCK (T/T) missense (His424Tyr) variant, which was validated by Sanger sequencing. Heterozygous C/T mutations were revealed in the parents. Discussion and Conclusion: This case highlights the importance of considering homozygous GCK mutations as a potential cause of persistent neonatal diabetes, especially in patients with a history of elevated glucose levels from infancy, a family history of early-onset non-progressive diabetes and gestational diabetes, and parental consanguinity. Genetic testing can help identify the underlying genetic etiology in such cases. Early diagnosis is crucial to guide appropriate treatment and management strategies. [ABSTRACT FROM AUTHOR] more...
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- 2024
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5. Feasibility of a 12 weeks supervised exercise training intervention among people with Maturity Onset Diabetes of the Young (MODY) or type 2 diabetes in Greenland.
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Motzfeldt, Laila, Ried-Larsen, Mathias, Hovden, Freya Jørgensen, Eika-Jørgensen, Marit, Pedersen, Michael Lynge, and Nielsen, Maja Hykkelbjerg
- Abstract
Preventing and managing Type 2 diabetes (T2D) involves adopting healthy lifestyle habits such as balanced nutrition and regular exercise. Maturity Onset Diabetes of The Young (MODY) shares diagnostic characteristics with T2D, but exercise responses in MODY remain unclear. In Greenland, MODY is 4–5 times more common than in other countries. No established exercise regimen exists for either T2D or MODY in Greenland. This study assessed the feasibility of a 12-week supervised exercise programme for MODY and T2D in Greenland, focusing on attendance, satisfaction, and effects on cardiovascular disease (CVD) risk factors and quality of life (QoL). Conducted as an experimental, two-armed, controlled trial, nine participants (4 with MODY) engaged in prescribed training sessions twice weekly for 45–60 minutes, while another nine (4 with MODY) formed the control group. Key outcomes included adherence rates, satisfaction levels, changes in HbA1c, body composition, aerobic fitness, blood pressure, CVD risk factors, and SF-12 scores. Although training adherence was modest at 56%, participant satisfaction remained high. Notable findings included a slight decrease of −0.3 mmol/l in HDL-cholesterol and a 5.7-point increase in the mental component (MCS) of SF-12 within the intervention group. However, the study underscores the need to refine the study design before supervised exercise programmes can be widely implemented in clinical settings in Greenland. [ABSTRACT FROM AUTHOR] more...
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- 2024
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6. Clinical characteristics, treatment, and treatment switch after molecular‐genetic classification in individuals with maturity‐onset diabetes of the young: Insights from the multicenter real‐world DPV registry.
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Lanzinger, Stefanie, Laubner, Katharina, Warncke, Katharina, Mader, Julia K., Kummer, Sebastian, Boettcher, Claudia, Biester, Torben, Galler, Angela, Klose, Daniela, and Holl, Reinhard W.
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TYPE 1 diabetes , *MATURITY onset diabetes of the young , *PANCREATIC beta cells , *ORAL medication , *INSULIN therapy - Abstract
Background: Individuals with maturity‐onset diabetes of the young (MODY) are often misdiagnosed as type 1 or type 2 diabetes and receive inappropriate care. We aimed to investigate the characteristics and treatment of all MODY types in a multicenter, real‐world setting. Methods: Individuals with MODY from the diabetes prospective follow‐up (DPV) registry were studied. We compared clinical parameters during the first year of diabetes and the most recent treatment year after MODY diagnosis. Results: A total of 1640 individuals were identified with GCK‐MODY (n = 941) and HNF1A‐MODY (n = 417) as the most frequent types. Among these, 912 individuals were available with information during the first and the most recent treatment year (median duration of follow‐up: 4.2 years [2.6–6.6]). Positive beta cell autoantibodies were present in 20.6% (15.2% IAA). Median age at diagnosis ranged from 9.9 years in GCK‐MODY (Q1–Q3: 6.2–13.1 years) and INS‐MODY (2.7–13.7 years) to 14.3 years (5.0–17.1) in KCNJ11‐MODY. Frequency of oral antidiabetic agents (OAD) use increased and insulin decreased in HNF4A‐MODY (OAD: 18% to 39%, insulin: 34% to 23%) and in HNF1A‐MODY (OAD: 18% to 31%, insulin: 35% to 25%). ABCC8‐MODY was characterized by a decrement in nonpharmacological treatment (26% to 16%) and "insulin only" treatment (53% to 42%), while the proportion of individuals treated with OAD but no insulin increased from 0% to 21%. Conclusions: Our results indicate that some teams caring for individuals with MODY are hesitant with regard to current recommendations. Registries are an essential source of information and provide a basis for discussing treatment guidelines for MODY. [ABSTRACT FROM AUTHOR] more...
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- 2024
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7. Modelling human diabetes ex vivo: a glance at maturity onset diabetes of the young.
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Ka, Moustapha, Hawkins, Eleanor, Pouponnot, Celio, and Duvillié, Bertrand
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MATURITY onset diabetes of the young ,TYPE 2 diabetes ,DRUG discovery ,METABOLIC disorders ,TRANSGENIC mice ,PANCREATIC beta cells ,ISLANDS of Langerhans - Abstract
Diabetes is a complex metabolic disease which most commonly has a polygenic origin; however, in rare cases, diabetes may be monogenic. This is indeed the case in both Maturity Onset Diabetes of the Young (MODY) and neonatal diabetes. These disease subtypes are believed to be simpler than Type 1 (T1D) and Type 2 Diabetes (T2D), which allows for more precise modelling. During the three last decades, many studies have focused on rodent models. These investigations provided a wealth of knowledge on both pancreas development and beta cell function. In particular, they allowed the establishment of a hierarchy of the transcription factors and highlighted the role of microenvironmental factors in the control of progenitor cell proliferation and differentiation. Transgenic mice also offered the possibility to decipher the mechanisms that define the functional identity of the pancreatic beta cells. Despite such interest in transgenic mice, recent data have also indicated that important differences exist between mice and human. To overcome these limitations, new human models are necessary. In the present review, we describe these ex vivo models, which are created using stem cells and organoids, and represent an important step toward islet cell therapy and drug discovery. [ABSTRACT FROM AUTHOR] more...
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- 2024
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8. Pedigree Analysis of Maturity-Onset Diabetes of the Young: ABCC8 Mutations?
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Xiaofang Fan, Lingxiao Wang, and Pingping Hong
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MATURITY onset diabetes of the young ,GENETIC testing ,GENEALOGY - Abstract
Background: Maturity-Onset Diabetes of the Young (MODY) is an autosomal dominant disease, caused by mutations in the ABCC8 gene, chromosome 11. Methods: A case suspected of MODY due to an ABCC8 mutation was examined using whole-genome exon heighthroughput sequencing. Selected variant sites were validated via Sanger sequencing. Results: A heterozygous mutation c.2060C>T (p.T687M) in exon 15 of the ABCC8 gene (Chr11-174494701) was identified in both the proband and the father. This mutation was initially linked to MODY based on clinical features. Conclusions: For patients with high suspicion of MODY, genetic test should conducted to improve their quality of life. [ABSTRACT FROM AUTHOR] more...
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- 2024
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9. Our Experiences and Learnings in Diagnosing MODY from Non-Institutional-Based Diabetes Care Clinics
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Arunkumar R. Pande, Santosh Chaubey, Dinesh Kumar, Kumar P. Chandra, Thenral Geetha, and Akshita Sharma
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hnf1a mody ,mody ,monogenic diabetes ,pediatric diabetes ,young diabetes ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Introduction: Maturity-onset diabetes of the young (MODY) is a rare group of disorders characterised by impaired functions or development of pancreatic islets and monogenic diabetes at a young age. Diagnosing MODY can be rewarding for both clinicians and patients as it can change the management from generic to targeted therapy. Methods: This study reports the retrospective analysis of data collected from four clinics between March 2016 and February 2023 from Lucknow, a city in northern India. Fifty-three individuals are suspected to be affected by MODY based on ISPAD guidelines. Following a detailed clinical evaluation, they were referred for genetic diagnostic testing. Results: The cohort consists of 19 females and 34 males with a mean age of diagnosis of 25.3 years and a body mass index of 22.3 Kg/m2. Genetic testing detected variants in 13/53 (~24.5%) individuals. Five cases had significant pathogenic/likely pathogenic variants, HNF1A gene in two [(p.Phe268LeufsTer74) (p.Arg200Gln)], one each in HNF4A (Arg311His), PDX1(p.Ala228GlyfsTer33), and a case with suggestive digenic variants in HNF1A gene (p.Arg200Gln) and HNF1B [(p.Leu13Met)]. Variants of uncertain significance (VUSs) with inconclusive evidence of pathogenicity were reported in eight patients, and five were considered to be clinically significant as they are lean young onset, sulfonylurea-responsive, and presented with diabetes without acanthosis nigricans and with high pretest probability. These individuals harboured variants in HNF1A (p.Thr425_Thr429delinsPro), HNF1B (p.Ser19Phe), CEL (p.Val681ArgfsTer6), ABCC8 (p.Ile872Met), and KCNJ11 (p.Arg221Cys) genes. Conclusion: We found a diagnostic yield of around 10% of pathogenic or likely pathogenic variants in individuals who were suspected to have MODY. As it is a field that is still evolving, we might consider starting with oral agents under close supervision in those individuals who have VUS; there are some proportions of individuals who might not have classical sulfonylurea-responsive genetic variants, but they might respond to it. more...
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- 2024
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10. A polygenic risk score derived from common variants of monogenic diabetes genes is associated with young-onset type 2 diabetes and cardiovascular–kidney complications.
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O, Chun-Kwan, Fan, Baoqi, Tsoi, Sandra T. F., Tam, Claudia H. T., Wan, Raymond, Lau, Eric S. H., Shi, Mai, Lim, Cadmon K. P., Yu, Gechang, Ho, Jane P. Y., Chow, Elaine Y. K., Kong, Alice P. S., Ozaki, Risa, So, Wing Yee, Ma, Ronald C. W., Luk, Andrea O. Y., and Chan, Juliana C. N. more...
- Abstract
Aims/hypothesis: Monogenic diabetes is caused by rare mutations in genes usually implicated in beta cell biology. Common variants of monogenic diabetes genes (MDG) may jointly influence the risk of young-onset type 2 diabetes (YOD, diagnosed before the age of 40 years) and cardiovascular and kidney events. Methods: Using whole-exome sequencing data, we constructed a weighted polygenic risk score (wPRS) consisting of 135 common variants (minor allele frequency >0.01) of 34 MDG based on r
2 >0.2 for linkage disequilibrium in a discovery case–control cohort of 453 adults with YOD (median [IQR] age 39.7 [34.9–46.9] years) and 405 without YOD (median [IQR] age 56.7 [50.3–61.0] years), followed by validation in an independent cross-sectional cohort with array-based genotyping for YOD and a prospective cohort of individuals with type 2 diabetes for cardiovascular and kidney events. Results: In the discovery cohort, the OR of the 135 common variants for YOD ranged from 1.00 to 2.61. In the validation cohort (920 YOD and 4910 non-YOD), top-10%-wPRS was associated with an OR of 1.42 (95% CI 1.03, 1.95, p=0.033) for YOD compared with bottom-10%-wPRS. In 2313 individuals with type 2 diabetes (median [IQR]: age 53.4 [45.4–61.7] years; disease duration 4.0 [1.0–9.0] years) observed for a median (IQR) of 17.5 (14.4–21.8) years, standardised wPRS was associated with increased HR for incident cardiovascular events (1.16 [95% CI 1.06, 1.27], p=0.001), kidney events (1.09 [95% CI 1.02, 1.16], p=0.013) and cardiovascular–kidney events (1.10 [95% CI 1.03, 1.16], p=0.003). Using the 'bottom-20%-wPRS plus baseline disease duration <5 years' group as referent, the 'top-20%-wPRS plus baseline disease duration 5 to <10 years' group had unadjusted and adjusted HR of 1.60 (95% CI 1.17, 2.19, p=0.003) and 1.62 (95% CI 1.16, 2.26, p=0.005), respectively, for cardiovascular–kidney events compared with 1.38 (95% CI 0.97, 1.98, p=0.075) and 1.06 (95% CI 0.72, 1.57, p=0.752) in the 'bottom-20%-wPRS plus baseline disease duration ≥10 years' group. Conclusions/interpretation: Common variants of MDG increased risk for YOD and cardiovascular–kidney events. [ABSTRACT FROM AUTHOR] more...- Published
- 2025
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11. Clinical Utility of Serial Monitoring of C-Peptide in Diagnostic Dilemmas of Young-Onset Diabetes: A Case-Based Discussion
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Praveen Gangadhara, Ranjit Mohan Anjana, Ranjit Unnikrishnan, and Viswanathan Mohan
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c-peptide ,mody ,young-onset diabetes ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Diabetes in the young has been traditionally defined as onset of diabetes below 35 years of age. In this age bracket, a variety of distinct types of diabetes might occur which poses a unique challenge in the diagnosis and management. Phenotypic features such as age of onset, presence of obesity and family history have traditionally been used in differentiating the various types of diabetes. With the increasing prevalence of obesity and T2DM in youth, these features have become less reliable in classifying diabetes in this age group. Along with detailed patient history and physical examination, biochemical parameters such as C-peptide and presence or absence of pancreatic autoantibodies (along with imaging studies for pancreatic pathology and genetic testing for monogenic forms of diabetes) are assuming greater importance in appropriate diagnosis and understanding the types of diabetes. C-peptide test which is a proxy for pancreatic beta cell function plays an important role in classifying type / subtypes of diabetes. When used appropriately it also helps in personalized approach to treatment and practice of Precision Diabetes. more...
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- 2024
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12. Characteristics of patients with diagnosis of maturity-onset diabetes of the young, according to the Russian diabetes registry
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N. V. Rusyaeva, I. V. Kononenko, O. K. Vikulova, M. A. Isakov, M. V. Shestakova, and N. G. Mokrysheva
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diabetes mellitus ,maturity-onset diabetes of the young ,mody ,diagnosis ,federal diabetes registry ,Nutritional diseases. Deficiency diseases ,RC620-627 - Abstract
BACKGROUND: Molecular genetic testing (MGT) is increasingly accessible, improving diagnosis of monogenic diabetes (DM), particularly maturity-onset diabetes of the young (MODY). While most MODY research focuses on pediatric populations, diagnosis is possible after age 18. The Federal Diabetes Registry (FDR) offers unique insights into real-world management of MODY patients.AIM: To analyze the clinical features of DM onset, carbohydrate metabolism, complications, and hypoglycemic therapy (HT) in patients with the main types of MODY based on the FDR data.MATERIALS AND METHODS: A cross-sectional analysis of the FDR was conducted. All patients with registered MODY diagnoses (MODY-1, MODY-2, MODY-3, or other) as of June 1, 2023, were included. The specified MODY type was considered indicative of prior MGT. Direct MGT results are not recorded in the FDR.RESULTS: The study included 640 patients. MODY2 was the most prevalent type (69.4%), followed by MODY1 (18.2%) and MODY3 (12.4%). The median age of DM diagnosis was 19 years for MODY1, 10 years for MODY2, and 14 years for MODY3. The majority of patients (71.4%) were diagnosed with MODY before the age of 18 years.While 61% of MODY2 patients received monotherapy with diet, others received various ADT. Sulfonylureas were commonly prescribed for MODY3 patients (45.8%), and for a smaller portion of MODY1 patients (14.1%). Insulin therapy was more frequent in MODY1 and 3 (35.9% and 31.2%, respectively). The target glycated hemoglobin level was achieved in 82% of MODY2 patients and in 50.7% and 52.9% of MODY1 and 3 patients, respectively.Diabetic complications were observed in 6.04% of MODY2 patients, 23.0% of MODY1 patients, and 22.0% of MODY3 patients. Specific complications included diabetic retinopathy (5.75%, 1.21%, and 3.39% in MODY1, MODY2, and MODY3, respectively), diabetic nephropathy (10.3%, 2.11%, and 11.9%), and diabetic polyneuropathy (14.9%, 4.53%, and 15.3%).CONCLUSION: The FDR analysis revealed real-world practice patterns in MODY management, highlighting a lack of standardized treatment approaches and potentially unnecessary insulin use. These findings, coupled with an expected rise in MODY diagnoses, underscore the need for clinical guidelines for this population. more...
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- 2024
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13. Clinical and Laboratory Characteristics of MODY Cases, Genetic Mutation Spectrum and Phenotype-genotype Relationship
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Elif Özsu, Semra Çetinkaya, Semih Bolu, Nihal Hatipoğlu, Şenay Savaş Erdeve, Olcay Evliyaoğlu, Firdevs Baş, Atilla Çayır, İsmail Dündar, Emine Demet Akbaş, Seyid Ahmet Uçaktürk, Merih Berberoğlu, Zeynep Şıklar, Şervan Özalkak, Nursel Muratoğlu Şahin, Melikşah Keskin, Ülkü Gül Şiraz, Hande Turan, Ayşe Pınar Öztürk, Eda Mengen, Elif Sağsak, Fatma Dursun, Nesibe Akyürek, Sevinç Odabaşı Güneş, and Zehra Aycan more...
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childhood ,mody ,diagnosis ,Pediatrics ,RJ1-570 ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
INTRODUCTION: 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. METHODS: MODY cases from 14 different pediatric endocrinology departments were included. Diagnosis, treatment, follow-up data, and results of genetic analysis were evaluated. RESULTS: 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 anti-diabetic treatment. DISCUSSION AND CONCLUSION: 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. more...
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- 2024
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14. Examining the clinical and genetic spectrum of maturity-onset diabetes of the young (MODY) in Iran
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Sara Asgarian, Hossein Lanjanian, Shiva Rahimipour Anaraki, Farzad Hadaegh, Maryam Moazzam-Jazi, Leila Najd-Hassan-Bonab, Sajedeh Masjoudi, Asiyeh Sadat Zahedi, Maryam Zarkesh, Bita Shalbafan, Mahdi Akbarzadeh, Sahand Tehrani Fateh, Davood Khalili, Amirabbas Momenan, Narges Sarbazi, Mehdi Hedayati, Fereidoun Azizi, and Maryam S. Daneshpour more...
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Maturity-onset diabetes of the young ,MODY ,Monogenic diabetes ,HNF1A ,HNF4A ,GCK ,Medicine ,Science - Abstract
Abstract Maturity-onset diabetes of the young (MODY) is an uncommon monogenic type of diabetes mellitus. Detecting genetic variants for MODY is a necessity for precise diagnosis and treatment. The majority of MODY genetic predisposition has been documented in European populations and a lack of information is present in Iranians which leads to misdiagnosis as a consequence of defects in unknown variants. In this study, using genetic variant information of 20,002 participants from the family-based TCGS (Tehran Cardiometabolic Genetic Study) cohort, we evaluated the genetic spectrum of MODY in Iran. We concentrated on previously discovered MODY-causing genes. Genetic variants were evaluated for their pathogenicity. We discovered 6 variants that were previously reported in the ClinVar as pathogenic/likely pathogenic (P/LP) for MODY in 45 participants from 24 families (INS in 21 cases, GCK in 13, HNF1B in 8, HNF4A, HNF1A, and CEL in 1 case). One potential MODY variant with Uncertain Risk Allele in ClinVar classification was also identified, which showed complete disease penetrance (100%) in four subjects from one family. This is the first family-based study to define the genetic spectrum and estimate the prevalence of MODY in Iran. The discovered variants need to be investigated by additional studies. more...
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- 2024
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15. Course of pregnancy and 10-year observation of twins diagnosed with GCK-MODY in the neonatal period: a case report.
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Katra, Barbara and Szopa, Magdalena
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MATURITY onset diabetes of the young ,DIETARY patterns ,FOOD habits ,MULTIPLE pregnancy ,GLUCOKINASE - Abstract
Monogenic diabetes accounts for 5% of all incidence of hyperglycemia and Maturity Onset Diabetes of the Young (MODY) is the most common form. In GCK-MODY, one of the most common forms of MODY, hyperglycemia is caused by a mutation of a gene responsible for coding glucokinase. At the clinical level, this condition presents as persistent, moderate and asymptomatic elevated fasting glucose levels and has a relatively low incidence of micro and macrovascular complications. In general, the treatment of choice is to follow and maintain a healthy lifestyle. The incidence of GCK-MODY during pregnancy is 2% on average (0-6%). In this report, we introduce a case of a woman diagnosed with GCK-MODY during the pregnancy with twins, a boy and a girl, diagnosed with GCK-MODY after birth. We discuss the course of pregnancy, the need for access to fast and uncomplicated genetic diagnostics in utero, and the impact of the MODY diagnosis on the life of the mother and that of her children. In our case, the diagnosis of GCK-MODY was associated with a feeling of relief, after years of uncertainty, and helped to introduce more appropriate eating behaviors and lifestyle changes for both the mother and her children. [ABSTRACT FROM AUTHOR] more...
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- 2024
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16. Monogenic Defects of Beta Cell Function: From Clinical Suspicion to Genetic Diagnosis and Management of Rare Types of Diabetes.
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Serbis, Anastasios, Kantza, Evanthia, Siomou, Ekaterini, Galli-Tsinopoulou, Assimina, Kanaka-Gantenbein, Christina, and Tigas, Stelios
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MATURITY onset diabetes of the young , *DIABETES in children , *TYPE 1 diabetes , *PANCREATIC beta cells , *GENETIC counseling - Abstract
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. [ABSTRACT FROM AUTHOR] more...
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- 2024
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17. Clinical Utility of Serial Monitoring of C-Peptide in Diagnostic Dilemmas of Young-Onset Diabetes: A Case-Based Discussion.
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Gangadhara, Praveen, Mohan Anjana, Ranjit, Unnikrishnan, Ranjit, and Mohan, Viswanathan
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DIAGNOSIS of diabetes ,OBESITY complications ,GENETICS of diabetes ,PANCREATIC physiology ,DIABETES prevention ,PHYSICAL diagnosis ,COMBINATION drug therapy ,METFORMIN ,RADIOIMMUNOASSAY ,GLYCOSYLATED hemoglobin ,PANCREATIC beta cells ,AUTOANTIBODIES ,DISEASE management ,ENZYME inhibitors ,HYPOGLYCEMIC agents ,DIABETIC acidosis ,TREATMENT effectiveness ,C-peptide ,AGE factors in disease ,PANCREAS ,INSULIN aspart ,TYPE 2 diabetes ,INDIVIDUALIZED medicine ,DIABETES ,PHENOTYPES ,GENETIC testing ,BIOMARKERS ,BLOOD sugar monitoring ,DISEASE risk factors ,SYMPTOMS ,ADULTS - Abstract
Diabetes in the young has been traditionally defined as onset of diabetes below 35 years of age. In this age bracket, a variety of distinct types of diabetes might occur which poses a unique challenge in the diagnosis and management. Phenotypic features such as age of onset, presence of obesity and family history have traditionally been used in differentiating the various types of diabetes. With the increasing prevalence of obesity and T2DM in youth, these features have become less reliable in classifying diabetes in this age group. Along with detailed patient history and physical examination, biochemical parameters such as C-peptide and presence or absence of pancreatic autoantibodies (along with imaging studies for pancreatic pathology and genetic testing for monogenic forms of diabetes) are assuming greater importance in appropriate diagnosis and understanding the types of diabetes. C-peptide test which is a proxy for pancreatic beta cell function plays an important role in classifying type / subtypes of diabetes. When used appropriately it also helps in personalized approach to treatment and practice of Precision Diabetes. [ABSTRACT FROM AUTHOR] more...
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- 2024
- Full Text
- View/download PDF
18. Whole Exome Sequencing in Children With Type 1 Diabetes Before Age 6 Years Reveals Insights Into Disease Heterogeneity.
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Ribeiro, Andreia Fiúza, Fitas, Ana Laura, Pires, Marcela Oliveira, Matoso, Paula, Ligeiro, Dário, Sobral, Daniel, Penha-Gonçalves, Carlos, Demengeot, Jocelyne, Caramalho, Íris, Limbert, Catarina, and Amrani, Abdelaziz more...
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TYPE 1 diabetes , *MATURITY onset diabetes of the young , *DISEASE risk factors , *DIABETES in children , *SYMPTOMS - Abstract
Aims: This study is aimed at comparing whole exome sequencing (WES) data with the clinical presentation in children with type 1 diabetes onset ≤ 5 years of age (EOT1D). Methods: WES was performed in 99 unrelated children with EOT1D with subsequent analysis to identify potentially deleterious rare variants in MODY genes. High‐resolution HLA class II haplotyping, SNP genotyping, and T1D‐genetic risk score (T1D‐GRS) were also evaluated. Results: Eight of the ninety‐nine EOT1D participants carried a potentially deleterious rare variant in a MODY gene. Rare variants affected five genes: GCK (n = 1), HNF1B (n = 2), HNF4A (n = 1), PDX1 (n = 2), and RFX6 (n = 2). At diagnosis, these children had a mean age of 3.0 years, a mean HbA1c of 10.5%, a detectable C‐peptide in 5/8, and a positive islet autoantibody in 6/7. Children with MODY variants tend to exhibit a lower number of pancreatic autoantibodies and a lower fasting C‐peptide compared to EOT1D without MODY rare variants. They also carried at least one high‐risk DR3‐DQ2 or DR4‐DQ8 haplotype and exhibited a T1D‐GRS similar to the other individuals in the EOT1D cohort, but higher than healthy controls. Conclusions: WES found potentially deleterious rare variants in MODY genes in 8.1% of EOT1D, occurring in the context of a T1D genetic background. Such genetic variants may contribute to disease precipitation by a β‐cell dysfunction mechanism. This supports the concept of different endotypes of T1D, and WES at T1D onset may be a prerequisite for the implementation of precision therapies in children with autoimmune diabetes. [ABSTRACT FROM AUTHOR] more...
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- 2024
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19. High prevalence of copy number variations in the Japanese participants with suspected MODY.
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Tanaka, Satoshi, Akagawa, Hiroyuki, Azuma, Kenkou, Higuchi, Sayaka, Ujiie, Atsushi, Hashimoto, Koshi, and Iwasaki, Naoko
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MATURITY onset diabetes of the young , *GENETIC testing , *DIABETES , *FUNCTIONAL analysis - Abstract
Maturity‐Onset Diabetes of the Young (MODY) is a diabetes mellitus subtype caused by a single gene. The detection rate of the responsible gene is 27% in the United Kingdom, indicating that the causative gene remains unknown in the majority of clinically diagnosed MODY cases. To improve the detection rate, we applied comprehensive genetic testing using whole exome sequencing (WES) followed by Multiplex Ligation‐dependent Probe Amplification (MLPA) and functional analyses. Twenty‐one unrelated Japanese participants with MODY were enrolled in the study. To detect copy number variations (CNVs), WES was performed first, followed by MLPA analysis for participants who were negative on the basis of WES. Undetermined variants were analyzed according to their functional properties. WES identified 7 pathogenic and 3 novel likely pathogenic variants in the 21 participants. Functional analyses revealed that 1 in 3 variants was pathogenic. MLPA analysis applied to the remaining 13 undetermined samples identified 4 cases with pathogenic CNVs: 3 in HNF4A and 1 in HNF1B. Pathogenic variants were identified in 12 participants (12/21, 57.1%) – relatively high rate reported to date. Notably, one‐third of the participants had CNVs in HNF4A or HNF1B, indicating a limitation of WES‐only screening. [ABSTRACT FROM AUTHOR] more...
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- 2024
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20. Our Experiences and Learnings in Diagnosing MODY from Non-Institutional-Based Diabetes Care Clinics.
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Pande, Arunkumar R., Chaubey, Santosh, Kumar, Dinesh, Chandra, Kumar P., Geetha, Thenral, and Sharma, Akshita
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MATURITY onset diabetes of the young ,DIABETES in children ,ACANTHOSIS nigricans ,BODY mass index ,ISLANDS of Langerhans - Abstract
Introduction: Maturity-onset diabetes of the young (MODY) is a rare group of disorders characterised by impaired functions or development of pancreatic islets and monogenic diabetes at a young age. Diagnosing MODY can be rewarding for both clinicians and patients as it can change the management from generic to targeted therapy. Methods: This study reports the retrospective analysis of data collected from four clinics between March 2016 and February 2023 from Lucknow, a city in northern India. Fifty-three individuals are suspected to be affected by MODY based on ISPAD guidelines. Following a detailed clinical evaluation, they were referred for genetic diagnostic testing. Results: The cohort consists of 19 females and 34 males with a mean age of diagnosis of 25.3 years and a body mass index of 22.3 Kg/m
2 . Genetic testing detected variants in 13/53 (~24.5%) individuals. Five cases had significant pathogenic/likely pathogenic variants, HNF1A gene in two [(p.Phe268LeufsTer74) (p.Arg200Gln)], one each in HNF4A (Arg311His), PDX1 (p.Ala228GlyfsTer33), and a case with suggestive digenic variants in HNF1A gene (p.Arg200Gln) and HNF1B [(p.Leu13Met)]. Variants of uncertain significance (VUSs) with inconclusive evidence of pathogenicity were reported in eight patients, and five were considered to be clinically significant as they are lean young onset, sulfonylurea-responsive, and presented with diabetes without acanthosis nigricans and with high pretest probability. These individuals harboured variants in HNF1A (p.Thr425_Thr429delinsPro), HNF1B (p.Ser19Phe), CEL (p.Val681ArgfsTer6), ABCC8 (p.Ile872Met), and KCNJ11 (p.Arg221Cys) genes. Conclusion: We found a diagnostic yield of around 10% of pathogenic or likely pathogenic variants in individuals who were suspected to have MODY. As it is a field that is still evolving, we might consider starting with oral agents under close supervision in those individuals who have VUS; there are some proportions of individuals who might not have classical sulfonylurea-responsive genetic variants, but they might respond to it. [ABSTRACT FROM AUTHOR] more...- Published
- 2024
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21. Clinical and Laboratory Characteristics of MODY Cases, Genetic Mutation Spectrum and Phenotype-genotype Relationship.
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Özsu, Elif, Çetinkaya, Semra, Bolu, Semih, Hatipoğlu, Nihal, Erdeve, Şenay Savaş, Evliyaoğlu, Olcay, Baş, Firdevs, Çayır, Atilla, Dündar, İsmail, Akbaş, Emine Demet, Uçaktürk, Seyid Ahmet, Berberoğlu, Merih, Şıklar, Zeynep, Özalkak, Şervan, Şahin, Nursel Muratoğlu, Keskin, Melikşah, Şiraz, Ülkü Gül, Turan, Hande, Öztürk, Ayşe Pınar, and Mengen, Eda more...
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METFORMIN ,MATURITY onset diabetes of the young ,TURKS ,HYPOGLYCEMIC agents ,ORAL drug administration ,DIABETIC acidosis ,DESCRIPTIVE statistics ,GENETIC variation ,HYPERGLYCEMIA ,GENETIC mutation ,INSULIN secretagogues ,DATA analysis software ,PHENOTYPES ,GENOTYPES ,GENETIC testing ,OBESITY ,CHILDREN - Abstract
Objective: 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. Methods: MODY cases from 14 different pediatric endocrinology departments were included. Diagnosis, treatment, follow-up data, and results of genetic analysis were evaluated. Results: 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 anti-diabetic treatment. Conclusion: 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. [ABSTRACT FROM AUTHOR] more...
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- 2024
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22. Examining the clinical and genetic spectrum of maturity-onset diabetes of the young (MODY) in Iran.
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Asgarian, Sara, Lanjanian, Hossein, Rahimipour Anaraki, Shiva, Hadaegh, Farzad, Moazzam-Jazi, Maryam, Najd-Hassan-Bonab, Leila, Masjoudi, Sajedeh, Zahedi, Asiyeh Sadat, Zarkesh, Maryam, Shalbafan, Bita, Akbarzadeh, Mahdi, Tehrani Fateh, Sahand, Khalili, Davood, Momenan, Amirabbas, Sarbazi, Narges, Hedayati, Mehdi, Azizi, Fereidoun, and Daneshpour, Maryam S. more...
- Abstract
Maturity-onset diabetes of the young (MODY) is an uncommon monogenic type of diabetes mellitus. Detecting genetic variants for MODY is a necessity for precise diagnosis and treatment. The majority of MODY genetic predisposition has been documented in European populations and a lack of information is present in Iranians which leads to misdiagnosis as a consequence of defects in unknown variants. In this study, using genetic variant information of 20,002 participants from the family-based TCGS (Tehran Cardiometabolic Genetic Study) cohort, we evaluated the genetic spectrum of MODY in Iran. We concentrated on previously discovered MODY-causing genes. Genetic variants were evaluated for their pathogenicity. We discovered 6 variants that were previously reported in the ClinVar as pathogenic/likely pathogenic (P/LP) for MODY in 45 participants from 24 families (INS in 21 cases, GCK in 13, HNF1B in 8, HNF4A, HNF1A, and CEL in 1 case). One potential MODY variant with Uncertain Risk Allele in ClinVar classification was also identified, which showed complete disease penetrance (100%) in four subjects from one family. This is the first family-based study to define the genetic spectrum and estimate the prevalence of MODY in Iran. The discovered variants need to be investigated by additional studies. [ABSTRACT FROM AUTHOR] more...
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- 2024
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23. MODY Only Monogenic? A Narrative Review of the Novel Rare and Low-Penetrant Variants.
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Hasballa, Iderina and Maggi, Davide
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MATURITY onset diabetes of the young , *DIABETES , *GENETIC mutation , *ETIOLOGY of diseases ,LITERATURE reviews - Abstract
Maturity-onset diabetes of the young (MODY) represents the most frequent form of monogenic diabetes mellitus (DM), currently classified in 14 distinct subtypes according to single gene mutations involved in the differentiation and function of pancreatic β-cells. A significant proportion of MODY has unknown etiology, suggesting that the genetic landscape is still to be explored. Recently, novel potentially MODY-causal genes, involved in the differentiation and function of β-cells, have been identified, such as RFX6, NKX2.2, NKX6.1, WFS1, PCBD1, MTOR, TBC1D4, CACNA1E, MNX1, AKT2, NEUROG3, EIF2AK3, GLIS3, HADH, and PTF1A. Genetic and clinical features of MODY variants remain highly heterogeneous, with no direct genotype–phenotype correlation, especially in the low-penetrant subtypes. This is a narrative review of the literature aimed at describing the current state-of-the-art of the novel likely MODY-associated variants. For a deeper understanding of MODY complexity, we also report some related controversies concerning the etiological role of some of the well-known pathological genes and MODY inheritance pattern, as well as the rare association of MODY with autoimmune diabetes. Due to the limited data available, the assessment of MODY-related genes pathogenicity remains challenging, especially in the setting of rare and low-penetrant subtypes. In consideration of the crucial importance of an accurate diagnosis, prognosis and management of MODY, more studies are warranted to further investigate its genetic landscape and the genotype–phenotype correlation, as well as the pathogenetic contribution of the nongenetic modifiers in this cohort of patients. [ABSTRACT FROM AUTHOR] more...
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- 2024
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24. Monogenic Diabetes: A Comprehensive Overview and Therapeutic Management of Subtypes of Mody.
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Sharma, Manisha, Maurya, Kajal, Nautiyal, Anuj, and Chitme, Havagiray R.
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MATURITY onset diabetes of the young , *TYPE 2 diabetes , *HYPERGLYCEMIA , *ETIOLOGY of diabetes , *DIABETES - Abstract
BackgroundMethodsResultsConclusionMonogenic diabetes often occurs as a result of single-gene mutations. The illness is minimally affected by environmental and behavioral factors, and it constitutes around one to five percent of all cases of diabetes.Newborn diabetes mellitus (NDM) and maturity-onset diabetes of the young (MODY) are the predominant causes of monogenic diabetes, accounting for a larger proportion of cases, while syndromic diabetes represents a smaller percentage. MODY, a group of inherited non-autoimmune diabetes mellitus disorders, is quite common. However, it remains frequently misdiagnosed despite increasing public awareness. The condition is characterized by insulin resistance, the development of diabetes at a young age (before 25 years), mild high blood sugar levels, inheritance in an autosomal dominant pattern, and the preservation of natural insulin production.Currently, there are 14 distinct subtypes of MODY that have been identified. Each subtype possesses distinct characteristics in terms of their frequency, clinical symptoms, severity of diabetes, related complications, and response to medicinal interventions. Due to the clinical similarities, lack of awareness, and high expense of genetic testing, distinguishing between type I (T1D) and type II diabetes mellitus (T2D) can be challenging, resulting in misdiagnosis of this type of diabetes. As a consequence, a significant number of individuals are being deprived of adequate medical attention. Accurate diagnosis enables the utilization of novel therapeutic strategies and enhances the management of therapy in comparison to type II and type I diabetes.This article offers a concise overview of the clinical subtypes and characteristics of monogenic diabetes. Furthermore, this article discusses the various subtypes of MODY, as well as the process of diagnosing, managing, and treating the condition. It also addresses the difficulties encountered in detecting and treating MODY. [ABSTRACT FROM AUTHOR] more...
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- 2024
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25. Diabetic Ketoacidosis in Patients with Maturity-Onset Diabetes of the Young.
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Müssig, Karsten
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MATURITY onset diabetes of the young , *DIABETIC acidosis , *PANCREATIC beta cells , *PEOPLE with diabetes , *GENETIC mutation - Abstract
Maturity-onset diabetes of the young (MODY) is the most frequent monogenetic diabetes form. It is caused by mutations in genes important for the development and function of pancreatic beta-cells, resulting in impaired insulin secretion capacity. Up to now, 14 different types have been described. The inheritance pattern is autosomal dominant, leading to a strong family history with more than three affected generations. Young age at diagnosis and lack of pancreatic autoantibodies are further characteristics of MODY. The presence of diabetic ketoacidosis (DKA) was long regarded as an exclusion criterion for MODY. However, in recent years, several case reports on MODY patients presenting with DKA have been published. The present study aimed to give an overview of the current knowledge of DKA in MODY patients, with a collection of published case studies as a prerequisite for this review. [ABSTRACT FROM AUTHOR] more...
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- 2024
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26. Challenges in diagnosis and treatment of KCNJ11-MODY
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Juliana Gonçalves, Helena Urbano Ferreira, Sara Ribeiro, Diogo Fernandes da Rocha, Selma B Souto, Jorge Pedro, Paula Freitas, and Joana Queirós
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diabetes mellitus ,mody ,gliclazide ,kcnj11 ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Maturity-onset diabetes of the young (MODY) is a subtype of monogenic diabetes and a rare type of diabetes, which accounts for 1–5% of cases and is often underdiagnosed. The importance of its diagnosis lies in the potential implications that it can have on disease management and offspring. We report a de novo KCNJ11-MODY case and the process of transition from insulin to sulfonylureas. A 24-year-old Caucasian woman was referred to the Endocrinology Department on account of newly diagnosed diabetes mellitus. Her past medical history was unremarkable; however, her family history was relevant, as three grandparents had diabetes. Blood tests showed elevated haemoglobin A1c (10.7%) and fasting glucose (278 mg/dL), prompting the initiation of insulin therapy. Further tests revealed a normal C-peptide level (2.75 ng/mL) and negative anti-glutamic acid decarboxylase and anti-insulin antibodies. The examination of past medical records revealed pre-diabetes since the age of 13. Genetic testing identified a heterozygous pathogenic variant p.(Glu227Lys) in the KCNJ11 gene. Excellent glycaemic control was achieved upon initiation of gliclazide, leading to the withdrawal of insulin treatment. KCNJ11-MODY is an extremely uncommon subtype of MODY, with only a few reported cases worldwide. This case is important, as it supports the use of sulfonylureas as an effective treatment for KCNJ11-MODY. more...
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- 2024
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27. Feasibility of a 12 weeks supervised exercise training intervention among people with Maturity Onset Diabetes of the Young (MODY) or type 2 diabetes in Greenland
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Laila Motzfeldt, Mathias Ried-Larsen, Freya Jørgensen Hovden, Marit Eika-Jørgensen, Michael Lynge Pedersen, and Maja Hykkelbjerg Nielsen
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Type 2 diabetes ,Maturity Onset Diabetes of the Young ,MODY ,exercise training ,intervention ,Greenland ,Arctic medicine. Tropical medicine ,RC955-962 - Abstract
Preventing and managing Type 2 diabetes (T2D) involves adopting healthy lifestyle habits such as balanced nutrition and regular exercise. Maturity Onset Diabetes of The Young (MODY) shares diagnostic characteristics with T2D, but exercise responses in MODY remain unclear. In Greenland, MODY is 4–5 times more common than in other countries. No established exercise regimen exists for either T2D or MODY in Greenland. This study assessed the feasibility of a 12-week supervised exercise programme for MODY and T2D in Greenland, focusing on attendance, satisfaction, and effects on cardiovascular disease (CVD) risk factors and quality of life (QoL). Conducted as an experimental, two-armed, controlled trial, nine participants (4 with MODY) engaged in prescribed training sessions twice weekly for 45–60 minutes, while another nine (4 with MODY) formed the control group. Key outcomes included adherence rates, satisfaction levels, changes in HbA1c, body composition, aerobic fitness, blood pressure, CVD risk factors, and SF-12 scores. Although training adherence was modest at 56%, participant satisfaction remained high. Notable findings included a slight decrease of −0.3 mmol/l in HDL-cholesterol and a 5.7-point increase in the mental component (MCS) of SF-12 within the intervention group. However, the study underscores the need to refine the study design before supervised exercise programmes can be widely implemented in clinical settings in Greenland. more...
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- 2024
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28. Editorial: Personalized therapies for monogenic diabetes.
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Delvecchio, Maurizio, Ming Liu, Rapini, Novella, and Barbetti, Fabrizio
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MATURITY onset diabetes of the young ,TYPE 1 diabetes ,TYPE 2 diabetes ,GESTATIONAL diabetes ,METABOLIC syndrome ,INSULIN - Abstract
The editorial discusses personalized therapies for monogenic diabetes, focusing on three main clinical forms: Maturity Onset Diabetes of the Young (MODY), Neonatal Diabetes Mellitus (NDM), and Severe Insulin Resistance syndromes. The article highlights the genetic basis of these conditions and treatment options, such as oral hypoglycemic agents for MODY and NDM, and human recombinant IGF1 for Severe Insulin Resistance syndromes. Additionally, the editorial emphasizes the importance of precision medicine in managing monogenic diabetes and explores potential therapeutic targets through Mendelian randomization. [Extracted from the article] more...
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- 2024
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29. Screening of Mutations in Maturity-onset Diabetes of the Young-related Genes and RFX6 in Children with Autoantibody-negative Type 1 Diabetes Mellitus
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Enver Şimşek, Oğuz Çilingir, Tülay Şimşek, Sinem Kocagil, Ebru Erzurumluoğlu Gökalp, Meliha Demiral, and Çiğdem Binay
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diabetes mellitus ,mutation ,mody ,rfx6 ,turkish children ,Pediatrics ,RJ1-570 ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
INTRODUCTION: Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes. To date, mutations have been identified in 14 different genes of patients with a clinical diagnosis of MODY. This study screened mutations in 14 MODY-related genes and the regulator factor X6 (RFX6) gene in children. METHODS: The presence of clinical features of MODY and negative results for three autoantibody markers of type 1 diabetes mellitus (T1DM) in children and adolescents were used as inclusion criteria for genetic testing. The screening panel for next-generation sequencing included 14 MODY-related genes (GCK, HNF4A, HNF1A, HNF1B, PDX1, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, and APPL1) and the RFX6 gene. RESULTS: Twenty-four different variants in MODY-related genes were identified in 49 children diagnosed with autoantibody-negative T1DM. Twelve variants were classified as pathogenic/likely pathogenic (P/LP) while 12 were interpreted as variant of unknown significance. Nine of the P/LP variants were found in GCK, two in HNF1B, and one in ABCC8. Three variants were novel, and one was a de novo variant. All but one of the variants exhibited heterozygotic inheritance. DISCUSSION AND CONCLUSION: The frequencies of the MODY subtypes differed from previous reports. Although GCK-MODY was the most frequent mutation in Turkish children, similar to previous studies, the second most prevalent MODY subtype was HNF1B-MODY. This study also established three additional novel mutations in different MODY genes. more...
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- 2024
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30. Stress Induced Hyperglycemia in Early Childhood as a Clue for the Diagnosis of NEUROD1-MODY
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Nur Berna Çelik, Naz Güleray Lafcı, Şenay Savaş-Erdeve, and Semra Çetinkaya
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mody ,neurod1 ,stress induced hyperglycemia ,early childhood ,Pediatrics ,RJ1-570 ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Maturity-onset diabetes of young ‘MODY’ type 6 is a rare form of monogenic diabetes caused by mutations in neuronal differentiation 1 (NEUROD1). Clinical features vary in a large spectrum in terms of age and body mass index (BMI) at diagnosis. Here, we reported the youngest patient with a NEUROD1 variant to the best of our knowledge. A 2.1-year-old girl was referred to pediatric endocrinology clinic for elevated fasting BG (104 mg/dL) which was detected at another center where she had been evaluated for loss of appetite. Her maternal aunt and uncle had been diagnosed with type 2 diabetes mellitus (DM) at the age of 40 and 45 years; they were obese (BMI: 30.2 and 30.6 kg/m2). At the age of 3.7 years old, she was hospitalized for buccal cellulitis and plasma glucose concentration was 239 mg/dL at admission. Targeted next-generation sequencing (NGS) was performed considering the stress induced hyperglycemia without serious illness, negative islet cell antibodies and insulin autoantibodies, age at the presentation, and family history of DM. NGS analysis revealed a previously reported heterozygous missense variant in NEUROD1. Segregation studies showed that the identified variant was inherited from her 44-year-old mother with a BMI of 27.2 kg/m2 and a normal oral glucose tolerance test. Heterozygous NEUROD1 mutations cause low-penetrant diabetes that is heterogeneous in terms of clinical features as some patients fulfill the classic MODY definition and others are mimicking type 2 DM. Clinical manifestations and family history should be carefully evaluated in patients with stress induced hyperglycemia to identify candidate cases for molecular testing, and proper follow-up should be initiated in affected individuals. more...
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- 2024
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31. Comparison of Bayesian approaches for developing prediction models in rare disease: application to the identification of patients with Maturity-Onset Diabetes of the Young
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Pedro Cardoso, Timothy J. McDonald, Kashyap A. Patel, Ewan R. Pearson, Andrew T. Hattersley, Beverley M. Shields, and Trevelyan J. McKinley
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MODY ,Bayesian modelling ,Rare diseases ,Prior elicitation ,Recalibration ,Medicine (General) ,R5-920 - Abstract
Abstract Background Clinical prediction models can help identify high-risk patients and facilitate timely interventions. However, developing such models for rare diseases presents challenges due to the scarcity of affected patients for developing and calibrating models. Methods that pool information from multiple sources can help with these challenges. Methods We compared three approaches for developing clinical prediction models for population screening based on an example of discriminating a rare form of diabetes (Maturity-Onset Diabetes of the Young - MODY) in insulin-treated patients from the more common Type 1 diabetes (T1D). Two datasets were used: a case-control dataset (278 T1D, 177 MODY) and a population-representative dataset (1418 patients, 96 MODY tested with biomarker testing, 7 MODY positive). To build a population-level prediction model, we compared three methods for recalibrating models developed in case-control data. These were prevalence adjustment (“offset”), shrinkage recalibration in the population-level dataset (“recalibration”), and a refitting of the model to the population-level dataset (“re-estimation”). We then developed a Bayesian hierarchical mixture model combining shrinkage recalibration with additional informative biomarker information only available in the population-representative dataset. We developed a method for dealing with missing biomarker and outcome information using prior information from the literature and other data sources to ensure the clinical validity of predictions for certain biomarker combinations. Results The offset, re-estimation, and recalibration methods showed good calibration in the population-representative dataset. The offset and recalibration methods displayed the lowest predictive uncertainty due to borrowing information from the fitted case-control model. We demonstrate the potential of a mixture model for incorporating informative biomarkers, which significantly enhanced the model’s predictive accuracy, reduced uncertainty, and showed higher stability in all ranges of predictive outcome probabilities. Conclusion We have compared several approaches that could be used to develop prediction models for rare diseases. Our findings highlight the recalibration mixture model as the optimal strategy if a population-level dataset is available. This approach offers the flexibility to incorporate additional predictors and informed prior probabilities, contributing to enhanced prediction accuracy for rare diseases. It also allows predictions without these additional tests, providing additional information on whether a patient should undergo further biomarker testing before genetic testing. more...
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- 2024
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32. MODY diabetes as an orphan disease: literature review
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A.V. Garnytska, O.S. Orlyk, L.M. Zenkina, and S.O. Osadcha
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diabetes ,mody ,monogenic diabetes ,microbiome ,diagnosis ,treatment ,Therapeutics. Pharmacology ,RM1-950 - Abstract
BACKGROUND. Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes, usually diagnosed before the age of 30 years in non-obese patients with a family history of diabetes mellitus (DM). MODY is relatively rare compared to type 1 and type 2 DM, with various literature estimates affecting only 1-2 % of people with diabetes, but because it is rare, clinicians may misdiagnose it as type 1 or type 2 DM, which happens in most cases. Unlike type 1 DM patients, patients with MODY have preserved pancreatic β-cell function, so lifestyle modification in combination with glucose-lowering therapy, which in some cases may include insulin, may be sufficient interventions as treatment. OBJECTIVE. With the help of literary sources, familiarize yourself with the classification, clinical manifestations, aspects of treatment and prognosis of the main forms of MODY diabetes. MATERIALS AND METHODS. Object: MODY diabetes as an orphan disease. Research method: a review of literary sources. RESULTS. MODY is most often an autosomal dominant disease and is divided into subtypes (MODY1 to MODY14) based on genetic mutation. Subtypes 1-3 are the most common, accounting for 95 % of cases. Treatment usually includes diet, exercise, and, in some cases, insulin or oral hypoglycemic drugs. In general, the prognosis can be quite favorable, provided that carbohydrate metabolism is compensated. CONCLUSIONS. MODY diabetes is a complex genetically determined pathology, and understanding the features of this disease, diagnosis and treatment are of great importance for patients and their families. The development of modern methods of treatment and monitoring of glucose, such as insulin pumps, 24-hour glycemic monitoring and other technologies, may improve the prognosis for patients with MODY. Each patient with MODY diabetes has individual characteristics, which leaves an imprint on the prognosis of the disease and approaches to treatment. The main goal is to maintain a normal level of glucose in the blood to avoid complications. more...
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- 2024
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33. Novel Approach for Treating Diabetes in a Patient With the Heterozygous Pathogenic Variant R46Q in the Insulin Gene.
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Laugesen, Kristina, Gregersen, Søren, and Støy, Julie
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SODIUM-glucose cotransporter 2 inhibitors , *MATURITY onset diabetes of the young , *CONTINUOUS glucose monitoring , *GLUCOSE tolerance tests , *GLYCEMIC control - Abstract
Maturity-onset diabetes of the young (MODY) is a monogenic disorder of glucose homeostasis with several subtypes, each defined by a distinct genetic etiology. Heterozygous pathogenic variants in the insulin gene are rare causes of MODY, and optimal treatment strategies remain uncertain. Herein we describe a patient with diabetes caused by the heterozygous pathogenic variant R46Q in the insulin gene and the glycemic response to selected antidiabetic treatment regimens. The R46Q pathogenic variant leads to secretion of both mutant and wild-type insulin. In vitro, the mutant insulin is associated with a lower insulin-receptor affinity compared with wild-type insulin and a decline in wildtype insulin secretion. In our patient, treatment with a combination of long- and short-acting insulin led to a decline in hemoglobin A1C (HbA1c), although not to the recommended target. A shift to metformin and subsequent add-on of a sodium-glucose cotransporter 2 inhibitor (SGLT2i) resulted in HbA1c levels of less than 7% (53 mmol/mol) and durable glycemic control. Continuous glucose monitoring and oral glucose tolerance tests confirmed that treatment with metformin and SGLT2i was superior to treatment with insulin. In conclusion, diabetes caused by the pathogenic variant R46Q in the insulin gene may be effectively treated with noninsulin. [ABSTRACT FROM AUTHOR] more...
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- 2024
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34. Comparison of the optical coherence tomography-angiography (OCT-A) vascular measurements between molecularly confirmed MODY and age-matched healthy controls.
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Çavdarlı, Cemal, Büyükyılmaz, Gönül, Çavdarlı, Büşranur, Çomçalı, Sebile, Topçu Yılmaz, Pınar, and Alp, Mehmet Numan
- Subjects
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PERIMETRY , *MATURITY onset diabetes of the young , *COHERENCE (Optics) , *TYPE 1 diabetes , *DIABETES in children , *TYPE 2 diabetes - Abstract
Aims: Previous structural, vascular density, and perfusion studies have mostly comprised type 1 and type 2 diabetes, even in the absence of retinopathy. The current study aimed to compare macular vessel density (VD) measurements between maturity-onset diabetes of the young (MODY) patients and controls. Methods: The macular VD of superficial, deep retina, and choriocapillaris (CC), and central macular thickness (CMT), foveal avascular zone (FAZ), FAZ perimetry, VD of the total retina at 300 µm around the FAZ (FD), and acirculatory index (AI) measurements were taken and analyzed via OCT-A (RTVue XR 100-2 Avanti, AngioVue) and were compared between molecularly confirmed MODY (glucokinase (GCK) variants) patients and healthy controls. Results: Twenty-five MODY patients and 30 healthy controls were included in the study. The mean plasma hemoglobin A1c level in the MODY group was 6.39 ± 0.38. The mean age was 13.8 ± 2.1 in the MODY group and was 12.6 ± 2.5 years among controls. There was no significant difference in terms of the age, superficial and deep retinal VD, FAZ, FAZ perimetry, CMT, FD, or AI between the groups. Compared to the healthy controls, a slight but significant increase in the CC-VD was detected in the MODY group, but only in the parafoveal and perifoveal regions (p = 0.034, p = 0.009). Conclusion: The significant CC-VD increase in the MODY group might be associated with hyperglycemia and/or relatively poor and vulnerable peripheral vascular CC perfusion compared to the central. Previous thickness and VD results of childhood or adolescent diabetes were distributed in a wider range, suggesting that various factors, including some not yet clearly defined, may affect the choroidal vasculature independently of glycemia or as a contributing factor. [ABSTRACT FROM AUTHOR] more...
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- 2024
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35. Pregnancy in various forms of monogenic diabetes: A systematic review.
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Aarthe, Veeraraghavan, Unnikrishnan, Ranjit, Anjana, Ranjit Mohan, Jaggi, Shalini, Chawla, Rajeev, and Mohan, Viswanathan
- Subjects
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DIAGNOSIS of diabetes , *TREATMENT of diabetes , *DIABETES complications , *INSULIN therapy , *GESTATIONAL diabetes , *MATURITY onset diabetes of the young , *HYPOGLYCEMIC agents , *SULFONYLUREAS , *PREGNANCY complications , *DIABETES , *GENETIC testing - Abstract
Monogenic diabetes (MD) represents a cluster of different types of diabetes produced by a mutation of a single gene. The commonest type of MD is maturity-onset diabetes of the young (MODY) which has several subtypes, and neonatal diabetes mellitus (NDM). With improved diagnostic facilities, more cases of monogenic diabetes are being described, and pregnancy is being reported in different forms of monogenic diabetes as these patients enter the reproductive age group. The treatment of monogenic diabetes may change once pregnancy sets in. For example, some forms of monogenic diabetes which respond to oral antidiabetic drugs (OHA), particularly the sulfonylurea agents (SUs), may need insulin during pregnancy. However, this depends on the fetal inheritance of mutation from the mother. This review attempts to put together published reports of pregnancy in various types of monogenic diabetes focussing on the most frequently seen forms of MD. [ABSTRACT FROM AUTHOR] more...
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- 2024
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36. Management of pregnancy in women with monogenic diabetes due to mutations in GCK, HNF1A and HNF4A genes.
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Crowley, M. T., Paponette, B., Bacon, S., and Byrne, M. M.
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MATURITY onset diabetes of the young ,SMALL for gestational age ,HEPATOCYTE nuclear factors ,PRENATAL care ,PUERPERAL disorders ,ADOLESCENCE ,INSULIN aspart ,BIRTH weight - Abstract
Women with maturity-onset diabetes of the young (MODY) need tailored antenatal care and monitoring of their offspring. Each MODY subtype has different implications for glycaemic targets, treatment choices and neonatal management. Hyperglycaemia of MODY is often first diagnosed in adolescence or early adulthood and therefore is clinically relevant to pregnant women. MODY remains an under-recognised and undiagnosed condition. Pregnancy represents an opportune time to make a genetic diagnosis of MODY and provide precision treatment. This review describes the nuance of antenatal care in women with MODY and the implications for pregnancies affected by a positive paternal genotype. Mutations in hepatic nuclear factor 1-alpha (HNF1A) and 4-alpha (HNF4A) genes are associated with progressive βcell dysfunction resulting in early onset diabetes. Patients are largely managed with sulphonylureas outside of pregnancy. Macrosomia and persistent neonatal hypoglycaemia are reported in 54% and 15% of HNF4A genotype positive offspring respectively with a median increase in birthweight of 790 g. Close observation of foetal growth in utero allows optimal timing of delivery to minimise peri- and postpartum materno-foetal complications. Glucokinase (GCK)-MODY causes mild fasting hyperglycaemia which does not require treatment outside of pregnancy. Birthweight of offspring of maternal carriers is dependent on foetal genotype; heterozygous mutation carriers are usually normal weight while genotype negative offspring are large for gestational age (600 g heavier). Affected offspring of paternal carriers may be small for gestational age (500 g lighter). Serial growth scans with measurement of the abdominal circumference indirectly differentiate foetal genotype. Measurement of cell free foetal DNA in maternal blood from the late first trimester is superior to traditionally used ultrasound to distinguish foetal genotype. Cost and accessibility may limit its use. [ABSTRACT FROM AUTHOR] more...
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- 2024
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37. The Importance of Molecular Genetic Testing for Precision Diagnostics, Management, and Genetic Counseling in MODY Patients.
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Butnariu, Lăcrămioara Ionela, Bizim, Delia Andreia, Oltean, Carmen, Rusu, Cristina, Pânzaru, Monica Cristina, Păduraru, Gabriela, Gimiga, Nicoleta, Ghiga, Gabriela, Moisă, Ștefana Maria, Țarcă, Elena, Starcea, Iuliana Magdalena, Popa, Setalia, and Trandafir, Laura Mihaela more...
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- *
MATURITY onset diabetes of the young , *GENETIC counseling , *GENETIC testing , *TYPE 1 diabetes - Abstract
Maturity-onset diabetes of the young (MODY) is part of the heterogeneous group of monogenic diabetes (MD) characterized by the non-immune dysfunction of pancreatic β-cells. The diagnosis of MODY still remains a challenge for clinicians, with many cases being misdiagnosed as type 1 or type 2 diabetes mellitus (T1DM/T2DM), and over 80% of cases remaining undiagnosed. With the introduction of modern technologies, important progress has been made in deciphering the molecular mechanisms and heterogeneous etiology of MD, including MODY. The aim of our study was to identify genetic variants associated with MODY in a group of patients with early-onset diabetes/prediabetes in whom a form of MD was clinically suspected. Genetic testing, based on next-generation sequencing (NGS) technology, was carried out either in a targeted manner, using gene panels for monogenic diabetes, or by analyzing the entire exome (whole-exome sequencing). GKC-MODY 2 was the most frequently detected variant, but rare forms of KCNJ11-MODY 13, specifically, HNF4A-MODY 1, were also identified. We have emphasized the importance of genetic testing for early diagnosis, MODY subtype differentiation, and genetic counseling. We presented the genotype–phenotype correlations, especially related to the clinical evolution and personalized therapy, also emphasizing the particularities of each patient in the family context. [ABSTRACT FROM AUTHOR] more...
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- 2024
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38. Autosomal Dominant, Long-Standing Dysglycemia in 2 Families with Unique Phenotypic Features.
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Hanukoglu, Aaron, Banne, Ehud, Lev, Dorit, and Wainstein, Julio
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PREDIABETIC state , *GLYCOSYLATED hemoglobin , *FOOD consumption , *BODY mass index , *GLYCEMIC control , *MATURITY onset diabetes of the young , *HYPOGLYCEMIC agents , *C-peptide , *BLOOD sugar , *HYPERGLYCEMIA , *FATHERS , *PHENOTYPES , *PATIENT aftercare , *FASTING , *GENETIC testing , *SEQUENCE analysis - Abstract
We describe 2 families with 5 members from 2 generations whose clinical and laboratory characteristics over up to 15 years were consistent with dysglycemia/impaired glucose tolerance. In both families (2 probands and 3 family members), long-term follow-up excluded diabetes type 1 and type 2. Diabetes type 1 antibodies were persistently negative and C-peptide levels were normal. In Family 1, the proband, during a follow-up of 7 years (10.3-17.5 years of age), exhibited persistently high HbA1c (>5.7%) with fasting blood glucose levels mostly higher than 100 mg/dl and postprandial glucose levels up to 180 mg/dl. She eventually required oral anti-diabetics with an improvement in glycemic balance. The father and sister also had persistent mild hyperglycemia with borderline high HbA1c (mostly > 5.7%) levels over 15 and 6.2 years respectively. In Family 2, the proband exhibited borderline high fasting hyperglycemia (>100 mg/dl) at age 16.2 years with increasing HbA1c levels (from 5.6%–5.9%) and impaired glucose tolerance at age 18.3 years (2 h blood glucose 156 mg/dl after 75 g glucose). His sister also exhibited borderline hyperglycemia with borderline high HbA1c over 2 years (13.6-15.4 years). These subjects shared a unique phenotype. They are tall and slim with decreased BMI. Three subjects from Generation II failed to thrive during infancy. In view of the data from 2 generations suggesting maturity-onset diabetes of the young (MODY) with autosomal dominant inheritance, we sought to analyze the MODY genes. In Family 1, the molecular analysis by the MODY panel including 11 genes and whole exome sequencing did not detect any mutation in the proband. In Family 2, the MODY panel was also negative in the proband's sister. These families may represent a hitherto unidentified syndrome. Unique features described in this report may help to reveal additional families with similar characteristics and to decipher the molecular basis of this syndrome. In selected cases, oral antidiabetics in adolescents may improve the glycemic balance. [ABSTRACT FROM AUTHOR] more...
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- 2024
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39. Comparison of Bayesian approaches for developing prediction models in rare disease: application to the identification of patients with Maturity-Onset Diabetes of the Young.
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Cardoso, Pedro, McDonald, Timothy J., Patel, Kashyap A., Pearson, Ewan R., Hattersley, Andrew T., Shields, Beverley M., and McKinley, Trevelyan J.
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MATURITY onset diabetes of the young ,PREDICTION models ,RARE diseases ,PEOPLE with diabetes ,TYPE 1 diabetes - Abstract
Background: Clinical prediction models can help identify high-risk patients and facilitate timely interventions. However, developing such models for rare diseases presents challenges due to the scarcity of affected patients for developing and calibrating models. Methods that pool information from multiple sources can help with these challenges. Methods: We compared three approaches for developing clinical prediction models for population screening based on an example of discriminating a rare form of diabetes (Maturity-Onset Diabetes of the Young - MODY) in insulin-treated patients from the more common Type 1 diabetes (T1D). Two datasets were used: a case-control dataset (278 T1D, 177 MODY) and a population-representative dataset (1418 patients, 96 MODY tested with biomarker testing, 7 MODY positive). To build a population-level prediction model, we compared three methods for recalibrating models developed in case-control data. These were prevalence adjustment ("offset"), shrinkage recalibration in the population-level dataset ("recalibration"), and a refitting of the model to the population-level dataset ("re-estimation"). We then developed a Bayesian hierarchical mixture model combining shrinkage recalibration with additional informative biomarker information only available in the population-representative dataset. We developed a method for dealing with missing biomarker and outcome information using prior information from the literature and other data sources to ensure the clinical validity of predictions for certain biomarker combinations. Results: The offset, re-estimation, and recalibration methods showed good calibration in the population-representative dataset. The offset and recalibration methods displayed the lowest predictive uncertainty due to borrowing information from the fitted case-control model. We demonstrate the potential of a mixture model for incorporating informative biomarkers, which significantly enhanced the model's predictive accuracy, reduced uncertainty, and showed higher stability in all ranges of predictive outcome probabilities. Conclusion: We have compared several approaches that could be used to develop prediction models for rare diseases. Our findings highlight the recalibration mixture model as the optimal strategy if a population-level dataset is available. This approach offers the flexibility to incorporate additional predictors and informed prior probabilities, contributing to enhanced prediction accuracy for rare diseases. It also allows predictions without these additional tests, providing additional information on whether a patient should undergo further biomarker testing before genetic testing. [ABSTRACT FROM AUTHOR] more...
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- 2024
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40. Stress Induced Hyperglycemia in Early Childhood as a Clue for the Diagnosis of NEUROD1-MODY.
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Çelik, Nur Berna, Lafcı, Naz Güleray, Savaş-Erdeve, Şenay, and Çetinkaya, Semra
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ENDOCRINOLOGY ,CELLULITIS ,TRANSCRIPTION factors ,MATURITY onset diabetes of the young ,FAMILY history (Medicine) ,HYPERGLYCEMIA ,BLOOD sugar ,PSYCHOLOGICAL stress ,TYPE 2 diabetes ,GENETIC techniques ,GENETIC testing ,MEDICAL referrals ,BIOMARKERS ,HOSPITAL care of children ,CHILDREN - Abstract
Maturity-onset diabetes of young ‘MODY’ type 6 is a rare form of monogenic diabetes caused by mutations in neuronal differentiation 1 (NEUROD1). Clinical features vary in a large spectrum in terms of age and body mass index (BMI) at diagnosis. Here, we reported the youngest patient with a NEUROD1 variant to the best of our knowledge. A 2.1-year-old girl was referred to pediatric endocrinology clinic for elevated fasting BG (104 mg/dL) which was detected at another center where she had been evaluated for loss of appetite. Her maternal aunt and uncle had been diagnosed with type 2 diabetes mellitus (DM) at the age of 40 and 45 years; they were obese (BMI: 30.2 and 30.6 kg/m² ). At the age of 3.7 years old, she was hospitalized for buccal cellulitis and plasma glucose concentration was 239 mg/dL at admission. Targeted next-generation sequencing (NGS) was performed considering the stress induced hyperglycemia without serious illness, negative islet cell antibodies and insulin autoantibodies, age at the presentation, and family history of DM. NGS analysis revealed a previously reported heterozygous missense variant in NEUROD1. Segregation studies showed that the identified variant was inherited from her 44-year-old mother with a BMI of 27.2 kg/m² and a normal oral glucose tolerance test. Heterozygous NEUROD1 mutations cause low-penetrant diabetes that is heterogeneous in terms of clinical features as some patients fulfill the classic MODY definition and others are mimicking type 2 DM. Clinical manifestations and family history should be carefully evaluated in patients with stress induced hyperglycemia to identify candidate cases for molecular testing, and proper follow-up should be initiated in affected individuals. [ABSTRACT FROM AUTHOR] more...
- Published
- 2024
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41. Screening of Mutations in Maturity-onset Diabetes of the Young-related Genes and RFX6 in Children with Autoantibody-negative Type 1 Diabetes Mellitus.
- Author
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Şimşek, Enver, Çilingir, Oğuz, Şimşek, Tülay, Kocagil, Sinem, Gökalp, Ebru Erzurumluoğlu, Demiral, Meliha, and Binay, Çiğdem
- Subjects
TYPE 1 diabetes ,CROSS-sectional method ,AUTOANTIBODIES ,MATURITY onset diabetes of the young ,DESCRIPTIVE statistics ,GENETIC variation ,GENE expression ,GENETIC mutation ,GENETIC techniques ,GENETIC testing ,SEQUENCE analysis ,BIOMARKERS ,CHILDREN - Abstract
Objective: Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes. To date, mutations have been identified in 14 different genes of patients with a clinical diagnosis of MODY. This study screened mutations in 14 MODY-related genes and the regulator factor X6 (RFX6) gene in children Methods: The presence of clinical features of MODY and negative results for three autoantibody markers of type 1 diabetes mellitus (T1DM) in children and adolescents were used as inclusion criteria for genetic testing. The screening panel for next-generation sequencing included 14 MODY-related genes (GCK, HNF4A, HNF1A, HNF1B, PDX1, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11, and APPL1) and the RFX6 gene. Results: Twenty-four different variants in MODY-related genes were identified in 49 children diagnosed with autoantibody-negative T1DM. Twelve variants were classified as pathogenic/likely pathogenic (P/LP) while 12 were interpreted as variant of unknown significance. Nine of the P/LP variants were found in GCK, two in HNF1B, and one in ABCC8. Three variants were novel, and one was a de novo variant. All but one of the variants exhibited heterozygotic inheritance. Conclusion: The frequencies of the MODY subtypes differed from previous reports. Although GCK-MODY was the most frequent mutation in Turkish children, similar to previous studies, the second most prevalent MODY subtype was HNF1B-MODY. This study also established three additional novel mutations in different MODY genes. [ABSTRACT FROM AUTHOR] more...
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- 2024
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42. Identification of rare variants in candidate genes associated with monogenic diabetes in polish mody-x patients.
- Author
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Jakiel, Paulina, Gadzalska, K., Juścińska, E., Gorządek, M., Płoszaj, T., Skoczylas, S., Borowiec, M., and Zmysłowska, A.
- Subjects
- *
MATURITY onset diabetes of the young , *GENETIC variation , *DIABETES , *PANCREATIC beta cells , *NUCLEOTIDE sequencing - Abstract
Purpose: Monogenic diabetes (MD) is caused by a mutation in a single gene and accounts for approximately 2.5–6% of all diabetes cases. Maturity-onset diabetes of the young (MODY) is the most common form of MD. To date, 14 different genes have been identified and associated with the presence of MODY phenotype. However, the number of potential candidate genes with relevance to beta cell function and glucose metabolism is increasing as more research is published. The aim of the study was to identify potentially causative variants in selected candidate genes in patients with a clinical diagnosis of MD. Methods: Targeted Next-Generation Sequencing (tNGS) on Illumina NextSeq 550 platform involving Agilent SureSelectQXT Target Enrichment protocol for 994 patients with suspected MD was performed. In the next step, the sequencing data of 617 patients with no pathogenic variants in main MD-related genes were reanalysed for the presence of causative variants in six candidate genes (MTOR, TBC1D4, CACNA1E, MNX1, SLC19A2, KCNH6). The presence of the selected variants was confirmed by Sanger sequencing. Results: Seven heterozygous possibly damaging variants were identified in four candidate genes (MTOR, TBC1D4, CACNA1E, MNX1). Five changes were assessed as novel variants, not previously described in available databases. None of the described variants were present among patients previously diagnosed with MODY diabetes due to causative, pathogenic variants in known MODY-related genes. Conclusions: The results obtained seem to confirm the effectiveness of the NGS method in identifying potentially causative variants in novel candidate genes associated with MODY diabetes. [ABSTRACT FROM AUTHOR] more...
- Published
- 2024
- Full Text
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43. Utility of Fasting C-Peptide for the Diagnostic Differentiation of Patients with Type 1, Type 2 Diabetes, MODY, and LADA.
- Author
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Alemán-Contreras, Ricardo, Gómez-Díaz, Rita A., Noyola-García, Maura E., Mondragón-González, Rafael, Wacher, Niels, and Ferreira-Hermosillo, Aldo
- Subjects
- *
TYPE 2 diabetes , *MATURITY onset diabetes of the young , *TYPE 1 diabetes , *C-peptide , *BODY mass index - Abstract
Background: The prevalence of obesity has increased in patients with type 1 diabetes (T1D) and latent autoimmune diabetes of the adult (LADA), limiting the use of clinical features such as the body mass index for its differentiation with type 2 diabetes (T2D). Additionally, some patients with maturity-onset diabetes of the young (MODY) or LADA are misdiagnosed as having T2D. The evaluation of autoantibodies and genetic testing are not fully available. We aimed to evaluate the utility of a widely available and less expensive diagnostic tool such as C-peptide to differentiate between T1D, T2D, MODY, and LADA. Methods: Our study included 38 patients with T1D, 49 with T2D, 13 with MODY, and 61 with LADA. We recorded anthropometric measurements, biochemical profiles, and antidiabetic treatment and determined C-peptide, anti-GAD65, and anti-IA2 antibodies. Results: C-peptide concentration differed significantly among populations (T1D: 0.2 ng/mL; T2D: 2.4 ng/mL; MODY: 1.14 ng/mL; LADA: 1.87 ng/mL). Through a ROC curve, we observed that the C-peptide cut-off point of 0.95 ng/mL allows differentiation between T1D and T2D (sensitivity 82%, specificity 77%); 0.82 ng/mL between T1D and LADA (sensitivity 82%, specificity 77%); and 1.65 ng/mL between T2D and MODY (sensitivity 72%, specificity 72%). Conclusions: C-peptide is useful for the diagnostic differentiation of patients with type 1, type 2 diabetes, MODY, and LADA. [ABSTRACT FROM AUTHOR] more...
- Published
- 2024
- Full Text
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44. Course of pregnancy and 10-year observation of twins diagnosed with GCK-MODY in the neonatal period: a case report
- Author
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Barbara Katra and Magdalena Szopa
- Subjects
diabetes ,monogenic ,MODY ,glucokinase ,autosomal dominant inheritance ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Monogenic diabetes accounts for 5% of all incidence of hyperglycemia and Maturity Onset Diabetes of the Young (MODY) is the most common form. In GCK-MODY, one of the most common forms of MODY, hyperglycemia is caused by a mutation of a gene responsible for coding glucokinase. At the clinical level, this condition presents as persistent, moderate and asymptomatic elevated fasting glucose levels and has a relatively low incidence of micro and macro-vascular complications. In general, the treatment of choice is to follow and maintain a healthy lifestyle. The incidence of GCK-MODY during pregnancy is 2% on average (0-6%). In this report, we introduce a case of a woman diagnosed with GCK-MODY during the pregnancy with twins, a boy and a girl, diagnosed with GCK-MODY after birth. We discuss the course of pregnancy, the need for access to fast and uncomplicated genetic diagnostics in utero, and the impact of the MODY diagnosis on the life of the mother and that of her children. In our case, the diagnosis of GCK-MODY was associated with a feeling of relief, after years of uncertainty, and helped to introduce more appropriate eating behaviors and lifestyle changes for both the mother and her children. more...
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- 2024
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45. Modelling human diabetes ex vivo: a glance at maturity onset diabetes of the young
- Author
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Moustapha Ka, Eleanor Hawkins, Celio Pouponnot, and Bertrand Duvillié
- Subjects
stem cells ,organoids ,pancreas ,islets ,diabetes ,MODY ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Diabetes is a complex metabolic disease which most commonly has a polygenic origin; however, in rare cases, diabetes may be monogenic. This is indeed the case in both Maturity Onset Diabetes of the Young (MODY) and neonatal diabetes. These disease subtypes are believed to be simpler than Type 1 (T1D) and Type 2 Diabetes (T2D), which allows for more precise modelling. During the three last decades, many studies have focused on rodent models. These investigations provided a wealth of knowledge on both pancreas development and beta cell function. In particular, they allowed the establishment of a hierarchy of the transcription factors and highlighted the role of microenvironmental factors in the control of progenitor cell proliferation and differentiation. Transgenic mice also offered the possibility to decipher the mechanisms that define the functional identity of the pancreatic beta cells. Despite such interest in transgenic mice, recent data have also indicated that important differences exist between mice and human. To overcome these limitations, new human models are necessary. In the present review, we describe these ex vivo models, which are created using stem cells and organoids, and represent an important step toward islet cell therapy and drug discovery. more...
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- 2024
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46. Editorial: Personalized therapies for monogenic diabetes
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Maurizio Delvecchio, Ming Liu, Novella Rapini, and Fabrizio Barbetti
- Subjects
monogenic diabetes ,personalized medicine ,MODY ,neonatal diabetes mellitus ,Rabson-Mendenhall syndrome ,severe insulin resistance syndrome ,Genetics ,QH426-470 - Published
- 2024
- Full Text
- View/download PDF
47. Re-diagnosis of diabetes mellitus type 1 to maturity-onset diabetes of the young type 2 (MODY 2) in a 26-year-old male: a case report
- Author
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Bartosz Siudek, Olgierd Dróżdż, Wiktoria Bińczyk, Karina Lissak, Bianka Nowińska, Patrycja Brzozowska, and Anna Wiśniewska
- Subjects
diabetes mellitus ,MODY ,insulin ,genetic testing ,Sports ,GV557-1198.995 ,Sports medicine ,RC1200-1245 - Abstract
Diabetes mellitus (DM) encompasses a spectrum of metabolic disorders characterized by hyperglycemia due to defects in insulin secretion, action, or both. Type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) are the most prevalent forms, whereas Maturity-Onset Diabetes of the Young (MODY) represents a monogenic subtype, often misdiagnosed due to its phenotypic overlap. This case study highlights a 26-year-old male initially diagnosed with T1DM at age 12, managed with insulin therapy. Upon admission, despite stable glycemic control and preserved C-peptide secretion, genetic testing revealed MODY 2 due to a variant in the GCK gene. Unlike T1DM and T2DM, MODY 2 is characterized by mild, persistent hyperglycemia with a low risk of complications, emphasizing the importance of genetic diagnosis for tailored management and family counseling. This case underscores the critical role of genetic evaluation in accurately diagnosing and managing atypical diabetes presentations. more...
- Published
- 2024
- Full Text
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48. Clinical prediction model for MODY type diabetes mellitus in children
- Author
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D. N. Laptev, E. A. Sechko, E. M. Romanenkova, I. A. Eremina, O. B. Bezlepkina, V. A. Peterkova, and N. G. Mokrysheva
- Subjects
diabetes mellitus in children ,mody ,monogenic diabetes mellitus ,clinical decision support system ,mody prediction model ,Nutritional diseases. Deficiency diseases ,RC620-627 - Abstract
BACKGROUND: MODY (maturity-onset diabetes of the young) is a rare monogenic form of diabetes mellitus, the gold standard of diagnosis is mutations detection in the genes responsible for the development of this form diabetes. Genetic test is expensive and takes a lot of time. The diagnostic criteria for MODY are well known. The development of clinical decision support system (CDSS) which allows physicians based on clinical data to determine who should have molecular genetic testing is relevant.AIM: Provided a retrospective analysis of clinical data of the patients with T1DM and MODY, from 0 to 18 years old, regardless of the duration of the disease to develop the model. Based on clinical data, a feedforward neural network (NN) was implemented - a multilayer perceptron.MATERIALS AND METHODS: Development of the most effective algorithm for predicting MODY in children based on available clinical indicators of 1710 patients with diabetes under the age of 18 years using a multilayer feedforward neural network.RESULTS: The sample consisted of 1710 children under the age of 18 years with T1DM (78%) and MODY (22%) diabetes. For the final configuration of NS the following predictors were selected: gender, age at passport age, age at the diagnosis with DM, HbA1c, BMI SDS, family history of DM, treatment. The performance (quality) assessment of the NN was carried out on a test sample (the area under the ROC (receiver operating characteristics) curve reached 0.97). The positive predictive value of PCPR was achieved at a cut-off value of 0.40 (predicted probability of MODY diabetes 40%). At which the sensitivity was 98%, specificity 93%, PCR with prevalence correction was 78%, and PCR with prevalence correction was 99%, the overall accuracy of the model was 94%.Based on the NN model, a CDSS was developed to determine whether a patient has MODY diabetes, implemented as an application.CONCLUSION: The clinical prediction model MODY developed in this work based on the NN, uses the clinical characteristic available for each patient to determine the probability of the patient having MODY. The use of the developed model in clinical practice will assist in the selection of patients for diagnostic genetic testing for MODY, which will allow for the efficient allocation of healthcare resources, the selection of personalized treatment and patient monitoring. more...
- Published
- 2024
- Full Text
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49. UDP-Glucose: A Cereblon-Dependent Glucokinase Protein Degrader.
- Author
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Yamamura, Hatsuo, Imai, Takeshi, Cho, Jaeyong, Miyagawa, Atsushi, Yamaguchi, Kazuki, Abe, Wakana, Tsugawa, Yoji, and Tsugawa, Yusuke
- Subjects
MODY ,PROTACs ,UDP-glucose ,diabetes ,glucokinase ,glucose ,insulin ,protein degrader ,Animals ,Diabetes Mellitus ,Type 2 ,Glucokinase ,Glucose ,Glucose-6-Phosphate ,Insulin ,Mice ,Mutation ,Uridine Diphosphate Glucose - Abstract
We previously reported that glucokinase is ubiquitinated and degraded by cereblon with an unknown endogenous glucokinase protein degrader. Here, we show that UDP-glucose is a glucokinase protein degrader. We identified that both glucose and UDP-glucose bind to glucokinase and that both uridine and UDP-glucose bind to cereblon in a similar way to thalidomide. From these results, UDP-glucose was identified as a molecular glue between cereblon and glucokinase. Glucokinase produces glucose-6-phosphate in the pancreas and liver. Especially in β-cells, glucokinase is the main target of glucose for glucose-induced insulin secretion. UDP-glucose administration ubiquitinated and degraded glucokinase, lowered glucose-6-phosphate production, and then reduced insulin secretion in β-cell lines and mice. Maturity-onset diabetes of the young type 2 (MODY2) glucokinaseE256K mutant protein was resistant to UDP-glucose induced ubiquitination and degradation. Taken together, glucokinase ubiquitination and degradation signaling might be impaired in MODY2 patients. more...
- Published
- 2022
50. Unraveling the genetic basis of MODY: insights from next-generation sequencing
- Author
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Eser, Metin, Hekimoglu, Gulam, and Dursun, Fatma
- Published
- 2024
- Full Text
- View/download PDF
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