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Bhattacharya S, Fernandez CJ, Kamrul-Hasan ABM, Pappachan JM. Monogenic diabetes: An evidence-based clinical approach. World J Diabetes 2025; 16:104787. [DOI: 10.4239/wjd.v16.i5.104787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/20/2025] [Accepted: 03/11/2025] [Indexed: 04/25/2025] Open
Abstract
Monogenic diabetes is a heterogeneous disorder characterized by hyperglycemia arising from defects in a single gene. Maturity-onset diabetes of the young (MODY) is the most common type with 14 subtypes, each linked to specific mutations affecting insulin synthesis, secretion and glucose regulation. Common traits across MODY subtypes include early-onset diabetes, a family history of autosomal dominant diabetes, lack of features of insulin resistance, and absent islet cell autoimmunity. Many cases are misdiagnosed as type 1 and type 2 diabetes mellitus. Biomarkers and scoring systems can help identify candidates for genetic testing. GCK-MODY, a common subtype, manifests as mild hyperglycemia and doesn’t require treatment except during pregnancy. In contrast, mutations in HNF4A, HNF1A, and HNF1B genes lead to progressive beta-cell failure and similar risks of complications as type 2 diabetes mellitus. Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes that usually presents within the first six months. Half of the cases are lifelong, while others experience transient remission. Permanent NDM is most commonly due to activating mutations in genes encoding the adenosine triphosphate-sensitive potassium channel (KCNJ11 or ABCC8) and can be transitioned to sulfonylurea after confirmation of diagnosis. Thus, in many cases, monogenic diabetes offers an opportunity to provide precision treatment. The scope has broadened with next-generation sequencing (NGS) technologies, replacing older methods like Sanger sequencing. NGS can be for targeted gene panels, whole-exome sequencing (WES), or whole-genome sequencing. Targeted gene panels offer specific information efficiently, while WES provides comprehensive data but comes with bioinformatic challenges. The surge in testing has also led to an increase in variants of unknown significance (VUS). Deciding whether VUS is disease-causing or benign can be challenging. Computational models, functional studies, and clinical knowledge help to determine pathogenicity. Advances in genetic testing technologies offer hope for improved diagnosis and personalized treatment but also raise concerns about interpretation and ethics.
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Affiliation(s)
| | - Cornelius J Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, Lincolnshire, United Kingdom
| | | | - Joseph M Pappachan
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, Greater Manchester, United Kingdom
- Department of Endocrinology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India
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Knorr S, Knudsen LL, Madsen AL, Madsen LR, Mortensen L, Thomsen HH, Sørensen LP, Ovesen PG, Fuglsang J, Kampmann U. Shortcut to the needle in the haystack? Screening for maturity onset diabetes of the young in a population of women with gestational diabetes. Diabet Med 2025; 42:e70021. [PMID: 40051305 PMCID: PMC12006555 DOI: 10.1111/dme.70021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Revised: 02/20/2025] [Accepted: 02/20/2025] [Indexed: 04/19/2025]
Abstract
AIMS Pregnant women are occasionally misdiagnosed with gestational diabetes (GDM) when they may have glucokinase monogenic diabetes (GCK-MODY). Differentiating between GCK-MODY and GDM is critical due to the distinct treatment strategies required during and after pregnancy. Since pregnancy often elicits the first glucose tolerance test, it provides a unique opportunity to identify individuals with GCK-MODY. However, testing all pregnant women with GDM for GCK-MODY is expensive, and the use of clinical criteria is warranted. An Irish study suggested using a combined criteria of a pre-pregnancy body mass index (BMI) <25 kg/m2 and fasting glucose ≥5.5 mmol/L to differentiate GCK-MODY from GDM. Therefore, we aimed to identify women with GCK-MODY during pregnancy using these combined criteria in a Danish population of women with GDM. Additionally, we aimed to screen for other MODY subtypes. METHODS We recruited women from the Central Denmark Region diagnosed with GDM between April 2019 and December 2022. Women meeting the criteria of pre-pregnancy BMI <25 kg/m2 and fasting glucose ≥5.5 mmol/L were offered screening for MODY (17 known genetic variants) using Illumina's Next Generation Sequencing. RESULTS Of the 1270 women with GDM, 46 met the MODY screening criteria. Of these, 41 were offered MODY screening, 34 participated and 1 woman was identified with MODY (MODY 8-CEL variant). CONCLUSION The current Danish GDM screening guidelines do not apply with recommending the use of pre-pregnancy BMI <25 kg/m2 and fasting glucose ≥5.5 mmol/L as criteria for identifying women with GCK-MODY among women with GDM in the Danish population.
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Affiliation(s)
- Sine Knorr
- Steno Diabetes Center Aarhus, Aarhus University HospitalAarhusDenmark
| | - Laura L. Knudsen
- Steno Diabetes Center Aarhus, Aarhus University HospitalAarhusDenmark
| | - Anne L. Madsen
- Steno Diabetes Center Aarhus, Aarhus University HospitalAarhusDenmark
| | - Lene R. Madsen
- Steno Diabetes Center Aarhus, Aarhus University HospitalAarhusDenmark
- Department of Internal MedicineGødstrup HospitalGødstrupDenmark
- Danish Diabetes AcademyOdense University HospitalOdenseDenmark
| | - Lene Mortensen
- Department of Internal MedicineHorsens Regional HospitalHorsensDenmark
| | - Henrik H. Thomsen
- Department of Internal MedicineViborg Regional HospitalViborgDenmark
- Department of Clinical MedicineAarhus UniversityAarhusDenmark
| | | | - Per G. Ovesen
- Steno Diabetes Center Aarhus, Aarhus University HospitalAarhusDenmark
- Department of Clinical MedicineAarhus UniversityAarhusDenmark
- Department of Gynecology and ObstetricsAarhus University HospitalAarhusDenmark
| | - Jens Fuglsang
- Steno Diabetes Center Aarhus, Aarhus University HospitalAarhusDenmark
- Department of Clinical MedicineAarhus UniversityAarhusDenmark
- Department of Gynecology and ObstetricsAarhus University HospitalAarhusDenmark
| | - Ulla Kampmann
- Steno Diabetes Center Aarhus, Aarhus University HospitalAarhusDenmark
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Aldharee H, Hamdan HZ. In Silico Analysis Identified Putative Pathogenic Missense Single Nucleotide Polymorphisms (SNPs) in the Human HNF1A Gene. Int J Mol Sci 2025; 26:3768. [PMID: 40332430 PMCID: PMC12027519 DOI: 10.3390/ijms26083768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2025] [Revised: 03/29/2025] [Accepted: 04/15/2025] [Indexed: 05/08/2025] Open
Abstract
Maturity-onset diabetes of the young (MODY) is a rare genetic condition that affects children, adolescents, and adults. Studies have shown that genetic changes in the HNF1A gene are associated with MODY-3. However, most of the causative variants and the molecular mechanisms remain underexplored. This study aims to better understand MODY-3 by investigating HNF1A-missense variants with clinical uncertainty. Various bioinformatics tools were utilised to address the clinical uncertainty of missense variants in the HNF1A gene that have not been linked with HNF1A-related conditions, sourced from the Genome Aggregation Database (GnomAD v4.1.0). Among the clinically uncertain 2444 variants, only 138 were classified as missense with clinically uncertain significance. Results show that four variants (Arg168Cys, Glu275Ala, Gly375Asp and Val411Phe) were consistently predicted as pathogenic by all tools. The allele frequency (AF) of the commonly predicted disease-causing variants was very low in the global population. The assessment of the secondary structure of filtered variants indicates that variants (Arg168Cys and Glu275Ala) are located in the helical region of the HNF1A protein. At the same time (Gly375Asp and Val411Phe) are found in the protein's coil, suggesting structural changes at the site of variations. The prediction of protein stability was conducted using I-Mutant and MuPro. Both tools collectively indicate decreased protein stability for the variants (Arg168Cys, Glu275Ala, Gly375Asp and Val411Phe). Predicting the protein's 3D structure for the HNF1A wild-type and mutants indicates potential structural damages in Arg168Cys and Gly375Asp. Additionally, results show that the amino acids at the variation sites of the variants (Arg168Cys, Glu275Ala, Gly375Asp and Val411Phe) were highly conserved. To conclude, 4 out of the 138 missense variants labelled as uncertain significance were found to be consistently pathogenic using in silico tools in this study. Our findings aim to support variant interpretation, understand the genotype-phenotype association of diabetes, and provide better healthcare services for patients with diabetes.
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Affiliation(s)
- Hitham Aldharee
- Department of Pathology, College of Medicine, Qassim University, Buraidah 51452, Saudi Arabia;
- Unit of Genetic Diabetes, Abdullah Al Othaim Diabetes Center, Medical City, Qassim University, Buraidah 51452, Saudi Arabia
| | - Hamdan Z. Hamdan
- Department of Pathology, College of Medicine, Qassim University, Buraidah 51452, Saudi Arabia;
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Phadnis A, Chawla D, Alex J, Jha P. Decoding MODY: exploring genetic roots and clinical pathways. Diabetol Int 2025; 16:257-271. [PMID: 40166432 PMCID: PMC11954780 DOI: 10.1007/s13340-025-00809-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 02/25/2025] [Indexed: 04/02/2025]
Abstract
Purpose Maturity-onset diabetes of the young (MODY) is a transformative factor in today's pattern of diabetes care. The definition of its genetic basis brings insight into the diabetes processes, opening up possibilities for its early detection through public health strategies and improvement in precision medicine. Current knowledge on MODY has been brought together in this review. Methods Extensive literature review on PubMed and Google Scholar databases was conducted. Studies encompassing (1) genetic underpinnings and their types, (2) the significance of its biomarkers, and (3) diagnostic techniques and treatment modalities were focused upon. Results The disease accounts for 1-2% of all cases of diabetes and is usually misdiagnosed as either Type 1 or Type 2 diabetes. Several genes are involved in the appropriate functioning of pancreatic β-cells and mutations in these genes lead to an impairment in glucose metabolism and insulin secretion. A mild degree of hyperglycaemia, but without ketosis, is typical of MODY, seen mostly in adolescents and young adults. Treatment varies, including sulfonylureas for HNF1A and HNF4A mutations, lifestyle management for GCK mutations, and emerging therapies like GLP1 receptor agonists. Conclusion Proper genetic diagnosis is cardinal to the best management of MODY. Genetic and clinical advances have been impressive in monogenic diabetes, but further research in novel therapies is needed to optimise outcomes with precision medicine.
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Affiliation(s)
- Anshuman Phadnis
- Department of Biological Sciences, Sunandan Divatia School of Science, NMIMS Deemed to Be University, Mumbai, Maharashtra India
| | - Diya Chawla
- Department of Biological Sciences, Sunandan Divatia School of Science, NMIMS Deemed to Be University, Mumbai, Maharashtra India
| | - Joanne Alex
- Department of Biological Sciences, Sunandan Divatia School of Science, NMIMS Deemed to Be University, Mumbai, Maharashtra India
| | - Pamela Jha
- Department of Biological Sciences, Sunandan Divatia School of Science, NMIMS Deemed to Be University, Mumbai, Maharashtra India
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Bazzazzadehgan S, Shariat-Madar Z, Mahdi F. Distinct Roles of Common Genetic Variants and Their Contributions to Diabetes: MODY and Uncontrolled T2DM. Biomolecules 2025; 15:414. [PMID: 40149950 PMCID: PMC11940602 DOI: 10.3390/biom15030414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/26/2025] [Accepted: 03/10/2025] [Indexed: 03/29/2025] Open
Abstract
Type 2 diabetes mellitus (T2DM) encompasses a range of clinical manifestations, with uncontrolled diabetes leading to progressive or irreversible damage to various organs. Numerous genes associated with monogenic diabetes, exhibiting classical patterns of inheritance (autosomal dominant or recessive), have been identified. Additionally, genes involved in complex diabetes, which interact with environmental factors to trigger the disease, have also been discovered. These genetic findings have raised hopes that genetic testing could enhance diagnostics, disease surveillance, treatment selection, and family counseling. However, the accurate interpretation of genetic data remains a significant challenge, as variants may not always be definitively classified as either benign or pathogenic. Research to date, however, indicates that periodic reevaluation of genetic variants in diabetes has led to more consistent findings, with biases being steadily eliminated. This has improved the interpretation of variants across diverse ethnicities. Clinical studies suggest that genetic risk information may motivate patients to adopt behaviors that promote the prevention or management of T2DM. Given that the clinical features of certain monogenic diabetes types overlap with T2DM, and considering the significant role of genetic variants in diabetes, healthcare providers caring for prediabetic patients should consider genetic testing as part of the diagnostic process. This review summarizes current knowledge of the most common genetic variants associated with T2DM, explores novel therapeutic targets, and discusses recent advancements in the pharmaceutical management of uncontrolled T2DM.
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Affiliation(s)
- Shadi Bazzazzadehgan
- Department of Pharmacy Administration, School of Pharmacy, University of Mississippi, University, MS 38677, USA;
| | - Zia Shariat-Madar
- Division of Pharmacology, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA;
| | - Fakhri Mahdi
- Division of Pharmacology, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA;
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Wong A, Alejandro EU. Post translational modification regulation of transcription factors governing pancreatic β-cell identity and functional mass. Front Endocrinol (Lausanne) 2025; 16:1562646. [PMID: 40134803 PMCID: PMC11932907 DOI: 10.3389/fendo.2025.1562646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2025] [Accepted: 02/17/2025] [Indexed: 03/27/2025] Open
Abstract
Dysfunction of the insulin-secreting β-cells is a key hallmark of Type 2 diabetes (T2D). In the natural history of the progression of T2D, factors such as genetics, early life exposures, lifestyle, and obesity dictate an individual's susceptibility risk to disease. Obesity is associated with insulin resistance and increased demand for insulin to maintain glucose homeostasis. Studies in both mouse and human islets have implicated the β-cell's ability to compensate through proliferation and survival (increasing functional β-cell mass) as a tipping point toward the development of disease. A growing body of evidence suggests the reduction of β-cell mass in T2D is driven majorly by loss of β-cell identity, rather than by apoptosis alone. The development and maintenance of pancreatic β-cell identity, function, and adaptation to stress is governed, in part, by the spatiotemporal expression of transcription factors (TFs), whose activity is regulated by signal-dependent post-translational modifications (PTM). In this review, we examine the role of these TFs in the developing pancreas and in the mature β-cell. We discuss functional implications of post-translational modifications on these transcription factors' activities and how an understanding of the pathways they regulate can inform therapies to promoteβ-cell regeneration, proliferation, and survival in diabetes.
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Affiliation(s)
- Alicia Wong
- Department of Genetics, Cell Biology, and Development, University of Minnesota Twin Cities, Minneapolis, MN, United States
| | - Emilyn U. Alejandro
- Department of Integrative Biology and Physiology, University of Minnesota Twin Cities, Minneapolis, MN, United States
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Xi X, Li J, Jia J, Meng Q, Li C, Wang X, Wei L, Zhang X. A mechanism-informed deep neural network enables prioritization of regulators that drive cell state transitions. Nat Commun 2025; 16:1284. [PMID: 39900922 PMCID: PMC11790924 DOI: 10.1038/s41467-025-56475-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Accepted: 01/15/2025] [Indexed: 02/05/2025] Open
Abstract
Cells are regulated at multiple levels, from regulations of individual genes to interactions across multiple genes. Some recent neural network models can connect molecular changes to cellular phenotypes, but their design lacks modeling of regulatory mechanisms, limiting the decoding of regulations behind key cellular events, such as cell state transitions. Here, we present regX, a deep neural network incorporating both gene-level regulation and gene-gene interaction mechanisms, which enables prioritizing potential driver regulators of cell state transitions and providing mechanistic interpretations. Applied to single-cell multi-omics data on type 2 diabetes and hair follicle development, regX reliably prioritizes key transcription factors and candidate cis-regulatory elements that drive cell state transitions. Some regulators reveal potential new therapeutic targets, drug repurposing possibilities, and putative causal single nucleotide polymorphisms. This method to analyze single-cell multi-omics data demonstrates how the interpretable design of neural networks can better decode biological systems.
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Affiliation(s)
- Xi Xi
- MOE Key Laboratory of Bioinformatics and Bioinformatics Division, BNRIST / Department of Automation, Tsinghua University, Beijing, China
| | - Jiaqi Li
- MOE Key Laboratory of Bioinformatics and Bioinformatics Division, BNRIST / Department of Automation, Tsinghua University, Beijing, China
| | - Jinmeng Jia
- MOE Key Laboratory of Bioinformatics and Bioinformatics Division, BNRIST / Department of Automation, Tsinghua University, Beijing, China
| | - Qiuchen Meng
- MOE Key Laboratory of Bioinformatics and Bioinformatics Division, BNRIST / Department of Automation, Tsinghua University, Beijing, China
| | - Chen Li
- MOE Key Laboratory of Bioinformatics and Bioinformatics Division, BNRIST / Department of Automation, Tsinghua University, Beijing, China
| | - Xiaowo Wang
- MOE Key Laboratory of Bioinformatics and Bioinformatics Division, BNRIST / Department of Automation, Tsinghua University, Beijing, China
| | - Lei Wei
- MOE Key Laboratory of Bioinformatics and Bioinformatics Division, BNRIST / Department of Automation, Tsinghua University, Beijing, China
| | - Xuegong Zhang
- MOE Key Laboratory of Bioinformatics and Bioinformatics Division, BNRIST / Department of Automation, Tsinghua University, Beijing, China.
- School of Life Sciences, Tsinghua University, Beijing, China.
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Werner C, Schmidt S, Kellner C, Burghardt K, Reuken PA, Kloos C, Wolf G. [Striking manifestation and unexpected therapeutic course of diabetes mellitus in a 22-year-old male patient]. INNERE MEDIZIN (HEIDELBERG, GERMANY) 2025; 66:236-240. [PMID: 39342034 PMCID: PMC11799017 DOI: 10.1007/s00108-024-01797-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 09/04/2024] [Indexed: 10/01/2024]
Abstract
The case of a 22-year-old male patient who presented with acute on chronic hyperglycemia in known MODY ("maturity onset diabetes of the young") 12 (ABCC8 gene) after 11 months of treatment cessation is reported. To emphasize the importance of the awareness of this therapeutically important entity of diabetes, the essential facts of this inherited disease are summarized.
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Affiliation(s)
- Christoph Werner
- Klinik für Innere Medizin III, FB Endokrinologie und Stoffwechselerkrankungen, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland.
| | - Sebastian Schmidt
- Klinik für Innere Medizin III, FB Endokrinologie und Stoffwechselerkrankungen, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
| | - Christiane Kellner
- Klinik für Innere Medizin III, FB Endokrinologie und Stoffwechselerkrankungen, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
| | - Katharina Burghardt
- Praxis für Humangenetik, Zentrum für ambulante Medizin, Universitätsklinikum Jena, Jena, Deutschland
| | - Philipp A Reuken
- Klinik für Innere Medizin IV, Universitätsklinikum Jena, Jena, Deutschland
| | - Christof Kloos
- Klinik für Innere Medizin III, FB Endokrinologie und Stoffwechselerkrankungen, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
| | - Gunter Wolf
- Klinik für Innere Medizin III, FB Endokrinologie und Stoffwechselerkrankungen, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
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Sharma M, Maurya K, Nautiyal A, Chitme HR. Monogenic Diabetes: A Comprehensive Overview and Therapeutic Management of Subtypes of Mody. Endocr Res 2025; 50:1-11. [PMID: 39106207 DOI: 10.1080/07435800.2024.2388606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Revised: 07/21/2024] [Accepted: 07/31/2024] [Indexed: 08/09/2024]
Abstract
BACKGROUND Monogenic 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. METHODS 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. RESULTS 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. CONCLUSION 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.
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Affiliation(s)
- Manisha Sharma
- Department of Pharmacy Practice, School of Pharmaceutical Sciences, Shri Guru Ram Rai University, Dehradun, Uttarakhand, India
| | - Kajal Maurya
- Department of Pharmacy Practice, School of Pharmaceutical Sciences, Shri Guru Ram Rai University, Dehradun, Uttarakhand, India
| | - Anuj Nautiyal
- Department of Pharmacy Practice, School of Pharmaceutical Sciences, Shri Guru Ram Rai University, Dehradun, Uttarakhand, India
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Golounina O, Minniakhmetov I, Salakhov R, Khusainova R, Zakharova E, Bychkov I, Mokrysheva N. Pathogenetic therapeutic approaches for endocrine diseases based on antisense oligonucleotides and RNA-interference. Front Endocrinol (Lausanne) 2025; 16:1525373. [PMID: 39944202 PMCID: PMC11813780 DOI: 10.3389/fendo.2025.1525373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Accepted: 01/13/2025] [Indexed: 05/09/2025] Open
Abstract
Molecular therapy uses nucleic acid-based therapeutics agents and becomes a promising alternative for disease conditions unresponsive to traditional pharmaceutical approaches. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are two well-known strategies used to modulate gene expression. RNA-targeted therapy can precisely modulate the function of target RNA with minimal off-target effects and can be rationally designed based on sequence data. ASOs and siRNA-based drugs have unique capabilities for using in target groups of patients or can be tailored as patient-customized N-of-1 therapeutic approach. Antisense therapy can be utilized not only for the treatment of monogenic diseases but also holds significant promise for addressing polygenic and complex diseases by targeting key genes and molecular pathways involved in disease pathogenesis. In the context of endocrine disorders, molecular therapy is particularly effective in modulating pathogenic mechanisms such as defective insulin signaling, beta-cell dysfunction and hormonal imbalances. Furthermore, siRNA and ASOs have the ability to downregulate overactive signaling pathways that contribute to complex, non-monogenic endocrine disorders, thereby addressing these conditions at their molecular origin. ASOs are also being studied worldwide as unique candidates for developing therapies for N-of-1 therapies. The sequence-specific ASOs binding provides exceptional accuracy in N-of-1 approaches, when the oligonucleotide can be targeted to a patient's exact mutant sequence. In this review we focus on diseases of the endocrine system and discuss potential RNA-targeted therapeutic opportunities in diabetes mellitus, including monogenic beta cell diabetes, and obesity, including syndrome obesity and monogenic obesity, as well as in non-monogenic or complex endocrine disorders. We also provide an overview of currently developed and available antisense molecules, and describe potentials of antisense-based therapeutics for the treatment of rare and «ultrarare» endocrine diseases.
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Affiliation(s)
- Olga Golounina
- Department of Clinical Endocrinology, Endocrinology Research Centre, Moscow, Russia
| | - Ildar Minniakhmetov
- Laboratory of Genomic Medicine, Endocrinology Research Centre, Moscow, Russia
| | - Ramil Salakhov
- Laboratory of Genomic Medicine, Endocrinology Research Centre, Moscow, Russia
| | - Rita Khusainova
- Laboratory of Genomic Medicine, Endocrinology Research Centre, Moscow, Russia
| | - Ekaterina Zakharova
- Selective Screening Laboratory, Research Centre for Medical Genetics, Moscow, Russia
| | - Igor Bychkov
- Laboratory of Experimental Gene Therapy for Inherited Metabolic Diseases, Research Centre for Medical Genetics, Moscow, Russia
| | - Natalia Mokrysheva
- Department of Clinical Endocrinology, Endocrinology Research Centre, Moscow, Russia
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Dzhemileva LU, Zakharova EN, Goncharenko AO, Vorontsova MV, Rumyantsev SA, Mokrysheva NG, Loguinova MY, Chekhonin VP. Current views on etiology, diagnosis, epidemiology and gene therapy of maturity onset diabetes in the young. Front Endocrinol (Lausanne) 2025; 15:1497298. [PMID: 39902162 PMCID: PMC11788143 DOI: 10.3389/fendo.2024.1497298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 12/27/2024] [Indexed: 02/05/2025] Open
Abstract
MODY, or maturity-onset diabetes of the young, is a group of monogenic diseases characterized by autosomal dominant inheritance of a non-insulin-dependent form of diabetes that classically manifests in adolescence or in young adults under 25 years of age. MODY is a rare cause of diabetes, accounting for 1% of all cases, and is often misdiagnosed as type 1 or type 2 diabetes. It is of great importance to accurately diagnose MODY, as this allows for the most appropriate treatment of patients and facilitates early diagnosis for them and their families. This disease has a high degree of phenotypic and genetic polymorphism. The most prevalent forms of the disease are attributed to mutations in three genes: GCK (MODY 2) and (HNF)1A/4A (MODY 3 and MODY 1). The remaining MODY subtypes, which are less prevalent, have been identified by next generation sequencing (NGS) in the last decade. Mutations in the GCK gene result in asymptomatic, stable fasting hyperglycemia, which does not require specific treatment. Mutations in the HNF1A and HNF4A genes result in pancreatic β-cell dysfunction, which in turn causes hyperglycemia. This often leads to diabetic angiopathy. The most commonly prescribed drugs for the treatment of hyperglycemia are sulfonylurea derivatives. Nevertheless, with advancing age, some patients may require insulin therapy due to the development of resistance to sulfonylurea drugs. The strategy of gene therapy for monogenic forms of MODY is still an experimental approach, and it is unlikely to be widely used in the clinic due to the peculiarities of MODY structure and the high genetic polymorphism and clinical variability even within the same form of the disease. Furthermore, there is a lack of clear gene-phenotypic correlations, and there is quite satisfactory curability in the majority of patients. This review presents the main clinical and genetic characteristics and mutation spectrum of common and rarer forms of MODY, with a detailed analysis of the field of application of AVV vectors in the correction of hyperglycemia and insulin resistance.
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Minniakhmetov IR, Khusainova RI, Laptev DN, Yalaev BI, Karpova YS, Deev RV, Salakhov RR, Panteleev DD, Smirnov KV, Melnichenko GA, Shestakova MV, Mokrysheva NG. Genetic Structure of Hereditary Forms of Diabetes Mellitus in Russia. Int J Mol Sci 2025; 26:740. [PMID: 39859454 PMCID: PMC11766241 DOI: 10.3390/ijms26020740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 12/30/2024] [Accepted: 12/31/2024] [Indexed: 01/27/2025] Open
Abstract
Analyzing the genetic architecture of hereditary forms of diabetes in different populations is a critical step toward optimizing diagnostic and preventive algorithms. This requires consideration of regional and population-specific characteristics, including the spectrum and frequency of pathogenic variants in targeted genes. As part of this study, we used a custom-designed NGS panel to screen for mutations in 28 genes associated with the pathogenesis of hereditary diabetes mellitus in 506 unrelated patients from Russia. The study identified 180 pathogenic or likely pathogenic variants across 13 genes (GCK, HNF1A, HNF1B, HNF4A, ABCC8, INS, INSR, KCNJ11, PAX4, PDX1, ZFP57, BLK, WFS1), representing 46.44% of the analyzed cohort (235 individuals). The glucokinase gene (GCK) had the highest number of identified variants, with 111 variants detected in 161 patients, 20 of which were identified for the first time. In the tissue-specific transcription factor genes HNF1A, HNF4A, and HNF1B, 34 variants were found in 38 patients, including 13 that were previously unreported. Seventeen variants were identified in the ABCC8 gene, which encodes the ATP-binding cassette transporter 8 of subfamily C, each found in a different patient; four of these were novel discoveries. Nine pathogenic or likely pathogenic variants were identified in the insulin gene (INS) and its receptor gene (INSR), including four previously unreported variants. Additionally, we identified 10 previously unreported variants in six other genes among 11 patients. Variants in the genes GCK, HNF1A, HNF1B, HNF4A, ABCC8, INS, and INSR were the main contributors to the genetic pathogenesis of hereditary diabetes mellitus in the Russian cohort. These findings enhance our understanding of the molecular mechanisms underlying the disease and provide a solid basis for future studies aimed at improving diagnostic accuracy and advancing personalized therapeutic strategies. This knowledge provides a foundation for developing region-specific genetic testing algorithms and personalized therapeutic strategies, which are critical for future initiatives in precision medicine.
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Affiliation(s)
- Ildar R. Minniakhmetov
- Endocrinology Research Center, Moscow 117292, Russia; (R.I.K.); (D.N.L.); (B.I.Y.); (Y.S.K.); (R.V.D.); (R.R.S.); (D.D.P.); (K.V.S.); (G.A.M.); (M.V.S.); (N.G.M.)
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13
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耿 荟, 汪 治. [Research advances in maturity-onset diabetes of the young]. ZHONGGUO DANG DAI ER KE ZA ZHI = CHINESE JOURNAL OF CONTEMPORARY PEDIATRICS 2025; 27:121-126. [PMID: 39825662 PMCID: PMC11750248 DOI: 10.7499/j.issn.1008-8830.2408070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Accepted: 11/20/2024] [Indexed: 01/20/2025]
Abstract
Maturity-onset diabetes of the young (MODY) is a special type of diabetes characterized by clinical features including early onset of diabetes (before 30 years of age), autosomal dominant inheritance, impaired glucose-induced insulin secretion, and hyperglycemia. So far, 14 types of MODY have been reported, accounting for about 1%-5% of the patients with diabetes. MODY often presents with an insidious onset, and although 14 subtypes have been identified for MODY, it is frequently misdiagnosed as type 1 or type 2 diabetes due to overlapping clinical features and high costs and limitations of genetic testing. This article reviews the clinical features of MODY subtypes in order to improve the accuracy of the diagnosis and treatment of MODY.
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Affiliation(s)
| | - 治华 汪
- 西安交通大学附属儿童医院内分泌遗传代谢科,陕西西安710003
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14
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Jia W, Chan JC, Wong TY, Fisher EB. Diabetes in China: epidemiology, pathophysiology and multi-omics. Nat Metab 2025; 7:16-34. [PMID: 39809974 DOI: 10.1038/s42255-024-01190-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 11/25/2024] [Indexed: 01/16/2025]
Abstract
Although diabetes is now a global epidemic, China has the highest number of affected people, presenting profound public health and socioeconomic challenges. In China, rapid ecological and lifestyle shifts have dramatically altered diabetes epidemiology and risk factors. In this Review, we summarize the epidemiological trends and the impact of traditional and emerging risk factors on Chinese diabetes prevalence. We also explore recent genetic, metagenomic and metabolomic studies of diabetes in Chinese, highlighting their role in pathogenesis and clinical management. Although heterogeneity across these multidimensional areas poses major analytic challenges in classifying patterns or features, they have also provided an opportunity to increase the accuracy and specificity of diagnosis for personalized treatment and prevention. National strategies and ongoing research are essential for improving diabetes detection, prevention and control, and for personalizing care to alleviate societal impacts and maintain quality of life.
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Affiliation(s)
- Weiping Jia
- Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology and Metabolism, Shanghai Diabetes Institute, Shanghai Clinical Center for Diabetes, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
- Institute for Proactive Healthcare, Shanghai Jiao Tong University, Shanghai, China.
| | - Juliana Cn Chan
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences and Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Tien Y Wong
- Tsinghua Medicine, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
- Singapore National Eye Center, SingHealth, Singapore, Singapore
| | - Edwin B Fisher
- Peers for Progress, Department of Health Behavior, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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15
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Chua C, Tan CSH, Lim SC, Vasanwala RF. A Unique Phenotype of Maturity-Onset Diabetes of the Young With a Novel Disease-Causing Insulin Gene Variant. JCEM CASE REPORTS 2025; 3:luae230. [PMID: 39717432 PMCID: PMC11663494 DOI: 10.1210/jcemcr/luae230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/31/2024] [Indexed: 12/25/2024]
Abstract
Maturity-onset diabetes of the young (MODY) represents 1% to 5% of patients with diabetes mellitus (DM), and numerous genes associated with MODY have been identified. While mutations of the insulin gene (INS) are known to cause permanent neonatal DM, rare disease-causing variants have also been found in MODY. These patients demonstrate variable clinical phenotypes-from milder forms requiring lifestyle or oral agent interventions to severe forms requiring lifelong insulin. We present a case of MODY arising from a novel disease-causing INS variant, in an adolescent with atypical features. He was obese with clinical evidence of insulin resistance, diagnosed with DM through opportunistic oral glucose tolerance testing. He developed symptomatic hyperglycemia with worsening glycemic trend, requiring treatment with high-dose insulin and metformin. After 2.5 years, his glycemic profile normalized following weight loss, and pharmacotherapy was discontinued. Targeted gene testing revealed a de novo novel missense variant in exon 2 of the INS gene (p.His29Tyr), confirmed using bidirectional Sanger sequencing. Insulin resistance in patients with MODY can worsen their clinical course and increase risks of long-term complications. Management of these patients should be individualized. This case highlights the utility of genetic testing in diagnosing uncommon and variable forms of MODY, particularly those with atypical features.
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Affiliation(s)
- Cherie Chua
- Department of Paediatric Endocrinology, Kandang Kerbau Women's and Children's Hospital, 229899 Singapore
| | - Clara Si Hua Tan
- Clinical Research Unit, Khoo Teck Puat Hospital, 768828 Singapore
| | - Su Chi Lim
- Diabetes Centre, Khoo Teck Puat Hospital, 768828 Singapore
- Department of Medicine, Khoo Teck Puat Hospital, 768828 Singapore
| | - Rashida Farhad Vasanwala
- Department of Paediatric Endocrinology, Kandang Kerbau Women's and Children's Hospital, 229899 Singapore
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16
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Kingsmore SF, Wright M, Smith LD, Liang Y, Mowrey WR, Protopsaltis L, Bainbridge M, Baker M, Batalov S, Blincow E, Cao B, Caylor S, Chambers C, Ellsworth K, Feigenbaum A, Frise E, Guidugli L, Hall KP, Hansen C, Kiel M, Van Der Kraan L, Krilow C, Kwon H, Madhavrao L, Lefebvre S, Leipzig J, Mardach R, Moore B, Oh D, Olsen L, Ontiveros E, Owen MJ, Reimers R, Scharer G, Schleit J, Shelnutt S, Mehtalia SS, Oriol A, Sanford E, Schwartz S, Wigby K, Willis MJ, Yandell M, Kunard CM, Defay T. Prequalification of genome-based newborn screening for severe childhood genetic diseases through federated training based on purifying hyperselection. Am J Hum Genet 2024; 111:2618-2642. [PMID: 39642867 PMCID: PMC11639087 DOI: 10.1016/j.ajhg.2024.10.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2024] [Revised: 10/29/2024] [Accepted: 10/30/2024] [Indexed: 12/09/2024] Open
Abstract
Genome-sequence-based newborn screening (gNBS) has substantial potential to improve outcomes in hundreds of severe childhood genetic disorders (SCGDs). However, a major impediment to gNBS is imprecision due to variants classified as pathogenic (P) or likely pathogenic (LP) that are not SCGD causal. gNBS with 53,855 P/LP variants, 342 genes, 412 SCGDs, and 1,603 therapies was positive in 74% of UK Biobank (UKB470K) adults, suggesting 97% false positives. We used the phenomenon of purifying hyperselection, which acts to decrease the frequency of SCGD causal diplotypes, to reduce false positives. Training of gene-disease-inheritance mode-diplotype tetrads in 618,290 control and affected subjects identified 293 variants or haplotypes and seven genes with variable inheritance contributing higher positive diplotype counts than consistent with purifying hyperselection and with little or no evidence of SCGD causality. With these changes, 2.0% of UKB470K adults were positive. In contrast, gNBS was positive in 7.2% of 3,118 critically ill children with suspected SCGDs and 7.9% of 705 infant deaths. When compared with rapid diagnostic genome sequencing (RDGS), gNBS had 99.1% recall. In eight true-positive children, gNBS was projected to decrease time to diagnosis by a median of 121 days and avoid life-threatening disease presentations in four children, organ damage in six children, ∼$1.25 million in healthcare cost, and ten (1.4%) infant deaths. Federated training predicated on purifying hyperselection provides a general framework to attain high precision in population screening. Federated training across many biobanks and clinical trials can provide a privacy-preserving mechanism for qualification of gNBS in diverse genetic ancestries.
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Affiliation(s)
- Stephen F Kingsmore
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA.
| | - Meredith Wright
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Laurie D Smith
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA
| | - Yupu Liang
- Alexion, AstraZeneca Rare Disease, Boston, MA 02210, USA
| | | | - Liana Protopsaltis
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Matthew Bainbridge
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Mei Baker
- Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA
| | - Sergey Batalov
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Eric Blincow
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Bryant Cao
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Sara Caylor
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Christina Chambers
- Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA
| | - Katarzyna Ellsworth
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Annette Feigenbaum
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA; Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA
| | - Erwin Frise
- Fabric Genomics, Inc., Oakland, CA 94612, USA
| | - Lucia Guidugli
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | | | - Christian Hansen
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Mark Kiel
- Genomenon Inc., Ann Arbor, MI 48108, USA
| | - Lucita Van Der Kraan
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | | | - Hugh Kwon
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Lakshminarasimha Madhavrao
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | | | | | - Rebecca Mardach
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA; Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA
| | - Barry Moore
- Department of Human Genetics, University of Utah, Salt Lake City, UT 84132, USA
| | - Danny Oh
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Lauren Olsen
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Eric Ontiveros
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Mallory J Owen
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Rebecca Reimers
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Scripps Research Translational Institute, La Jolla, CA 92037, USA
| | - Gunter Scharer
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA
| | - Jennifer Schleit
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA
| | | | | | - Albert Oriol
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Erica Sanford
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA
| | | | - Kristen Wigby
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Rady Children's Hospital, San Diego, CA 92123, USA
| | - Mary J Willis
- Rady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA
| | - Mark Yandell
- Department of Human Genetics, University of Utah, Salt Lake City, UT 84132, USA
| | | | - Thomas Defay
- Alexion, AstraZeneca Rare Disease, Boston, MA 02210, USA
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17
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Motzfeldt L, Ried-Larsen M, Hovden FJ, Eika-Jørgensen M, Pedersen ML, Nielsen MH. 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. Int J Circumpolar Health 2024; 83:2403794. [PMID: 39303209 PMCID: PMC11418061 DOI: 10.1080/22423982.2024.2403794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 09/09/2024] [Accepted: 09/10/2024] [Indexed: 09/22/2024] Open
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.
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Affiliation(s)
- Laila Motzfeldt
- Queen Ingrid’s Hospital, Steno Diabetes Center Greenland, Nuuk, Greenland
- Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
| | - Mathias Ried-Larsen
- Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Odense, Denmark
| | | | - Marit Eika-Jørgensen
- Queen Ingrid’s Hospital, Steno Diabetes Center Greenland, Nuuk, Greenland
- Greenland Center for Health Research, Department of Health and Nature, Ilisimatusarfik/University of Greenland, Nuuk, Greenland
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
- Center for Public Health in Greenland, University of Southern Denmark, Copenhagen, Denmark
| | - Michael Lynge Pedersen
- Queen Ingrid’s Hospital, Steno Diabetes Center Greenland, Nuuk, Greenland
- Greenland Center for Health Research, Department of Health and Nature, Ilisimatusarfik/University of Greenland, Nuuk, Greenland
- Department of Public Health, University of Copenhagen, Copenhagen, Denmark
| | - Maja Hykkelbjerg Nielsen
- Queen Ingrid’s Hospital, Steno Diabetes Center Greenland, Nuuk, Greenland
- Greenland Center for Health Research, Department of Health and Nature, Ilisimatusarfik/University of Greenland, Nuuk, Greenland
- Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
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18
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Yilmaz-Aydogan H, Kanca-Demirci D, Gul N, Aydogan C, Poyrazoglu S, Tutuncu Y, Malikova F, Ozturk O, Satman I. Target gene variations of PPAR isoforms may contribute to MODY heterogeneity: A preliminary comparative study with type 2 diabetes. Diabetes Res Clin Pract 2024; 218:111932. [PMID: 39551189 DOI: 10.1016/j.diabres.2024.111932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Revised: 10/30/2024] [Accepted: 11/11/2024] [Indexed: 11/19/2024]
Abstract
AIMS The objective of this study was to evaluate the associations of several genetic variants of peroxisome proliferator-activated receptors (PPARs) on clinical and laboratory parameters in patients with maturity-onset diabetes of the young (MODY), and possible contribution to heterogeneity of the disease. METHODS The study groups comprised patients with MODY (genetically confirmed (n = 28), clinically relevant but genetically unconfirmed; MODYX (n = 56)), type 2 diabetes mellitus (T2DM; n = 94) and healthy controls (n = 153). PPARA-L162V-(rs1800206), PPARG-C161T-(rs3856806), P12A-(rs1801282), and PPARB/D + 294 T/C-(rs2016520) polymorphisms were genotyped by real-time-PCR. RESULTS The results demonstrated that the frequencies of PPARA-LL162 (p = 0.002), PPARG-CC161 (p = 0.002), and PPARG-ProPro (p = 0.012) genotypes were significantly higher in the MODY group compared to the controls. Furthermore, total-MODY and MODYX groups had a higher frequency of PPARA-LL162 genotype than T2DM (p = 0.005 and p = 0.006, respectively). The frequency of the PPARB/D + 294 T allele was significantly higher in individuals with T2DM than in genetically-determined MODY group (p = 0.019). The PPARA-LL162 genotype was associated with early-onset diabetes in total-MODY (p = 0.022) and T2DM (p < 0.05) groups. CONCLUSIONS The association of PPARA-L162V polymorphism with early-onset diabetes in both T2DM and MODY is a noteworthy finding. Considering these results, we suggested that genetic polymorphisms in PPAR isoforms may contribute to the clinical and metabolic heterogeneity of MODY.
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Affiliation(s)
- Hulya Yilmaz-Aydogan
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Türkiye.
| | - Deniz Kanca-Demirci
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Türkiye; Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Halic University, Istanbul, Türkiye.
| | - Nurdan Gul
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye.
| | - Cagatay Aydogan
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Türkiye.
| | - Sukran Poyrazoglu
- Pediatric Endocrinology Unit, Department of Pediatrics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye.
| | - Yıldız Tutuncu
- Department of KUTTAM Immunology, Faculty of Medicine, Koc University, Istanbul, Türkiye.
| | - Fidan Malikova
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Türkiye.
| | - Oguz Ozturk
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Türkiye.
| | - Ilhan Satman
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Türkiye.
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19
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Lanzinger S, Laubner K, Warncke K, Mader JK, Kummer S, Boettcher C, Biester T, Galler A, Klose D, Holl RW. 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. J Diabetes 2024; 16:e70028. [PMID: 39511990 PMCID: PMC11544032 DOI: 10.1111/1753-0407.70028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 08/30/2024] [Accepted: 10/20/2024] [Indexed: 11/15/2024] Open
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.
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Affiliation(s)
- Stefanie Lanzinger
- Institute of Epidemiology and Medical Biometry, CAQM, Ulm University, Ulm, Germany
- Munich-Neuherberg, German Center for Diabetes Research (DZD), Munich, Germany
| | - Katharina Laubner
- Division of Endocrinology and Diabetology, Department of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Katharina Warncke
- Department of Pediatrics, Kinderklinik München Schwabing, Technical University of Munich School of Medicine, Munich, Germany
| | - Julia K Mader
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Sebastian Kummer
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Claudia Boettcher
- Paediatric Endocrinology and Diabetology, University Children's Hospital, University of Bern, Bern, Switzerland
| | - Torben Biester
- AUF DER BULT, Diabetes-Center for Children and Adolescents, Hannover, Germany
| | - Angela Galler
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Sozialpädiatrisches Zentrum, Paediatric Diabetology, Berlin, Germany
| | - Daniela Klose
- Division of Pediatric Endocrinology und Diabetes, Department of Pediatrics, University of Heidelberg, Heidelberg, Germany
| | - Reinhard W Holl
- Institute of Epidemiology and Medical Biometry, CAQM, Ulm University, Ulm, Germany
- Munich-Neuherberg, German Center for Diabetes Research (DZD), Munich, Germany
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20
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Lv X, Gao J, Yang J, Zou Y, Chen J, Sun Y, Song J, Liu Y, Wang L, Xia L, Yu S, Wei Z, Chen L, Hou X. Clinical and functional characterization of a novel KCNJ11 (c.101G > A, p.R34H) mutation associated with maturity-onset diabetes mellitus of the young type 13. Endocrine 2024; 86:515-527. [PMID: 38761346 DOI: 10.1007/s12020-024-03873-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 05/09/2024] [Indexed: 05/20/2024]
Abstract
PURPOSE This study aimed to describe the clinical features, diagnostic and therapeutic course of a patient with MODY13 caused by KCNJ11 (c.101G > A, p.R34H) and how it contributes to the pathogenesis of MODY13, and to explore new therapeutic targets. METHODS Whole-exome sequencing was used to screen prediagnosed individuals and family members with clinically suspected KCNJ11 mutations. Real-time fluorescence quantitative PCR, western blotting, thallium flux of potassium channels, glucose-stimulated insulin secretion (GSIS), and immunofluorescence assays were used to analyze the regulation of insulin secretion by the KCNJ11 mutant in MIN6 cells. Daily blood glucose levels were continuously monitored for 14 days in the proband using the ambulatory blood glucose meter (SIBIONICS). RESULTS Mutation screening of the entire exon of the gene identified a heterozygous KCNJ11 (c.101G > A, p.R34H) mutation in the proband and his mother. Cell-based GSIS assays after transfection of MIN6 using wild-type and mutant plasmids revealed that this mutation impaired insulin secretory function. Furthermore, we found that this impaired secretory function is associated with reduced functional activity of the mutant KCNJ11 protein and reduced expression of the insulin secretion-associated exocytosis proteins STXBP1 and SNAP25. CONCLUSION For the first time, we revealed the pathogenic mechanism of KCNJ11 (c.101G > A, p.R34H) associated with MODY13. This mutant can cause alterations in KATP channel activity, reduce sensitivity to glucose stimulation, and impair pancreatic β-cell secretory function by downregulating insulin secretion-associated exocytosis proteins. Therefore, oral sulfonylurea drugs can lower blood glucose levels through pro-insulinotropic effects and are more favorable for patients with this mutation.
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Affiliation(s)
- Xiaoyu Lv
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Jing Gao
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Jingwen Yang
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Ying Zou
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Jun Chen
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Yujing Sun
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Jia Song
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Yiran Liu
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Liming Wang
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Longqing Xia
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Shijia Yu
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Zichun Wei
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Li Chen
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, Shandong, China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, China
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, Shandong, China
| | - Xinguo Hou
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, Shandong, China.
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, China.
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, Shandong, China.
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21
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Bauer R, Parker C, Gorsic LK, Hayes MG, Kunselman AR, Legro RS, Welt CK, Urbanek M. Rare variation in LMNA underlies polycystic ovary syndrome (PCOS) pathogenesis in two independent cohorts. J Clin Endocrinol Metab 2024:dgae761. [PMID: 39484826 DOI: 10.1210/clinem/dgae761] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Revised: 10/09/2024] [Accepted: 10/29/2024] [Indexed: 11/03/2024]
Abstract
CONTEXT Polycystic ovary syndrome (PCOS) is a common, heritable endocrinopathy that is a common cause of anovulatory infertility in reproductive age women. Variants in LMNA cause partial lipodystrophy, a syndrome with overlapping features to PCOS. OBJECTIVE We tested the hypothesis that rare variation in LMNA contributes to PCOS pathogenesis and selects a lipodystrophy-like subtype of PCOS. DESIGN, SETTING, AND PARTICIPANTS We sequenced LMNA by targeted sequencing a discovery cohort of 811 PCOS patients and 164 healthy controls. We then analyzed LMNA from whole-exome sequencing (WES) of a replication cohort of 718 PCOS patients and 281 healthy controls. MAIN OUTCOME MEASURES Variation in the LMNA gene, hormone and lipid profiles of participants. RESULTS In the discovery cohort, we identified 8 missense variants in 15/811 cases, and 1 variant in 1/172 reproductively healthy controls. There is strong evidence for association between the variants and PCOS compared to gnomAD non-Finnish European population controls (χ2=17, p=3.7x10-5, OR=2.9). In the replication cohort, we identified 11 unique variants in 15/718 cases, and 1 variant in 281 reproductively healthy controls. Again, there is strong evidence for association with population controls (χ2=30.5, p=3.4x10-8, OR= 4.0). In both the discovery and replication cohorts, variants in LMNA identify women with PCOS with high triglycerides and extreme insulin resistance. CONCLUSIONS Rare missense variation in LMNA is reproducibly associated with PCOS and identifies some individuals with lipodystrophy-like features. The overlap between this PCOS phenotype and genetic partial lipodystrophy syndromes warrants further investigation into additional lipodystrophy genes and their potential in PCOS etiology.
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Affiliation(s)
- Rosemary Bauer
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
- Center for Reproductive Science, Northwestern University, Chicago IL 60611
| | - Chloe Parker
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - Lidija K Gorsic
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
| | - M Geoffrey Hayes
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
- Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
- Department of Anthropology, Northwestern University, Evanston, IL 60208
| | - Allen R Kunselman
- Public Health Sciences, Penn State College of Medicine, Hershey, PA 17033
| | - Richard S Legro
- Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, PA 17033
| | - Corrine K Welt
- Division of Endocrinology, Metabolism, and Diabetes, University of Utah, Salt Lake City, Utah 84132
| | - Margrit Urbanek
- Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
- Center for Reproductive Science, Northwestern University, Chicago IL 60611
- Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611
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22
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Katte JC, Dehayem MY, Colclough K, Sobngwi E. Treatment switch from multiple daily insulin injections to sulphonylureas in an African young adult diagnosed with HNF1A MODY: a case report. J Med Case Rep 2024; 18:506. [PMID: 39420387 PMCID: PMC11488176 DOI: 10.1186/s13256-024-04850-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Accepted: 09/23/2024] [Indexed: 10/19/2024] Open
Abstract
BACKGROUND Maturity onset diabetes of the young is one of the commonest causes of monogenic diabetes and can easily be mistaken for type 1 diabetes. A diagnosis of maturity onset diabetes of the young can have direct implications for genetic counseling, family screening, and precision diabetes treatment. However, the cost of genetic testing and identifying individuals to test are the main challenges for diagnosis and management in sub-Saharan Africa. We report the very first documented case of HNF1A maturity onset diabetes of the young in the sub-Saharan African region. CASE PRESENTATION A 20-year-old female Black African young adult diagnosed with type 1 diabetes aged 14 presented for routine out-patient diabetes consultation. She was on multiple daily insulin injections; total combined dose 0.79 IU/kg/day with an HbA1c of 7.7%. The rest of her laboratory examinations were normal. On extended laboratory analysis, she had good residual insulin secretion with post-meal plasma C-peptide levels at 1150 pmol/L. She tested negative for glutamic acid decarboxylase (GAD65), islet antigen-2 (IA-2), and zinc transporter 8 (ZnT8) islet autoantibodies. Targeted next-generation sequencing (t-NGS) for monogenic diabetes was performed using DNA extracted from a buccal sample. She was diagnosed with HNF1A maturity onset diabetes of the young, with the c.607C > T; p.(Arg203Cys) pathogenic variant, which has never been reported in sub-Saharan Africa. Her clinical practitioners provided genetic and therapeutic counseling. Within 10 months following the diagnosis of maturity onset diabetes of the young, she was successfully switched from multiple daily insulin injections to oral antidiabetic tablets (sulphonylurea) while maintaining stable glycemic control (HBA1c of 7.0%) and reducing hypoglycemia. She expressed a huge relief from the daily finger pricks for blood glucose monitoring. CONCLUSION This case reveals that HNF1A maturity onset diabetes of the young (and probably other causes of monogenic diabetes) can present in sub-Saharan Africa. A diagnosis of maturity onset diabetes of the young can have significant life-changing therapeutic implications.
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Affiliation(s)
- Jean Claude Katte
- Department of Clinical and Biomedical Science, Faculty of Life and Health Science, University of Exeter Medical School, Exeter, UK.
- National Obesity Centre and the Endocrinology and Metabolic Diseases Unit, Yaoundé Central Hospital, Yaoundé, Cameroon.
- Department of Non-Communicable Diseases, RSD Institute, Yaoundé, Cameroon.
| | - Mesmin Y Dehayem
- National Obesity Centre and the Endocrinology and Metabolic Diseases Unit, Yaoundé Central Hospital, Yaoundé, Cameroon
- Department of Internal Medicine and Specialities, Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Yaoundé, Cameroon
| | - Kevin Colclough
- Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK
| | - Eugene Sobngwi
- National Obesity Centre and the Endocrinology and Metabolic Diseases Unit, Yaoundé Central Hospital, Yaoundé, Cameroon
- Department of Non-Communicable Diseases, RSD Institute, Yaoundé, Cameroon
- Department of Internal Medicine and Specialities, Faculty of Medicine and Biomedical Sciences, University of Yaoundé 1, Yaoundé, Cameroon
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Kong Y, Jiang J, Kong W, Qin S. DRCTdb: disease-related cell type analysis to decode cell type effect and underlying regulatory mechanisms. Commun Biol 2024; 7:1205. [PMID: 39341994 PMCID: PMC11439014 DOI: 10.1038/s42003-024-06833-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2024] [Accepted: 09/03/2024] [Indexed: 10/01/2024] Open
Abstract
Understanding the molecular mechanisms underlying genetic diseases is challenging due to environmental and genetic factors. Genome-wide association studies (GWAS) have identified numerous genetic loci, but their functional implications are largely unknown. Single-cell multiomics sequencing has emerged as a powerful tool to study disease-specific cell types and their relationship with genetic variants. However, comprehensive databases for exploring these mechanisms across different tissues are lacking. We present the Disease-Related Cell Type database (DRCTdb), integrating GWAS and single-cell multiomics data to identify disease-related cell types and elucidate their regulatory mechanisms. DRCTdb contains well-processed data from 16 studies, covering 4 million cells within 28 tissues. Users can browse relationships and regulatory mechanisms between SNPs of 42 genetic diseases and cell types based on GWAS and single-cell data. DRCTdb also offers data downloads and is available at https://singlecellatlas.top/DRCTDB .
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Affiliation(s)
- Yunhui Kong
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China
- Institute of Modern Biology, Nanjing University, Nanjing, China
| | - Junyao Jiang
- School of Life Sciences, Westlake University, Hangzhou, China.
| | - Weikang Kong
- School of Environmental Science and Engineering, University of Science and Technology of Suzhou, Suzhou, Jiangsu, China
| | - Sheng Qin
- Jiangsu Key Laboratory of Sericultural Biology and Biotechnology, School of Biotechnology, Jiangsu University of Science and Technology, Zhenjiang, China.
- Key Laboratory of Silkworm and Mulberry Genetic Improvement, Ministry of Agriculture and Rural Affairs, Sericultural Research Institute, Chinese Academy of Agricultural Science, Zhenjiang, China.
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24
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Han JY, Gwack J, Kim TY, Park J. A Korean Family Presenting with Renal Cysts and Maturity-Onset Diabetes of the Young Caused by a Novel In-Frame Deletion of HNF1B. Int J Mol Sci 2024; 25:9823. [PMID: 39337310 PMCID: PMC11432569 DOI: 10.3390/ijms25189823] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 09/09/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Maturity-onset diabetes of the young (MODY; OMIM # 606391) comprises a cluster of inherited disorders within non-autoimmune diabetes mellitus (DM), typically emerging during adolescence or young adulthood. We report a novel in-frame deletion of HNF1B in a family with renal cysts and MODY, furthering our understanding of HNF1B-related phenotypes. We conducted sequential genetic testing to investigate the glucose intolerance, renal cysts, hepatic cysts, and agenesis of the dorsal pancreas observed in the proband. A comprehensive clinical exome sequencing approach using a Celemics G-Mendeliome Clinical Exome Sequencing Panel was employed. Considering the clinical manifestations observed in the proband, gene panel sequencing identified a heterozygous HNF1B variant, c.36_38delCCT/p.(Leu13del) (reference transcript ID: NM_000458.4), as the most likely cause of MODY in the proband. The patient's clinical presentation was consistent with MODY caused by the HNF1B variant, showing signs of glucose intolerance, renal cysts, hepatic cysts, and agenesis of the dorsal pancreas. Sanger sequencing confirmed the same HNF1B variant and established the paternally inherited autosomal dominant status of the heterozygous variant in the patient, as well as in his father and sister. The presence of early-onset diabetes, renal cysts, a family history of the condition, and nephropathy appearing before or after the diagnosis of diabetes mellitus (DM) suggests a diagnosis of HNF1B-MODY5. Early diagnosis is crucial for preventing complications of DM, enabling family screening, providing pre-conceptional genetic counseling, and monitoring kidney function decline.
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Affiliation(s)
- Ji Yoon Han
- Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
| | - Jin Gwack
- Department of Preventive Medicine, Jeonbuk National University Medical School, Jeonju 54907, Republic of Korea;
- Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Republic of Korea
| | - Tae Yun Kim
- Department of Thoracic and Cardiovascular Surgery, Jeonbuk National University Medical School and Hospital, Jeonju 54907, Republic of Korea
| | - Joonhong Park
- Research Institute of Clinical Medicine of Jeonbuk National University-Biomedical Research Institute of Jeonbuk National University Hospital, Jeonju 54907, Republic of Korea
- Department of Laboratory Medicine, Jeonbuk National University Medical School and Hospital, Jeonju 54907, Republic of Korea
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25
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Özsu E, Çetinkaya S, Bolu S, Hatipoğlu N, Erdeve ŞS, Evliyaoğlu O, Baş F, Çayır A, Dündar İ, Akbaş ED, Uçaktürk SA, Berberoğlu M, Şıklar Z, Özalkak Ş, Şahin NM, Keskin M, Şiraz ÜG, Turan H, Öztürk AP, Mengen E, Sağsak E, Dursun F, Akyürek N, Güneş SO, Aycan Z. Clinical and Laboratory Characteristics of MODY Cases, Genetic Mutation Spectrum and Phenotype-genotype Relationship. J Clin Res Pediatr Endocrinol 2024; 16:297-305. [PMID: 38665000 PMCID: PMC11590772 DOI: 10.4274/jcrpe.galenos.2024.2023-10-16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 03/25/2024] [Indexed: 09/06/2024] Open
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.
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Affiliation(s)
- Elif Özsu
- Ankara University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey
| | - Semra Çetinkaya
- Dr. Sami Ulus Obstetrics and Gynecology, Pediatric Health and Disease Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey
| | - Semih Bolu
- Adıyaman Training and Research Hospital, Clinic of Pediatric Endocrinology, Adıyaman, Turkey
| | - Nihal Hatipoğlu
- Erciyes University Faculty of Medicine, Department of Pediatric Endocrinology, Kayseri, Turkey
| | - Şenay Savaş Erdeve
- Dr. Sami Ulus Obstetrics and Gynecology, Pediatric Health and Disease Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey
| | - Olcay Evliyaoğlu
- İstanbul University Cerrahpaşa-Cerrahpaşa Faculty of Medicine, Department of Pediatric Endocrinology, İstanbul, Turkey
| | - Firdevs Baş
- İstanbul University, İstanbul Faculty of Medicine, Department of Pediatric Endocrinology, İstanbul, Turkey
| | - Atilla Çayır
- Erzurum Regional Training and Research Hospital, Clinic of Pediatric Endocrinology, Erzurum, Turkey
| | - İsmail Dündar
- Malatya Training and Research Hospital, Clinic of Pediatric Endocrinology, Malatya, Turkey
| | - Emine Demet Akbaş
- Adana Training and Research Hospital, Clinic of Pediatric Endocrinology, Adana, Turkey
| | - Seyid Ahmet Uçaktürk
- Adana Training and Research Hospital, Clinic of Pediatric Endocrinology, Adana, Turkey
| | - Merih Berberoğlu
- Ankara University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey
| | - Zeynep Şıklar
- Ankara University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey
| | - Şervan Özalkak
- Dr. Sami Ulus Obstetrics and Gynecology, Pediatric Health and Disease Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey
| | - Nursel Muratoğlu Şahin
- Dr. Sami Ulus Obstetrics and Gynecology, Pediatric Health and Disease Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey
| | - Melikşah Keskin
- Dr. Sami Ulus Obstetrics and Gynecology, Pediatric Health and Disease Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey
| | - Ülkü Gül Şiraz
- Erciyes University Faculty of Medicine, Department of Pediatric Endocrinology, Kayseri, Turkey
| | - Hande Turan
- İstanbul University Cerrahpaşa-Cerrahpaşa Faculty of Medicine, Department of Pediatric Endocrinology, İstanbul, Turkey
| | - Ayşe Pınar Öztürk
- İstanbul University, İstanbul Faculty of Medicine, Department of Pediatric Endocrinology, İstanbul, Turkey
| | - Eda Mengen
- Çukurova University Faculty of Medicine, Department of Pediatric Endocrinology, Adana, Turkey
| | - Elif Sağsak
- Yeditepe University Faculty of Medicine, Department of Pediatric Endocrinology İstanbul, Turkey
| | - Fatma Dursun
- Ümraniye Training and Research Hospital, Clinic of Pediatric Endocrinology, İstanbul, Turkey
| | - Nesibe Akyürek
- Başkent University, Konya Training and Research Hospital, Clinic of Pediatric Endocrinology, Konya, Turkey
| | - Sevinç Odabaşı Güneş
- Gülhane Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey
| | - Zehra Aycan
- Ankara University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey
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26
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Perez JA. Glucose Disorders. Prim Care 2024; 51:375-390. [PMID: 39067965 DOI: 10.1016/j.pop.2024.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Glucose disorders are the most common endocrine condition in the primary care setting. The conditions overlap and are better viewed as a spectrum rather than discrete entities. Multiple treatment agents are now available for diabetes mellitus which include long-acting and short-acting insulins and medications targeting the various pathways of diabetes including liver gluconeogenesis, increasing peripheral insulin sensitivity, stimulating pancreatic insulin production, eliminating glucose renally, decreasing carbohydrate gastrointestinal absorption, and targeting the body's incretin system. Various endocrine conditions can cause secondary hyperglycemia or hypoglycemia. Medications and physiologic stress can affect glucose levels. Genetic syndromes causing enzyme deficiencies underlie a small portion of glucose disorders.
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Affiliation(s)
- Juan A Perez
- Department of Family and Community Medicine Residency Program, Penn State Health-St. Joseph Hospital, 145 N. 6th Street, 2nd floor, Reading, PA 19601, USA.
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27
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Welsch S, Harvengt A, Gallo P, Martin M, Beckers D, Mouraux T, Seret N, Lebrethon MC, Helaers R, Brouillard P, Vikkula M, Lysy PA. A New Tool to Identify Pediatric Patients with Atypical Diabetes Associated with Gene Polymorphisms. Diabetes Metab J 2024; 48:949-959. [PMID: 38523249 PMCID: PMC11449816 DOI: 10.4093/dmj.2023.0166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 11/25/2023] [Indexed: 03/26/2024] Open
Abstract
BACKGRUOUND Recent diabetes subclassifications have improved the differentiation between patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus despite several overlapping features, yet without considering genetic forms of diabetes. We sought to facilitate the identification of monogenic diabetes by creating a new tool that we validated in a pediatric maturity-onset diabetes of the young (MODY) cohort. METHODS We first created the DIAgnose MOnogenic DIAbetes (DIAMODIA) criteria based on the pre-existing, but incomplete, MODY calculator. This new score is composed of four strong and five weak criteria, with patients having to display at least one weak and one strong criterion. RESULTS The effectiveness of the DIAMODIA criteria was evaluated in two patient cohorts, the first consisting of patients with confirmed MODY diabetes (n=34) and the second of patients with T1DM (n=390). These DIAMODIA criteria successfully detected 100% of MODY patients. Multiple correspondence analysis performed on the MODY and T1DM cohorts enabled us to differentiate MODY patients from T1DM. The three most relevant variables to distinguish a MODY from T1DM profile were: lower insulin-dose adjusted A1c score ≤9, glycemic target-adjusted A1c score ≤4.5, and absence of three anti-islet cell autoantibodies. CONCLUSION We validated the DIAMODIA criteria, as it effectively identified all monogenic diabetes patients (MODY cohort) and succeeded to differentiate T1DM from MODY patients. The creation of this new and effective tool is likely to facilitate the characterization and therapeutic management of patients with atypical diabetes, and promptly referring them for genetic testing which would markedly improve clinical care and counseling, as well.
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Affiliation(s)
- Sophie Welsch
- Pediatrics Unit, Institute for Experimental and Clinical Research, UCLouvain, Brussels, Belgium
| | - Antoine Harvengt
- Pediatrics Unit, Institute for Experimental and Clinical Research, UCLouvain, Brussels, Belgium
| | - Paola Gallo
- Pediatric Endocrinology Unit, Saint-Luc University Clinics, Brussels, Belgium
| | - Manon Martin
- Louvain Institute of Biomolecular Science and Technology (IBST) Unit, UCLouvain, Brussels, Belgium
| | - Dominique Beckers
- Pediatric Endocrinology and Diabetology Unit, CHU-UCL Namur sites Saint-Elisabeth and Mont-Godinne, Namur, Belgium
| | - Thierry Mouraux
- Pediatric Endocrinology and Diabetology Unit, CHU-UCL Namur sites Saint-Elisabeth and Mont-Godinne, Namur, Belgium
| | - Nicole Seret
- Pediatric Endocrinology and Diabetology Unit, Clinique CHC MontLégia (CHC MontLégia Clinic), Liège, Belgium
| | | | - Raphaël Helaers
- Human Molecular Genetics, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Pascal Brouillard
- Human Molecular Genetics, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Miikka Vikkula
- Human Molecular Genetics, de Duve Institute, UCLouvain, Brussels, Belgium
| | - Philippe A. Lysy
- Pediatrics Unit, Institute for Experimental and Clinical Research, UCLouvain, Brussels, Belgium
- Pediatric Endocrinology Unit, Saint-Luc University Clinics, Brussels, Belgium
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Peghinelli VV, De Sibio MT, Depra IDC, Teles Bezerra MG, Sakalem ME, Júnior AFDM, da Rocha PB, Tilli HP, Gonçalves BM, Vieira EM, Lourenço MM, Nogueira CR. MODY calculator applied in patients with clinical diagnosis of type 1 diabetes mellitus: Is a higher cutoff needed? Heliyon 2024; 10:e36006. [PMID: 39224250 PMCID: PMC11367115 DOI: 10.1016/j.heliyon.2024.e36006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/14/2024] [Accepted: 08/07/2024] [Indexed: 09/04/2024] Open
Abstract
Aim This study aimed to evaluate the mean post-test probability (PTP) of the Maturity-onset diabetes of the young (MODY) calculator in a multiethnic cohort of patients previously diagnosed with type 1 diabetes (T1DM). Materials and methods The MODY probability calculator proposed by Shields and colleagues (2012) was applied to 117 patients from a T1DM outpatient clinic at a tertiary hospital in Brazil. Additionally, two exons of the HNF1A gene were sequenced in eight patients who hadn't received insulin treatment within six months after the diagnosis. Results 17.1 % of patients achieved PTP >10 %; 11.1 % achieved PTP >25 % (and all patients >30 %), and 7.7 % achieved PTP >40 %. Among the patients who were selected for genetic sequencing, 100 % presented PTP >30 %, with 66.6 % achieving PTP >40 % and 41.6 % achieving PTP >75 %. These cutoffs are as suggested for the Brazilian population, according to previous investigations. No mutation was observed in the sequenced exons. Conclusion Considering that only around 10 % of the evaluated cases achieved PTP >30 %, it is highly probable that the most suitable cutoff to select patients for genetic sequencing in a Brazilian cohort of T1DM is higher than the cutoff used in Caucasian populations.
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Affiliation(s)
| | - Maria Teresa De Sibio
- Departament of Internal Medicine, São Paulo State University (UNESP), Medical School, Botucatu, Sao Paulo, Brazil
| | - Igor de Carvalho Depra
- Departament of Internal Medicine, São Paulo State University (UNESP), Medical School, Botucatu, Sao Paulo, Brazil
| | - Milena Gurgel Teles Bezerra
- Grupo de Diabetes Monogênico (Monogenic Diabetes Group), Unidade de Endocrinologia, Genética (LIM25), Unidade de Diabetes, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo (HCFMUSP), São Paulo, SP, 01246-903, Brazil
| | - Marna Eliana Sakalem
- Departament of Anatomy, State University of Londrina – UEL, Londrina, PR, Brazil
| | | | - Paula Barreto da Rocha
- Departament of Internal Medicine, São Paulo State University (UNESP), Medical School, Botucatu, Sao Paulo, Brazil
| | - Helena Paim Tilli
- Departament of Internal Medicine, São Paulo State University (UNESP), Medical School, Botucatu, Sao Paulo, Brazil
| | - Bianca Mariani Gonçalves
- Departament of Internal Medicine, São Paulo State University (UNESP), Medical School, Botucatu, Sao Paulo, Brazil
| | - Ester Mariane Vieira
- Departament of Internal Medicine, São Paulo State University (UNESP), Medical School, Botucatu, Sao Paulo, Brazil
| | - Mariana Menezes Lourenço
- Departament of Internal Medicine, São Paulo State University (UNESP), Medical School, Botucatu, Sao Paulo, Brazil
| | - Célia Regina Nogueira
- Departament of Internal Medicine, São Paulo State University (UNESP), Medical School, Botucatu, Sao Paulo, Brazil
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Lee Y, Lee K. Pancreatic Diseases: Genetics and Modeling Using Human Pluripotent Stem Cells. Int J Stem Cells 2024; 17:253-269. [PMID: 38664226 PMCID: PMC11361847 DOI: 10.15283/ijsc24036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 04/01/2024] [Accepted: 04/01/2024] [Indexed: 08/31/2024] Open
Abstract
Pancreas serves endocrine and exocrine functions in the body; thus, their pathology can cause a broad range of irreparable consequences. Endocrine functions include the production of hormones such as insulin and glucagon, while exocrine functions involve the secretion of digestive enzymes. Disruption of these functions can lead to conditions like diabetes mellitus and exocrine pancreatic insufficiency. Also, the symptoms and causality of pancreatic cancer very greatly depends on their origin: pancreatic ductal adenocarcinoma is one of the most fatal cancer; however, most of tumor derived from endocrine part of pancreas are benign. Pancreatitis, an inflammation of the pancreatic tissues, is caused by excessive alcohol consumption, the bile duct obstruction by gallstones, and the premature activation of digestive enzymes in the pancreas. Hereditary pancreatic diseases, such as maturity-onset diabetes of the young and hereditary pancreatitis, can be a candidate for disease modeling using human pluripotent stem cells (hPSCs), due to their strong genetic influence. hPSC-derived pancreatic differentiation has been established for cell replacement therapy for diabetic patients and is robustly used for disease modeling. The disease modeling platform that allows interactions between immune cells and pancreatic cells is necessary to perform in-depth investigation of disease pathogenesis.
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Affiliation(s)
- Yuri Lee
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea
| | - Kihyun Lee
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea
- College of Pharmacy, Ewha Womans University, Seoul, Korea
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Asgarian S, Lanjanian H, Rahimipour Anaraki S, Hadaegh F, Moazzam-Jazi M, Najd-Hassan-Bonab L, Masjoudi S, Zahedi AS, Zarkesh M, Shalbafan B, Akbarzadeh M, Tehrani Fateh S, Khalili D, Momenan A, Sarbazi N, Hedayati M, Azizi F, Daneshpour MS. Examining the clinical and genetic spectrum of maturity-onset diabetes of the young (MODY) in Iran. Sci Rep 2024; 14:19860. [PMID: 39191897 PMCID: PMC11349921 DOI: 10.1038/s41598-024-70864-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Accepted: 08/22/2024] [Indexed: 08/29/2024] Open
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.
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Affiliation(s)
- Sara Asgarian
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, P.O. Box 19195-4763, Tehran, Iran
| | - Hossein Lanjanian
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, P.O. Box 19195-4763, Tehran, Iran.
| | | | - Farzad Hadaegh
- Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Moazzam-Jazi
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, P.O. Box 19195-4763, Tehran, Iran
| | - Leila Najd-Hassan-Bonab
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, P.O. Box 19195-4763, Tehran, Iran
| | - Sajedeh Masjoudi
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, P.O. Box 19195-4763, Tehran, Iran
| | - Asiyeh Sadat Zahedi
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, P.O. Box 19195-4763, Tehran, Iran
| | - Maryam Zarkesh
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, P.O. Box 19195-4763, Tehran, Iran
| | - Bita Shalbafan
- Clinical Research Development Center of Labbafinejad Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahdi Akbarzadeh
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, P.O. Box 19195-4763, Tehran, Iran
| | | | - Davood Khalili
- Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amirabbas Momenan
- Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Narges Sarbazi
- Prevention of Metabolic Disorders Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehdi Hedayati
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, P.O. Box 19195-4763, Tehran, Iran
| | - Fereidoun Azizi
- Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, P.O. Box 19195-4763, Tehran, Iran
| | - Maryam S Daneshpour
- Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, P.O. Box 19195-4763, Tehran, Iran.
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Hasballa I, Maggi D. MODY Only Monogenic? A Narrative Review of the Novel Rare and Low-Penetrant Variants. Int J Mol Sci 2024; 25:8790. [PMID: 39201476 PMCID: PMC11354648 DOI: 10.3390/ijms25168790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 07/26/2024] [Accepted: 08/12/2024] [Indexed: 09/02/2024] Open
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.
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Affiliation(s)
- Iderina Hasballa
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, 16132 Genoa, Italy
| | - Davide Maggi
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy
- Diabetes Clinic, IRCCS Ospedale Policlinico San Martino Genoa, 16132 Genoa, Italy
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Narasimhegowda M, Nagarajappa VH, Palany R. A case series of maturity-onset diabetes of the young highlighting atypical presentations and the implications of genetic diagnosis. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2024; 68:e230239. [PMID: 39420905 PMCID: PMC11326734 DOI: 10.20945/2359-4292-2023-0239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 03/05/2024] [Indexed: 10/19/2024]
Abstract
Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous group of monogenic diabetes characterized by onset at a young age and an autosomal dominant mode of inheritance. Notably, MODY accounts for 2%-5% of all diabetes cases, and its distinction from types 1 (T1DM) and 2 (T2DM) diabetes mellitus is often challenging. We report herein the cases of two girls and a boy who presented initially with diabetic ketoacidosis. In view of the strong family history of diabetes in all three of them, the diagnosis of MODY was considered and confirmed by molecular testing. The patient in Case 1 (a 10-year-old girl) had a variation in the HNF1A gene (MODY 3). The patient in Case 2 (a 13-year-old girl) had a variation in the HNF1B gene (MODY 5) and was also clinically diagnosed with HNF1B MODY due to short stature, abnormal renal function, renal cysts, unicornuate uterus, and diabetic ketoacidosis at presentation. The patient in Case 3 (a 14-year-old boy) had a variation in the KCNJ11 gene (MODY 13) and presented with diabetic ketoacidosis; after initially being treated as having T1DM, he developed progressive weight gain, acanthosis nigricans, and decreased requirement of insulin. The patients in Cases 1 and 3 were subsequently treated with oral sulfonylureas and insulin was gradually tapered and interrupted, resulting in drastic improvement in glucose control. The patient in Case 2 remained on insulin, as this is the appropriate management for MODY 5. This case series demonstrates that atypical cases of MODY with ketoacidosis do occur, underscoring the potential for this complication within the phenotypic spectrum of MODY. In patients with atypical presentations, a thorough family history taking may reveal the diagnosis of MODY.
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Affiliation(s)
- Meghana Narasimhegowda
- Division of Pediatric and Adolescent EndocrinologyIndira Gandhi Institute of Child HealthBengaluruIndia Division of Pediatric and Adolescent Endocrinology, Indira Gandhi Institute of Child Health, Bengaluru, India
| | - Vani Hebbal Nagarajappa
- Division of Pediatric and Adolescent EndocrinologyIndira Gandhi Institute of Child HealthBengaluruIndia Division of Pediatric and Adolescent Endocrinology, Indira Gandhi Institute of Child Health, Bengaluru, India
| | - Raghupathy Palany
- Division of Pediatric and Adolescent EndocrinologyIndira Gandhi Institute of Child HealthBengaluruIndia Division of Pediatric and Adolescent Endocrinology, Indira Gandhi Institute of Child Health, Bengaluru, India
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Francis D, Chacko AM, Anoop A, Nadimuthu S, Venugopal V. Evolution of biosynthetic human insulin and its analogues for diabetes management. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 142:191-256. [PMID: 39059986 DOI: 10.1016/bs.apcsb.2024.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
Hormones play a crucial role in maintaining the normal human physiology. By acting as chemical messengers that facilitate the communication between different organs, tissues and cells of the body hormones assist in responding appropriately to external and internal stimuli that trigger growth, development and metabolic activities of the body. Any abnormalities in the hormonal composition and balance can lead to devastating health consequences. Hormones have been important therapeutic agents since the early 20th century, when it was realized that their exogenous supply could serve as a functional substitution for those hormones which are not produced enough or are completely lacking, endogenously. Insulin, the pivotal anabolic hormone in the body, was used for the treatment of diabetes mellitus, a metabolic disorder due to the absence or intolerance towards insulin, since 1921 and is the trailblazer in hormone therapeutics. At present the largest market share for therapeutic hormones is held by insulin. Many other hormones were introduced into clinical practice following the success with insulin. However, for the six decades following the introduction the first therapeutic hormone, there was no reliable method for producing human hormones. The most common source for hormones were animals, although semisynthetic and synthetic hormones were also developed. However, none of these were optimal because of their allergenicity, immunogenicity, lack of consistency in purity and most importantly, scalability. The advent of recombinant DNA technology was a game changer for hormone therapeutics. This revolutionary molecular biology tool made it possible to synthesize human hormones in microbial cell factories. The approach allowed for the synthesis of highly pure hormones which were structurally and biochemically identical to the human hormones. Further, the fermentation techniques utilized to produce recombinant hormones were highly scalable. Moreover, by employing tools such as site directed mutagenesis along with recombinant DNA technology, it became possible to amend the molecular structure of the hormones to achieve better efficacy and mimic the exact physiology of the endogenous hormone. The first recombinant hormone to be deployed in clinical practice was insulin. It was called biosynthetic human insulin to reflect the biological route of production. Subsequently, the biochemistry of recombinant insulin was modified using the possibilities of recombinant DNA technology and genetic engineering to produce analogues that better mimic physiological insulin. These analogues were tailored to exhibit pharmacokinetic and pharmacodynamic properties of the prandial and basal human insulins to achieve better glycemic control. The present chapter explores the principles of genetic engineering applied to therapeutic hormones by reviewing the evolution of therapeutic insulin and its analogues. It also focuses on how recombinant analogues account for the better management of diabetes mellitus.
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Affiliation(s)
- Dileep Francis
- Department of Life Sciences, Kristu Jayanti College, Autonomous, Bengaluru, Karnataka, India.
| | - Aksa Mariyam Chacko
- Department of Life Sciences, Kristu Jayanti College, Autonomous, Bengaluru, Karnataka, India
| | - Anagha Anoop
- Department of Life Sciences, Kristu Jayanti College, Autonomous, Bengaluru, Karnataka, India
| | - Subramani Nadimuthu
- Department of Life Sciences, Kristu Jayanti College, Autonomous, Bengaluru, Karnataka, India
| | - Vaishnavi Venugopal
- Department of Life Sciences, Kristu Jayanti College, Autonomous, Bengaluru, Karnataka, India
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Çavdarlı C, Büyükyılmaz G, Çavdarlı B, Çomçalı S, Topçu Yılmaz P, Alp MN. Comparison of the optical coherence tomography-angiography (OCT-A) vascular measurements between molecularly confirmed MODY and age-matched healthy controls. Acta Diabetol 2024; 61:917-924. [PMID: 38565685 DOI: 10.1007/s00592-024-02273-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 03/10/2024] [Indexed: 04/04/2024]
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.
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Affiliation(s)
- Cemal Çavdarlı
- Department of Ophthalmology, Ankara City Hospital, Bilkent, Ankara, 06800, Turkey.
| | - Gönül Büyükyılmaz
- Department of Pediatric Endocrinology, Ankara City Hospital, Bilkent, Ankara, 06800, Turkey
| | - Büşranur Çavdarlı
- Department of Medical Genetics, Ankara City Hospital, Bilkent, Ankara, 06800, Turkey
| | - Sebile Çomçalı
- Department of Ophthalmology, Ankara City Hospital, Bilkent, Ankara, 06800, Turkey
| | | | - Mehmet Numan Alp
- Department of Ophthalmology, Ankara City Hospital, Health Sciences University, Bilkent, Ankara, 06800, Turkey
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Zečević K, Volčanšek Š, Katsiki N, Rizzo M, Milardović TM, Stoian AP, Banach M, Muzurović E. Maturity-onset diabetes of the young (MODY) - in search of ideal diagnostic criteria and precise treatment. Prog Cardiovasc Dis 2024; 85:14-25. [PMID: 38513726 DOI: 10.1016/j.pcad.2024.03.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 03/17/2024] [Indexed: 03/23/2024]
Abstract
Maturity-onset diabetes of the young (MODY) is a spectrum of clinically heterogenous forms of monogenic diabetes mellitus characterized by autosomal dominant inheritance, onset at a young age, and absence of pancreatic islets autoimmunity. This rare form of hyperglycemia, with clinical features overlapping with type 1 and type 2 diabetes mellitus, has 14 subtypes with differences in prevalence and complications occurrence which tailor therapeutic approach. MODY phenotypes differ based on the gene involved, gene penetrance and expressivity. While MODY 2 rarely leads to diabetic complications and is easily managed with lifestyle interventions alone, more severe subtypes, such as MODY 1, 3, and 6, require an individualized treatment approach to maintain a patient's quality of life and prevention of complications. This review summarizes current evidence on the presentation, diagnosis, and management of MODY, an example of a genetic cause of hyperglycemia that calls for a precision medicine approach.
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Affiliation(s)
- Ksenija Zečević
- Faculty of Medicine, University of Montenegro, Podgorica, Montenegro
| | - Špela Volčanšek
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia; Medical Faculty Ljubljana, Ljubljana, Slovenia
| | - Niki Katsiki
- Department of Nutritional Sciences and Dietetics, International Hellenic University, Thessaloniki, Greece; School of Medicine, European University Cyprus, Nicosia, Cyprus
| | - Manfredi Rizzo
- Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy; Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
| | - Tanja Miličević Milardović
- Internal Medicine Department, Endocrinology, Diabetology, and Metabolism Division, University Hospital of Split, Split, Croatia; University of Split School of Medicine, Split, Croatia
| | - Anca Pantea Stoian
- Diabetes, Nutrition and Metabolic diseases Department, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - Maciej Banach
- Department of Preventive Cardiology and Lipidology, Medical University of Łódź, Lodz, Poland; Department of Cardiology and Adult Congenital Heart Diseases, Polish Mother's Memorial Hospital Research Institute, Łódź, Poland; Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Emir Muzurović
- Faculty of Medicine, University of Montenegro, Podgorica, Montenegro; Department of Internal Medicine, Endocrinology Section, Clinical Center of Montenegro, Podgorica, Montenegro.
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Bhattacharya S, Pappachan JM. Monogenic diabetes in children: An underdiagnosed and poorly managed clinical dilemma. World J Diabetes 2024; 15:1051-1059. [PMID: 38983823 PMCID: PMC11229976 DOI: 10.4239/wjd.v15.i6.1051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2023] [Revised: 03/06/2024] [Accepted: 04/22/2024] [Indexed: 06/11/2024] Open
Abstract
Monogenic diabetes, constituting 1%-2% of global diabetes cases, arises from single gene defects with distinctive inheritance patterns. Despite over 50 ass-ociated genetic disorders, accurate diagnoses and management of monogenic diabetes remain inadequate, underscoring insufficient clinician awareness. The disease spectrum encompasses maturity-onset diabetes of the young (MODY), characterized by distinct genetic mutations affecting insulin secretion, and neonatal diabetes mellitus (NDM) - a heterogeneous group of severe hyperglycemic disorders in infants. Mitochondrial diabetes, autoimmune monogenic diabetes, genetic insulin resistance and lipodystrophy syndromes further diversify the monogenic diabetes landscape. A tailored approach based on phenotypic and biochemical factors to identify candidates for genetic screening is recommended for suspected cases of MODY. NDM diagnosis warrants immediate molecular genetic testing for infants under six months. Identifying these genetic defects presents a unique opportunity for precision medicine. Ongoing research aimed to develop cost-effective genetic testing methods and gene-based therapy can facilitate appropriate identification and optimize clinical outcomes. Identification and study of new genes offer a valuable opportunity to gain deeper insights into pancreatic cell biology and the pathogenic mechanisms underlying common forms of diabetes. The clinical review published in the recent issue of World Journal of Diabetes is such an attempt to fill-in our knowledge gap about this enigmatic disease.
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Affiliation(s)
| | - Joseph M Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, Preston PR2 9HT, United Kingdom
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom
- Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, United Kingdom
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Butnariu LI, Bizim DA, Oltean C, Rusu C, Pânzaru MC, Păduraru G, Gimiga N, Ghiga G, Moisă ȘM, Țarcă E, Starcea IM, Popa S, Trandafir LM. The Importance of Molecular Genetic Testing for Precision Diagnostics, Management, and Genetic Counseling in MODY Patients. Int J Mol Sci 2024; 25:6318. [PMID: 38928025 PMCID: PMC11204182 DOI: 10.3390/ijms25126318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Revised: 05/31/2024] [Accepted: 06/05/2024] [Indexed: 06/28/2024] Open
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.
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Affiliation(s)
- Lăcrămioara Ionela Butnariu
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (C.R.); (S.P.)
| | - Delia Andreia Bizim
- Department of Diabetes, Saint Mary’s Emergency Children Hospital, 700309 Iasi, Romania; (D.A.B.); (C.O.)
| | - Carmen Oltean
- Department of Diabetes, Saint Mary’s Emergency Children Hospital, 700309 Iasi, Romania; (D.A.B.); (C.O.)
| | - Cristina Rusu
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (C.R.); (S.P.)
| | - Monica Cristina Pânzaru
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (C.R.); (S.P.)
| | - Gabriela Păduraru
- Department of Mother and Child, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (G.P.); (N.G.); (G.G.); (Ș.M.M.); (I.M.S.); (L.M.T.)
| | - Nicoleta Gimiga
- Department of Mother and Child, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (G.P.); (N.G.); (G.G.); (Ș.M.M.); (I.M.S.); (L.M.T.)
| | - Gabriela Ghiga
- Department of Mother and Child, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (G.P.); (N.G.); (G.G.); (Ș.M.M.); (I.M.S.); (L.M.T.)
| | - Ștefana Maria Moisă
- Department of Mother and Child, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (G.P.); (N.G.); (G.G.); (Ș.M.M.); (I.M.S.); (L.M.T.)
| | - Elena Țarcă
- Department of Surgery II—Pediatric Surgery, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Iuliana Magdalena Starcea
- Department of Mother and Child, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (G.P.); (N.G.); (G.G.); (Ș.M.M.); (I.M.S.); (L.M.T.)
| | - Setalia Popa
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (C.R.); (S.P.)
| | - Laura Mihaela Trandafir
- Department of Mother and Child, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (G.P.); (N.G.); (G.G.); (Ș.M.M.); (I.M.S.); (L.M.T.)
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Mendonça M, Barros P, Santa Cruz L, Pastilha AC, Cordeiro R. Maturity-Onset Diabetes of the Young Type 3 (MODY 3): A Rare Presentation of Diabetes in Primary Care. Cureus 2024; 16:e63119. [PMID: 39055415 PMCID: PMC11271687 DOI: 10.7759/cureus.63119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/25/2024] [Indexed: 07/27/2024] Open
Abstract
Maturity-onset diabetes of the young (MODY) is a genetic form of diabetes with an autosomal dominant pattern of transmission characterized by dysfunction in pancreatic β-cells. MODY type 3 (MODY 3) is caused by heterozygous mutations in the hepatocyte nuclear factor 1-α (HNF1A) gene and is sensitive to treatment with sulfonylureas. This case report approaches the diagnostic journey of a 46-year-old woman who was initially misdiagnosed with type 2 diabetes. Despite adherence to pharmacological and lifestyle interventions, her glycemic control deteriorated. A comprehensive family history revealed a strong familial prevalence of diabetes. Genetic testing confirmed MODY 3, leading to the initiation of sulfonylurea therapy and subsequent glycemic control. This case emphasizes the diagnostic hurdles associated with MODY in primary care and the critical role of a genogram analysis in revealing familial patterns and giving strategies for personalized treatment.
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Affiliation(s)
- Mariana Mendonça
- Family Medicine, Unidade de Saúde Familiar (USF) Mondego, Coimbra, PRT
| | - Paulo Barros
- Family Medicine, Unidade de Saúde Familiar (USF) Mealhada, Mealhada, PRT
| | - Liliana Santa Cruz
- Family Medicine, Unidade de Saúde Familiar (USF) Coimbra Sul, Coimbra, PRT
| | - Ana C Pastilha
- Family Medicine, Unidade de Saúde Familiar (USF) Mondego, Coimbra, PRT
| | - Rita Cordeiro
- Family Medicine, Unidade de Saúde Familiar (USF) Mondego, Coimbra, PRT
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Ruiz-Urbaez R, Villagómez-Estrada MV, Reyes-Silva C, Quishpe-López D, Males-Maldonado D, Salazar-Vega J, Gea-Izquierdo E. Diabetic Nephropathy, Retinopathy, and Functional Hypogonadism in a Patient with MODY10: A Case Report. MEDICINA (KAUNAS, LITHUANIA) 2024; 60:830. [PMID: 38793013 PMCID: PMC11123248 DOI: 10.3390/medicina60050830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/09/2024] [Accepted: 04/20/2024] [Indexed: 05/26/2024]
Abstract
(1) Background and objectives: Maturity-onset diabetes of the young (MODY) is a group of diabetes caused by gene defects related to insulin secretion. MODY1, MODY2, and MODY3 are the most common and account for approximately 80% of all cases. Other types are relatively rare. This study describes the clinical, analytical, and genetic characteristics of a patient with MODY10, and diabetic nephropathy, retinopathy, and functional hypogonadism diagnosis. (2) Materials and methods: A clinical case was analyzed and whole exome generation sequencing (WES) was used to detect mutations related to a monogenic variant. (3) Results: A seventeen-year-old male patient, who was diagnosed with apparent type 1 diabetes at the age of eight was started with insulin therapy. He came to the emergency room with glycemic decompensation, facial, and lower limb edema. During his evaluation, he had near-nephrotic range proteinuria of 2902 mg/24 h, a kidney ultrasound showing mild pyelocalyceal dilation, proliferative diabetic retinopathy, and was also diagnosed with functional hypogonadotropic hypogonadism. These comorbidities improved with adequate glycemic control. WES showed missense variant c.94G>A (p.Gly32Ser) in the INS gene, according to Clinvar corresponding to MODY10. It was a "de novo" variant not reported in his parents. (4) Conclusions: Monogenic diabetes (MD) is rare and MODY10 is among the less frequent types. MODY should be suspected in patients with type 1 phenotype with negative autoimmunity even in the absence of a family history of diabetes. To the best of our knowledge, we present here the first patient with these phenotypic traits of MODY10 reported in Latin America.
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Affiliation(s)
- Rossana Ruiz-Urbaez
- Unit of Endocrinology and Diabetes, Eugenio Espejo Hospital, Quito 170403, Ecuador
| | | | | | | | | | - Jorge Salazar-Vega
- Unit of Endocrinology and Diabetes, Eugenio Espejo Hospital, Quito 170403, Ecuador
- Faculty of Medicine, Pontifical Catholic University of Ecuador, Quito 170143, Ecuador
| | - Enrique Gea-Izquierdo
- Faculty of Medicine, Pontifical Catholic University of Ecuador, Quito 170143, Ecuador
- Department of Medical Specialties and Public Health, Rey Juan Carlos University, 28922 Madrid, Spain
- María Zambrano Program-European Union, Rey Juan Carlos University, 28922 Madrid, Spain
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Shi P, Tian Y, Xu F, Liu LN, Wu WH, Shi YZ, Dai AQ, Fang HY, Li KX, Xu C. Assessment of pathogenicity and functional characterization of APPL1 gene mutations in diabetic patients. World J Diabetes 2024; 15:275-286. [PMID: 38464380 PMCID: PMC10921161 DOI: 10.4239/wjd.v15.i2.275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 11/22/2023] [Accepted: 01/09/2024] [Indexed: 02/04/2024] Open
Abstract
BACKGROUND Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) plays a crucial role in regulating insulin signaling and glucose metabolism. Mutations in the APPL1 gene have been associated with the development of maturity-onset diabetes of the young type 14 (MODY14). Currently, only two mutations [c.1655T>A (p.Leu552*) and c.281G>A p.(Asp94Asn)] have been identified in association with this disease. Given the limited understanding of MODY14, it is imperative to identify additional cases and carry out comprehensive research on MODY14 and APPL1 mutations. AIM To assess the pathogenicity of APPL1 gene mutations in diabetic patients and to characterize the functional role of the APPL1 domain. METHODS Patients exhibiting clinical signs and a medical history suggestive of MODY were screened for the study. Whole exome sequencing was performed on the patients as well as their family members. The pathogenicity of the identified APPL1 variants was predicted on the basis of bioinformatics analysis. In addition, the pathogenicity of the novel APPL1 variant was preliminarily evaluated through in vitro functional experiments. Finally, the impact of these variants on APPL1 protein expression and the insulin pathway were assessed, and the potential mechanism underlying the interaction between the APPL1 protein and the insulin receptor was further explored. RESULTS A total of five novel mutations were identified, including four missense mutations (Asp632Tyr, Arg633His, Arg532Gln, and Ile642Met) and one intronic mutation (1153-16A>T). Pathogenicity prediction analysis revealed that the Arg532Gln was pathogenic across all predictions. The Asp632Tyr and Arg633His variants also had pathogenicity based on MutationTaster. In addition, multiple alignment of amino acid sequences showed that the Arg532Gln, Asp632Tyr, and Arg633His variants were conserved across different species. Moreover, in in vitro functional experiments, both the c.1894G>T (at Asp632Tyr) and c.1595G>A (at Arg532Gln) mutations were found to downregulate the expression of APPL1 on both protein and mRNA levels, indicating their pathogenic nature. Therefore, based on the patient's clinical and family history, combined with the results from bioinformatics analysis and functional experiment, the c.1894G>T (at Asp632Tyr) and c.1595G>A (at Arg532Gln) mutations were classified as pathogenic mutations. Importantly, all these mutations were located within the phosphotyrosine-binding domain of APPL1, which plays a critical role in the insulin sensitization effect. CONCLUSION This study provided new insights into the pathogenicity of APPL1 gene mutations in diabetes and revealed a potential target for the diagnosis and treatment of the disease.
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Affiliation(s)
- Ping Shi
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Yang Tian
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Feng Xu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Lu-Na Liu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Wan-Hong Wu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Ying-Zhou Shi
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - An-Qi Dai
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Hang-Yu Fang
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Kun-Xia Li
- Department of Pediatric, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai 264099, Shandong Province, China
| | - Chao Xu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
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Jeeyavudeen MS, Murray SR, Strachan MWJ. Management of monogenic diabetes in pregnancy: A narrative review. World J Diabetes 2024; 15:15-23. [PMID: 38313847 PMCID: PMC10835499 DOI: 10.4239/wjd.v15.i1.15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 11/13/2023] [Accepted: 12/08/2023] [Indexed: 01/12/2024] Open
Abstract
Pregnancy in women with monogenic diabetes is potentially complex, with significant implications for both maternal and fetal health. Among these, maturity-onset diabetes of the young (MODY) stands out as a prevalent monogenic diabetes subtype frequently encountered in clinical practice. Each subtype of MODY requires a distinct approach tailored to the pregnancy, diverging from management strategies in non-pregnant individuals. Glucokinase MODY (GCK-MODY) typically does not require treatment outside of pregnancy, but special considerations arise when a woman with GCK-MODY becomes pregnant. The glycemic targets in GCK-MODY pregnancies are not exclusively dictated by the maternal/paternal MODY genotype but are also influenced by the genotype of the developing fetus. During pregnancy, the choice between sulfonylurea or insulin for treating hepatocyte nuclear factor 1-alpha (HNF1A)-MODY and HNF4A-MODY depends on the mother's specific circumstances and the available expertise. Management of other rarer MODY subtypes is individualized, with decisions made on a case-by-case basis. Therefore, a collaborative approach involving expert diabetes and obstetric teams is crucial for the comprehensive management of MODY pregnancies.
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Affiliation(s)
| | - Sarah R Murray
- MRC Centre for Reproductive Health, University of Edinburgh Queen’s Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom
| | - Mark W J Strachan
- Metabolic Unit, Western General Hospital, Edinburgh EH4 2XU, United Kingdom
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Mancera-Rincón P, Luna-España MC, Rincon O, Guzmán I, Alvarez M. Maturity-onset Diabetes of the Young Type 7 (MODY7) and the Krüppellike Factor 11 Mutation (KLF11). A Review. Curr Diabetes Rev 2024; 20:e210323214817. [PMID: 36944622 DOI: 10.2174/1573399819666230321114456] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 01/04/2023] [Accepted: 01/17/2023] [Indexed: 03/23/2023]
Abstract
INTRODUCTION Maturity-onset diabetes of the young (MODY) is a rare disease due to a single gene mutation that affects several family members in most cases. The Krüppel-like factor 11 (KLF11) gene mutation is associated with decreased insulin sensitivity to high glucose levels. KLF 11 has been implicated in the pathogenesis of MODY type 7 but given its low prevalence, prolonged subclinical period, and the emergence of new information, doubts are raised about its association. METHODS A literature search of the PubMed, Scopus, and EBSCO databases was performed. The terms "Diabetes Mellitus, Type 2/genetics", "Mason-Type Diabetes" , "Maturity-Onset diabetes of the young", "KLF11 protein, human", and "Maturity-Onset Diabetes of the Young, Type 7" were used"., "Diagnosis" The search selection was not standardized. RESULTS The KLF1 mutation is rare and represents <1% of the mutations associated with monogenic diabetes. Its isolation in European family lines in the first studies and the emergence of new variants pose new diagnostic challenges. This article reviews the definition, epidemiology, pathophysiology, diagnosis, and treatment of MODY type 7. CONCLUSION MODY type 7 diabetes represents a rare form of monogenic diabetes with incomplete penetrance. Given its rarity, its association with impaired glucose metabolism has been questioned. Strict evaluation of glycemic control and the appearance of microvascular complications are key areas in the follow-up of patients diagnosed with MODY 7. More studies will be required to characterize the population with KLF11 mutation and clarify its correlation with MODY.
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Affiliation(s)
| | | | - Oswaldo Rincon
- Endocronology Department, Hospital Militar Central, Bogota, Colombia
| | - Issac Guzmán
- Endocronology Department, Hospital Militar Central, Bogota, Colombia
| | - Mauricio Alvarez
- Endocronology Department, Hospital Militar Central, Bogota, Colombia
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Aksenova M, Zaikova N, Tozliyan E. Renal Fanconi syndrome and hypoglycemia: lessons for clinical nephrologists. J Nephrol 2023; 36:2633-2636. [PMID: 37530939 DOI: 10.1007/s40620-023-01719-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/23/2023] [Indexed: 08/03/2023]
Affiliation(s)
- Marina Aksenova
- Nephrology Department, Y. Veltischev Research and Clinical Institute for Pediatrics and Pediatric Surgery at N. Pirogov, Russian National Research Medical University, Taldomskaya Str.2, 125412, Moscow, Russia.
| | - Natalia Zaikova
- Nephrology Department, Y. Veltischev Research and Clinical Institute for Pediatrics and Pediatric Surgery at N. Pirogov, Russian National Research Medical University, Taldomskaya Str.2, 125412, Moscow, Russia
| | - Elena Tozliyan
- Consultative Department, Y. Veltischev Research and Clinical Institute for Pediatrics and Pediatric Surgery at N. Pirogov, Russian National Research Medical University, Taldomskaya Str.2, 125412, Moscow, Russia
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Adadey SM, Mensah JA, Acquah KS, Abugri J, Osei-Yeboah R. Early-onset diabetes in Africa: A mini-review of the current genetic profile. Eur J Med Genet 2023; 66:104887. [PMID: 37995864 DOI: 10.1016/j.ejmg.2023.104887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 11/15/2023] [Accepted: 11/17/2023] [Indexed: 11/25/2023]
Abstract
Early-onset diabetes is poorly diagnosed partly due to its heterogeneity and variable presentations. Although several genes have been associated with the disease, these genes are not well studied in Africa. We sought to identify the major neonatal, early childhood, juvenile, or early-onset diabetes genes in Africa; and evaluate the available molecular methods used for investigating these gene variants. A literature search was conducted on PubMed, Scopus, Africa-Wide Information, and Web of Science databases. The retrieved records were screened and analyzed to identify genetic variants associated with early-onset diabetes. Although 319 records were retrieved, 32 were considered for the current review. Most of these records (22/32) were from North Africa. The disease condition was genetically heterogenous with most cases possessing unique gene variants. We identified 22 genes associated with early-onset diabetes, 9 of which had variants (n = 19) classified as pathogenic or likely pathogenic (PLP). Among the PLP variants, IER3IP1: p.(Leu78Pro) was the variant with the highest number of cases. There was limited data from West Africa, hence the contribution of genetic variability to early-onset diabetes in Africa could not be comprehensively evaluated. It is worth mentioning that most studies were focused on natural products as antidiabetics and only a few studies reported on the genetics of the disease. ABCC8 and KCNJ11 were implicated as major contributors to early-onset diabetes gene networks. Gene ontology analysis of the network associated ion channels, impaired glucose tolerance, and decreased insulin secretions to the disease. Our review highlights 9 genes from which PLP variants have been identified and can be considered for the development of an African diagnostic panel. There is a gap in early-onset diabetes genetic research from sub-Saharan Africa which is much needed to develop a comprehensive, efficient, and cost-effective genetic panel that will be useful in clinical practice on the continent and among the African diasporas.
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Affiliation(s)
- Samuel Mawuli Adadey
- West African Centre for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Accra, Ghana; School of Medicine and Health Science, University for Development Studies, Tamale, Ghana.
| | | | - Kojo Sekyi Acquah
- Department of Microbiology and Immunology, University of Michigan, Ann Arbor, MI, USA.
| | - James Abugri
- Department of Biochemistry and Forensic Sciences, School of Chemical and Biochemical Sciences, C.K. Tedam University of Technology and Applied Sciences, Navrongo, Ghana.
| | - Richard Osei-Yeboah
- Centre for Global Health, University of Edinburgh, Edinburgh, United Kingdom.
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Kim H, Kim HY, Kim JH, Seo SH, Park KU. Novel pathogenic PDX1 gene variant in a Korean family with maturity-onset diabetes of the young. Cold Spring Harb Mol Case Stud 2023; 9:a006305. [PMID: 37652665 PMCID: PMC10815283 DOI: 10.1101/mcs.a006305] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 08/22/2023] [Indexed: 09/02/2023] Open
Abstract
The diagnosis of maturity-onset diabetes of the young (MODY), a monogenic form of diabetes mellitus caused by a mutation in a single gene, is often uncertain until genetic testing is performed. We report a 13-yr-old Korean boy who was initially diagnosed with type 2 diabetes (T2DM). MODY was suspected because of his nonobese body habitus and family history of multiple affected members. Targeted panel sequencing of all MODY-related genes was performed using the NextSeq 550Dx platform (Illumina). Sanger sequencing was performed using blood samples from the parents, siblings, and other relatives. A frameshift variant in the 3' region of the last exon of PDX1 was detected in the patient and his family members with diabetes. PP1_Moderate criterion was applied and this variant was confirmed to be the genetic cause of diabetes in the family and classified as likely pathogenic. The study highlights the importance of genetic testing for nonobese, early-onset diabetic patients with multiple affected family members. Increased awareness and aggressive genetic testing for MODY are needed.
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Affiliation(s)
- Hyunji Kim
- Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Hwa Young Kim
- Department of Pediatrics, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Jae Hyun Kim
- Department of Pediatrics, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Soo Hyun Seo
- Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea;
| | - Kyung Un Park
- Department of Laboratory Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
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Wu HX, Chu TY, Iqbal J, Jiang HL, Li L, Wu YX, Zhou HD. Cardio-cerebrovascular Outcomes in MODY, Type 1 Diabetes, and Type 2 Diabetes: A Prospective Cohort Study. J Clin Endocrinol Metab 2023; 108:2970-2980. [PMID: 37093977 DOI: 10.1210/clinem/dgad233] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/09/2023] [Accepted: 04/20/2023] [Indexed: 04/26/2023]
Abstract
CONTEXT Cardio-cerebrovascular events are severe complications of diabetes. OBJECTIVE We aim to compare the incident risk of cardio-cerebrovascular events in maturity onset diabetes of the young (MODY), type 1 diabetes, and type 2 diabetes. METHODS Type 1 diabetes, type 2 diabetes, and MODY were diagnosed by whole exome sequencing. The primary endpoint was the occurrence of the first major adverse cardiovascular event (MACE), including acute myocardial infarction, heart failure, stroke, unstable angina pectoris, and cardio-cerebrovascular-related mortality. Cox proportional hazards models were applied and adjusted to calculate hazard ratios (HRs) and 95% CIs for the incident risk of MACE in type 1 diabetes, type 2 diabetes, MODY, and MODY subgroups compared with people without diabetes (control group). RESULTS Type 1 diabetes, type 2 diabetes, and MODY accounted for 2.7%, 68.1%, and 11.4% of 26 198 participants with diabetes from UK Biobank. During a median follow-up of 13 years, 1028 MACEs occurred in the control group, contrasting with 70 events in patients with type 1 diabetes (HR 2.15, 95% CI 1.69-2.74, P < .05), 5020 events in patients with type 2 diabetes (HR 7.02, 95% CI 6.56-7.51, P < .05), and 717 events in MODY (HR 5.79, 95% CI 5.26-6.37, P < .05). The hazard of MACE in HNF1B-MODY was highest among MODY subgroups (HR 11.00, 95% CI 5.47-22.00, P = 1.5 × 10-11). CONCLUSION MODY diagnosed by genetic analysis represents higher prevalence than the clinical diagnosis in UK Biobank. The risk of incident cardio-cerebrovascular events in MODY ranks between type 1 diabetes and type 2 diabetes.
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Affiliation(s)
- Hui-Xuan Wu
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Key Laboratory of Diabetes Immunology Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Tian-Yao Chu
- Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 41000, Hunan, China
| | - Junaid Iqbal
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Key Laboratory of Diabetes Immunology Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Hong-Li Jiang
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Key Laboratory of Diabetes Immunology Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Long Li
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Key Laboratory of Diabetes Immunology Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
| | - Yan-Xuan Wu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin 15000, China
| | - Hou-De Zhou
- National Clinical Research Center for Metabolic Diseases, Hunan Provincial Key Laboratory for Metabolic Bone Diseases, Key Laboratory of Diabetes Immunology Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China
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Tovar A, Kyono Y, Nishino K, Bose M, Varshney A, Parker SCJ, Kitzman JO. Using a modular massively parallel reporter assay to discover context-specific regulatory grammars in type 2 diabetes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.08.561391. [PMID: 37873175 PMCID: PMC10592691 DOI: 10.1101/2023.10.08.561391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Recent genome-wide association studies have established that most complex disease-associated loci are found in noncoding regions where defining their function is nontrivial. In this study, we leverage a modular massively parallel reporter assay (MPRA) to uncover sequence features linked to context-specific regulatory activity. We screened enhancer activity across a panel of 198-bp fragments spanning over 10k type 2 diabetes- and metabolic trait-associated variants in the 832/13 rat insulinoma cell line, a relevant model of pancreatic beta cells. We explored these fragments' context sensitivity by comparing their activities when placed up-or downstream of a reporter gene, and in combination with either a synthetic housekeeping promoter (SCP1) or a more biologically relevant promoter corresponding to the human insulin gene ( INS ). We identified clear effects of MPRA construct design on measured fragment enhancer activity. Specifically, a subset of fragments (n = 702/11,656) displayed positional bias, evenly distributed across up- and downstream preference. A separate set of fragments exhibited promoter bias (n = 698/11,656), mostly towards the cell-specific INS promoter (73.4%). To identify sequence features associated with promoter preference, we used Lasso regression with 562 genomic annotations and discovered that fragments with INS promoter-biased activity are enriched for HNF1 motifs. HNF1 family transcription factors are key regulators of glucose metabolism disrupted in maturity onset diabetes of the young (MODY), suggesting genetic convergence between rare coding variants that cause MODY and common T2D-associated regulatory variants. We designed a follow-up MPRA containing HNF1 motif-enriched fragments and observed several instances where deletion or mutation of HNF1 motifs disrupted the INS promoter-biased enhancer activity, specifically in the beta cell model but not in a skeletal muscle cell line, another diabetes-relevant cell type. Together, our study suggests that cell-specific regulatory activity is partially influenced by enhancer-promoter compatibility and indicates that careful attention should be paid when designing MPRA libraries to capture context-specific regulatory processes at disease-associated genetic signals.
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Arslanoğlu I, Eröz R, Yavuzyılmaz F, Doğan M, Bolu S, Karaca S. VARIATIONS IN MONOGENIC DIABETES AND DIABETES SUSCEPTIBILITY GENES IN PEDIATRIC CASES: SINGLE CENTER EXPERIENCE. ACTA ENDOCRINOLOGICA (BUCHAREST, ROMANIA : 2005) 2023; 19:512-522. [PMID: 38933241 PMCID: PMC11197833 DOI: 10.4183/aeb.2023.512] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/28/2024]
Abstract
Context Diabetes is a chronic disorder with a complex pathogenetic background including monogenic, polygenic, and environmental causes. Objective The aim of the present paper is to share the information related to genetic and clinical data of large pediatric diabetes cohort. Design The present study retrospectively analyzes genetic and clinical findings of subjects diagnosed with diabetes under the age of 18 year and are in follow-up in a pediatric diabetes referral center. Subjects and Methods Out of 1205 children with diabetes (902 treated with insulin) 246 underwent genetic tests on the basis of clinical selection criteria since 2007. Results One hundred and ten variants related to diabetes were found in 89 of them. Age at presentation was 9.5±4.02 years (F/M 44/45). In total 49 pathogenic and likely pathogenic, 11 "hot and warm" of unknown significance variants were found in fourteen MODY and fifteen non-MODY genes according to criteria developed by American College of Medical Genetics. Thirty novel mutations were found. GCK (26.6%) and ABCC8 (10%) were two most frequently affected genes. Antibody testing revealed negative results in 80% of cases. Conclusions Genetic interpretation in selected cases is important to understand the nature of the disease better. Improvement in testing opportunity and awareness might increase the prevalence of genetically explained diabetes cases. The distribution of subtypes differs between countries and even regions of the same country.
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Affiliation(s)
- I. Arslanoğlu
- Duzce University Medical School - Department of Pediatric Endocrinology, Duzce
| | - R. Eröz
- Aksaray University, Faculty of Medicine, Department of Medical Genetics, Aksaray
| | - F. Yavuzyılmaz
- Duzce University Medical School - Department of Pediatric Endocrinology, Duzce
| | - M. Doğan
- Ministry of Health Başakşehir State Hospital - Department of Medical Genetics, Istanbul, Başakşehir
| | - S. Bolu
- Bolu Abant İzzet Baysal University Gölköy Campus - Pediatric Endocrinology, Bolu
| | - S. Karaca
- Ankara University, Faculty of Medicine - Department of Pediatric Endocrinology, Ankara, Turkey
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Chandra A, Yoon S, Michieletto MF, Goldman N, Ferrari EK, Abedi M, Johnson I, Fasolino M, Pham K, Joannas L, Kee BL, Henao-Mejia J, Vahedi G. Quantitative control of Ets1 dosage by a multi-enhancer hub promotes Th1 cell differentiation and protects from allergic inflammation. Immunity 2023; 56:1451-1467.e12. [PMID: 37263273 PMCID: PMC10979463 DOI: 10.1016/j.immuni.2023.05.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Revised: 05/06/2023] [Accepted: 05/08/2023] [Indexed: 06/03/2023]
Abstract
Multi-enhancer hubs are spatial clusters of enhancers present across numerous developmental programs. Here, we studied the functional relevance of these three-dimensional structures in T cell biology. Mathematical modeling identified a highly connected multi-enhancer hub at the Ets1 locus, comprising a noncoding regulatory element that was a hotspot for sequence variation associated with allergic disease in humans. Deletion of this regulatory element in mice revealed that the multi-enhancer connectivity was dispensable for T cell development but required for CD4+ T helper 1 (Th1) differentiation. These mice were protected from Th1-mediated colitis but exhibited overt allergic responses. Mechanistically, the multi-enhancer hub controlled the dosage of Ets1 that was required for CTCF recruitment and assembly of Th1-specific genome topology. Our findings establish a paradigm wherein multi-enhancer hubs control cellular competence to respond to an inductive cue through quantitative control of gene dosage and provide insight into how sequence variation within noncoding elements at the Ets1 locus predisposes individuals to allergic responses.
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Affiliation(s)
- Aditi Chandra
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Sora Yoon
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Michaël F Michieletto
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Protective Immunity, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Naomi Goldman
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Emily K Ferrari
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Maryam Abedi
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Isabelle Johnson
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Maria Fasolino
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Kenneth Pham
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Leonel Joannas
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Protective Immunity, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Barbara L Kee
- Department of Pathology, Committees on Cancer Biology and Immunology, University of Chicago, Chicago, IL 60637, USA
| | - Jorge Henao-Mejia
- Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Protective Immunity, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA 19104, USA.
| | - Golnaz Vahedi
- Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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Szilberhorn L, Zelei T, Vellekoop H, Huygens S, Versteegh M, Mölken MRV, Koleva-Kolarova R, Tsiachristas A, Wordsworth S, Nagy B. Cost-effectiveness and budget impact analysis of screening strategies for maturity-onset diabetes of the young in three European countries. Per Med 2023; 20:387-399. [PMID: 37665262 DOI: 10.2217/pme-2023-0017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
Background: Correct diagnosis of maturity-onset diabetes of the young (MODY), which is often misdiagnosed as Type 1 or 2 diabetes, is important for providing appropriate treatment. Materials & Methods: A diabetes model was adapted to Hungary, the Netherlands, and the UK to analyse the cost-effectiveness and budget impact of different screening strategies for MODY with 20 years time horizon. Results: Compared with no screening, screening with the MODY calculator then genetic testing is considered cost-effective with respect to each country's willingness to pay threshold. The addition of autoantibody testing dominated the no screening strategy. The budget impact of the strategies ranges between 0.001 and 0.025% of annual public healthcare spending. Conclusion: The analysed strategies are considered good value for money with potential cost savings in the long term.
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Affiliation(s)
| | - Tamás Zelei
- Syreon Research Institute, 1142, Budapest, Hungary
| | - Heleen Vellekoop
- Institute for Medical Technology Assessment, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands
| | - Simone Huygens
- Institute for Medical Technology Assessment, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands
| | - Matthijs Versteegh
- Institute for Medical Technology Assessment, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands
| | - Maureen Rutten-van Mölken
- Institute for Medical Technology Assessment, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands
- Erasmus School of Health Policy & Management, Erasmus University Rotterdam, P.O. Box 1738, 3000 DR, Rotterdam, The Netherlands
| | | | | | - Sarah Wordsworth
- Health Economics Research Centre, University of Oxford, OX3 7LF, Oxford, UK
| | - Balázs Nagy
- Syreon Research Institute, 1142, Budapest, Hungary
- Center for Health Technology Assessment, Semmelweis University, 1091, Budapest, Hungary
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