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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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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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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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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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Jafri AD, Dhar SK, Brahmadarshini Bhuyan T, Tudu PK, Zeenat M, Rizvi K. Atypical Presentation of Flatbush Diabetes During a Febrile Illness: A Case Report and Review of Literature. Cureus 2024; 16:e72998. [PMID: 39634998 PMCID: PMC11616898 DOI: 10.7759/cureus.72998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/04/2024] [Indexed: 12/07/2024] Open
Abstract
Flatbush diabetes is a significant clinical condition that is gaining recognition on a global scale. Although it's commonly believed that individuals who exhibit symptoms of diabetic ketoacidosis (DKA) have type 1 diabetes and need to take insulin continuously for the rest of their lives, this isn't always the case. Understanding the differences between the natural histories of type 1 and 2 diabetes mellitus (DM) and Flatbush diabetes will aid in early diagnosis and appropriate management. We present a very unusual case of Flatbush diabetes in a young male who presents with recurrent episodes of DKA during febrile illness. Only a few such cases have been documented in the medical literature, despite recent advancements in diabetes research.
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Affiliation(s)
| | - Srikant K Dhar
- Internal Medicine, Institute of Medical Sciences (IMS) and Sum Hospital, Bhubaneswar, IND
| | | | - Promod K Tudu
- Internal Medicine, Institute of Medical Sciences (IMS) and Sum Hospital, Bhubaneswar, IND
| | - Mareya Zeenat
- General Medicine, Sum Ultimate Medicare, Bhubaneswar, IND
| | - Kayenaat Rizvi
- Pharmacology, Era's Lucknow Medical College and Hospital, Lucknow, IND
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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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Daniels Gatward LF, King AJF. Matching model with mechanism: Appropriate rodent models for studying various aspects of diabetes pathophysiology. Methods Cell Biol 2024; 192:39-68. [PMID: 39863393 DOI: 10.1016/bs.mcb.2024.05.003] [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: 01/27/2025]
Abstract
Many rodent models are available for preclinical diabetes research making it a challenge for researchers to choose the most appropriate one for their experimental question. To aid in this, models have classically been categorized according to which type of diabetes they represent, and further into whether the model is induced, spontaneous or the result of genetic manipulation. This fails to capture the complexity of pathogenesis seen in diabetes in humans. This includes pathogenesis specifically involving the beta cell, which is no longer considered to be innocuous in the development and progression of diabetes. In this chapter we explore rodent models that incorporate the initiating factors believed to be involved in type 1 diabetes (autoimmunity) and type 2 diabetes (insulin resistance), before further discussing rodents that can be used to model specific mechanisms involved in a failure of functional beta cell mass (impaired beta cell function and beta cell apoptosis). We segregate models of beta cell pathogenesis based on the beta cell stressor predominantly associated with phenotype, but it is important to consider that most rodent models will exhibit more than one beta cell stressor. Similarly, many models exhibit more than one pathogenic mechanism, for example the same model may show insulin resistance, impaired beta cell function as well as beta cell loss. This can complicate interpretation of results and should be considered, and the model thoroughly researched, during the experimental planning stage.
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Affiliation(s)
- Lydia F Daniels Gatward
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, United Kingdom
| | - Aileen J F King
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London, London, United Kingdom.
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Chand S, Tripathi AS, Dewani AP, Sheikh NWA. Molecular targets for management of diabetes: Remodelling of white adipose to brown adipose tissue. Life Sci 2024; 345:122607. [PMID: 38583857 DOI: 10.1016/j.lfs.2024.122607] [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: 12/24/2023] [Revised: 03/28/2024] [Accepted: 04/01/2024] [Indexed: 04/09/2024]
Abstract
Diabetes mellitus is a disorder characterised metabolic dysfunction that results in elevated glucose level in the bloodstream. Diabetes is of two types, type1 and type 2 diabetes. Obesity is considered as one of the major reasons intended for incidence of diabetes hence it turns out to be essential to study about the adipose tissue which is responsible for fat storage in body. Adipose tissues play significant role in maintaining the balance between energy stabilization and homeostasis. The three forms of adipose tissue are - White adipose tissue (WAT), Brown adipose tissue (BAT) and Beige adipose tissue (intermediate form). The amount of BAT gets reduced, and WAT starts to increase with the age. WAT when exposed to certain stimuli gets converted to BAT by the help of certain transcriptional regulators. The browning of WAT has been a matter of study to treat the metabolic disorders and to initiate the expenditure of energy. The three main regulators responsible for the browning of WAT are PRDM16, PPARγ and PGC-1α via various cellular and molecular mechanism. Presented review article includes the detailed elaborative aspect of genes and proteins involved in conversion of WAT to BAT.
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Affiliation(s)
- Shushmita Chand
- Amity Institute of Pharmacy, Amity University, Sector 125, Noida, Uttar Pradesh, India
| | - Alok Shiomurti Tripathi
- Department of Pharmacology, ERA College of Pharmacy, ERA University, Lucknow, Uttar Pradesh, India.
| | - Anil P Dewani
- Department of Pharmacology, P. Wadhwani College of Pharmacy, Yavatmal, Maharashtra, India
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Daniali M, Nikfar S, Abdollahi M. Advancements in pharmacotherapy options for treating diabetes in children and adolescents. Expert Rev Endocrinol Metab 2024; 19:37-47. [PMID: 38078451 DOI: 10.1080/17446651.2023.2290491] [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: 05/23/2023] [Accepted: 11/29/2023] [Indexed: 01/03/2024]
Abstract
INTRODUCTION This study compares diabetes management between pediatric and adult patients and identifies treatment challenges and gaps. AREAS COVERED We searched PubMed and Clinicaltrails.gov databases for studies published from 2001 to 2023 on diabetes management in different age groups. EXPERT OPINION Research shows children have lower insulin sensitivity, clearance, and β cell function than adults. The US FDA only allows insulin, metformin, and liraglutide as antidiabetic medication options for children. However, some off-label drugs, like meglitinides, sulfonylureas, and alogliptin, have demonstrated positive results in treating certain types of diabetes caused by gene mutations. It's crucial to adopt personalized and precise approaches to managing diabetes in pediatrics, which vary from those used for adult patients. New studies support the classification of type 2 diabetes into several subtypes based on age, BMI, glycemia, homeostasis model estimates, varying insulin resistance, different rates of complications, and islet autoantibodies. With this insight, prevention, treatment, and precision medicine of diabetes might be changed. More research is necessary to assess the safety and efficacy of different antidiabetic drugs and improve diabetes treatment for children and adolescents.
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Affiliation(s)
- Marzieh Daniali
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
| | - Shekoufeh Nikfar
- Department of Pharmacoeconomics and Pharmaceutical Administration, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Personalized Medicine Research Center (PMRC), the Endocrinology and Metabolism Research Institute (EMRI), Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Abdollahi
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), Tehran University of Medical Sciences, Tehran, Iran
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Kumar A, Kumar A, Samadarshi S, Manrai M, Tevatia MS, Dawra S. Unknown presentation of a rare genetic disorder: Monogenic diabetes in young type 4 presenting with hepatic cysts and procoagulant state. Med J Armed Forces India 2023; 79:S297-S300. [PMID: 38144640 PMCID: PMC10746807 DOI: 10.1016/j.mjafi.2021.11.001] [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: 07/30/2021] [Accepted: 11/06/2021] [Indexed: 11/23/2022] Open
Abstract
Maturity onset diabetes in young (MODY) is the most common form of monogenic diabetes, which characteristically presents in adolescents and young adults. Till date, pathogenic variations involving 14 different genes have been causally implicated with the development of MODY. Maturity onset diabetes in young type 4 (MODY-4) is a very rare form of MODY. We present here case of 28-year-old nonobese male patient with distinct family history of diabetes spanning two generations, incidentally, detected to have a rare form of diabetes on genetic analysis when he presented with recurrent thromboembolic manifestations: deep vein thrombosis and pulmonary thromboembolism. Our case highlights a previously unknown disease association of a rare genetic disorder. Increasing awareness about this genetic disorder and early identification of such cases will enhance our understanding of hitherto unknown disease associations and the pathophysiological role of genetic mutations. This may contribute to the improved treatment and prevention of debilitating diseases such as diabetes.
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Affiliation(s)
- Anupam Kumar
- Senior Advisor (Endocrinology), Command Hospital (Southern Command), Pune, India
| | - Ankit Kumar
- Resident (Medicine), Command Hospital (Southern Command), Pune, India
| | - Samir Samadarshi
- Resident (Medicine), Command Hospital (Southern Command), Pune, India
| | - Manish Manrai
- Professor, Department of Internal Medicine, Armed Forces Medical College, Pune, India
| | | | - Saurabh Dawra
- Classified Specialist (Gastroenterology), Command Hospital (Southern Command), Pune, India
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Ustianowski Ł, Udzik J, Szostak J, Gorący A, Ustianowska K, Pawlik A. Genetic and Epigenetic Factors in Gestational Diabetes Mellitus Pathology. Int J Mol Sci 2023; 24:16619. [PMID: 38068941 PMCID: PMC10706782 DOI: 10.3390/ijms242316619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2023] [Revised: 11/14/2023] [Accepted: 11/20/2023] [Indexed: 12/18/2023] Open
Abstract
Gestational diabetes (GDM) is the carbohydrate intolerance occurring during pregnancy. The risk factors of GDM include obesity, advanced maternal age, polycystic ovary syndrome, multigravidity, a sedentary lifestyle, and pre-existing hypertension. Additionally, complex genetic and epigenetic processes are also believed to play a crucial role in the development of GDM. In this narrative review, we discuss the role of genetic and epigenetic factors in gestational diabetes mellitus pathogenesis.
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Affiliation(s)
- Łukasz Ustianowski
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (Ł.U.); (J.U.); (K.U.)
| | - Jakub Udzik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (Ł.U.); (J.U.); (K.U.)
- Department of Cardiac Surgery, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Joanna Szostak
- Department of Experimental and Clinical Pharmacology, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Anna Gorący
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University, 70-111 Szczecin, Poland;
| | - Klaudia Ustianowska
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (Ł.U.); (J.U.); (K.U.)
| | - Andrzej Pawlik
- Department of Physiology, Pomeranian Medical University, 70-111 Szczecin, Poland; (Ł.U.); (J.U.); (K.U.)
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Firdous P, Nissar K, Masoodi SR, Ganai BA. Biomarkers: Tools for Discriminating MODY from Other Diabetic Subtypes. Indian J Endocrinol Metab 2022; 26:223-231. [PMID: 36248040 PMCID: PMC9555386 DOI: 10.4103/ijem.ijem_266_21] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 02/24/2022] [Accepted: 05/29/2022] [Indexed: 11/29/2022] Open
Abstract
Maturity Onset Diabetes of Young (MODY), characterized by the pancreatic b-cell dysfunction, the autosomal dominant mode of inheritance and early age of onset (often ≤25 years). It differs from normal type 1 and type 2 diabetes in that it occurs at a low rate of 1-5%, three-generational autosomal dominant patterns of inheritance and lacks typical diabetic features such as obesity. MODY patients can be managed by diet alone for many years, and sulfonylureas are also recommended to be very effective for managing glucose levels for more than 30 years. Despite rapid advancements in molecular disease diagnosis methods, MODY cases are frequently misdiagnosed as type 1 or type 2 due to overlapping clinical features, genetic testing expenses, and a lack of disease understanding. A timely and accurate diagnosis method is critical for disease management and its complications. An early diagnosis and differentiation of MODY at the clinical level could reduce the risk of inappropriate insulin or sulfonylurea treatment therapy and its associated side effects. We present a broader review to highlight the role and efficacy of biomarkers in MODY differentiation and patient selection for genetic testing analysis.
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Affiliation(s)
- Parveena Firdous
- Centre of Research for Development (CORD), University of Kashmir, Srinagar, Jammu and Kashmir
| | - Kamran Nissar
- Centre of Research for Development (CORD), University of Kashmir, Srinagar, Jammu and Kashmir
- Department of Clinical Biochemistry, University of Kashmir, Srinagar, Jammu and Kashmir
| | | | - Bashir Ahmad Ganai
- Centre of Research for Development (CORD), University of Kashmir, Srinagar, Jammu and Kashmir
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Kind L, Raasakka A, Molnes J, Aukrust I, Bjørkhaug L, Njølstad PR, Kursula P, Arnesen T. Structural and biophysical characterization of transcription factor HNF-1A as a tool to study MODY3 diabetes variants. J Biol Chem 2022; 298:101803. [PMID: 35257744 PMCID: PMC8988010 DOI: 10.1016/j.jbc.2022.101803] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 02/15/2022] [Accepted: 02/20/2022] [Indexed: 11/05/2022] Open
Abstract
Hepatocyte nuclear factor 1A (HNF-1A) is a transcription factor expressed in several embryonic and adult tissues, modulating the expression of numerous target genes. Pathogenic variants in the HNF1A gene are known to cause maturity-onset diabetes of the young 3 (MODY3 or HNF1A MODY), a disease characterized by dominant inheritance, age of onset before 25 to 35 years of age, and pancreatic β-cell dysfunction. A precise diagnosis can alter management of this disease, as insulin can be exchanged with sulfonylurea tablets and genetic counseling differs from polygenic forms of diabetes. Therefore, more knowledge on the mechanisms of HNF-1A function and the level of pathogenicity of the numerous HNF1A variants is required for precise diagnostics. Here, we structurally and biophysically characterized an HNF-1A protein containing both the DNA-binding domain and the dimerization domain, and determined the folding and DNA-binding capacity of two established MODY3 HNF-1A variant proteins (P112L, R263C) and one variant of unknown significance (N266S). All three variants showed reduced functionality compared to the WT protein. Furthermore, while the R263C and N266S variants displayed reduced binding to an HNF-1A target promoter, we found the P112L variant was unstable in vitro and in cells. Our results support and mechanistically explain disease causality for these investigated variants and present a novel approach for the dissection of structurally unstable and DNA-binding defective variants. This study indicates that structural and biochemical investigation of HNF-1A is a valuable tool in reliable variant classification needed for precision diabetes diagnostics and management.
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Affiliation(s)
- Laura Kind
- Department of Biomedicine, University of Bergen, Bergen, Norway.
| | - Arne Raasakka
- Department of Biomedicine, University of Bergen, Bergen, Norway
| | - Janne Molnes
- Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
| | - Ingvild Aukrust
- Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
| | - Lise Bjørkhaug
- Department of Safety, Chemistry, and Biomedical Laboratory Sciences, Western Norway University of Applied Sciences, Bergen, Norway
| | - Pål Rasmus Njølstad
- Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway; Section of Endocrinology and Metabolism, Children and Youth Clinic, Haukeland University Hospital, Bergen, Norway.
| | - Petri Kursula
- Department of Biomedicine, University of Bergen, Bergen, Norway; Faculty of Biochemistry and Molecular Medicine & Biocenter Oulu, University of Oulu, Oulu, Finland
| | - Thomas Arnesen
- Department of Biomedicine, University of Bergen, Bergen, Norway; Department of Biological Sciences, University of Bergen, Bergen, Norway; Department of Surgery, Haukeland University Hospital, Bergen, Norway.
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14
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Li LM, Jiang BG, Sun LL. HNF1A：From Monogenic Diabetes to Type 2 Diabetes and Gestational Diabetes Mellitus. Front Endocrinol (Lausanne) 2022; 13:829565. [PMID: 35299962 PMCID: PMC8921476 DOI: 10.3389/fendo.2022.829565] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 02/03/2022] [Indexed: 12/12/2022] Open
Abstract
Diabetes, a disease characterized by hyperglycemia, has a serious impact on the lives and families of patients as well as on society. Diabetes is a group of highly heterogeneous metabolic diseases that can be classified as type 1 diabetes (T1D), type 2 diabetes (T2D), gestational diabetes mellitus (GDM), or other according to the etiology. The clinical manifestations are more or less similar among the different types of diabetes, and each type is highly heterogeneous due to different pathogenic factors. Therefore, distinguishing between various types of diabetes and defining their subtypes are major challenges hindering the precise treatment of the disease. T2D is the main type of diabetes in humans as well as the most heterogeneous. Fortunately, some studies have shown that variants of certain genes involved in monogenic diabetes also increase the risk of T2D. We hope this finding will enable breakthroughs regarding the pathogenesis of T2D and facilitate personalized treatment of the disease by exploring the function of the signal genes involved. Hepatocyte nuclear factor 1 homeobox A (HNF1α) is widely expressed in pancreatic β cells, the liver, the intestines, and other organs. HNF1α is highly polymorphic, but lacks a mutation hot spot. Mutations can be found at any site of the gene. Some single nucleotide polymorphisms (SNPs) cause maturity-onset diabetes of the young type 3 (MODY3) while some others do not cause MODY3 but increase the susceptibility to T2D or GDM. The phenotypes of MODY3 caused by different SNPs also differ. MODY3 is among the most common types of MODY, which is a form of monogenic diabetes mellitus caused by a single gene mutation. Both T2D and GDM are multifactorial diseases caused by both genetic and environmental factors. Different types of diabetes mellitus have different clinical phenotypes and treatments. This review focuses on HNF1α gene polymorphisms, HNF1A-MODY3, HNF1A-associated T2D and GDM, and the related pathogenesis and treatment methods. We hope this review will provide a valuable reference for the precise and individualized treatment of diabetes caused by abnormal HNF1α by summarizing the clinical heterogeneity of blood glucose abnormalities caused by HNF1α mutation.
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Affiliation(s)
- Li-Mei Li
- Research Center for Translational Medicine, Key Laboratory of Arrhythmias of the Ministry of Education of China, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
| | - Bei-Ge Jiang
- Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
- *Correspondence: Bei-Ge Jiang, ; Liang-Liang Sun,
| | - Liang-Liang Sun
- Department of Endocrinology and Metabolism, Changzheng Hospital, Naval Medical University, Shanghai, China
- *Correspondence: Bei-Ge Jiang, ; Liang-Liang Sun,
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15
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Yalçıntepe S, Özgüç Çömlek F, Gürkan H, Demir S, Atlı Eİ, Atlı E, Eker D, Tütüncüler Kökenli F. The Application of Next Generation Sequencing Maturity Onset Diabetes of the Young Gene Panel in Turkish Patients from Trakya Region. J Clin Res Pediatr Endocrinol 2021; 13:320-331. [PMID: 33565752 PMCID: PMC8388052 DOI: 10.4274/jcrpe.galenos.2021.2020.0285] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
OBJECTIVE The aim of this study was to investigate the molecular basis of maturity-onset diabetes of the young (MODY) by targeted-gene sequencing of 20 genes related to monogenic diabetes, estimate the frequency and describe the clinical characteristics of monogenic diabetes and MODY in the Trakya Region of Turkey. METHODS A panel of 20 monogenic diabetes related genes were screened in 61 cases. Illumina NextSeq550 system was used for sequencing. Pathogenicity of the variants were assessed by bioinformatics prediction software programs and segregation analyses. RESULTS In 29 (47.5%) cases, 31 pathogenic/likely pathogenic variants in the GCK, ABCC8, KCNJ11, HNF1A, HNF4A genes and in 11 (18%) cases, 14 variants of uncertain significance (VUS) in the GCK, RFX6, CEL, PDX1, KCNJ11, HNF1A, G6PC2, GLIS3 and KLF11 genes were identified. There were six different pathogenic/likely pathogenic variants and six different VUS which were novel. CONCLUSION This is the first study including molecular studies of twenty monogenic diabetes genes in Turkish cases in the Trakya Region. The results showed that pathogenic variants in the GCK gene are the leading cause of MODY in our population. A high frequency of novel variants (32.4%-12/37) in the current study, suggests that multiple gene analysis provides accurate genetic diagnosis in MODY.
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Affiliation(s)
- Sinem Yalçıntepe
- Trakya University Faculty of Medicine, Department of Medical Genetics, Edirne, Turkey,* Address for Correspondence: Trakya University Faculty of Medicine, Department of Medical Genetics, Edirne, Turkey Phone: +90 537 716 86 91 E-mail:
| | - Fatma Özgüç Çömlek
- Trakya University Faculty of Medicine, Department of Pediatric Endocrinology, Edirne, Turkey
| | - Hakan Gürkan
- Trakya University Faculty of Medicine, Department of Medical Genetics, Edirne, Turkey
| | - Selma Demir
- Trakya University Faculty of Medicine, Department of Medical Genetics, Edirne, Turkey
| | - Emine İkbal Atlı
- Trakya University Faculty of Medicine, Department of Medical Genetics, Edirne, Turkey
| | - Engin Atlı
- Trakya University Faculty of Medicine, Department of Medical Genetics, Edirne, Turkey
| | - Damla Eker
- Trakya University Faculty of Medicine, Department of Medical Genetics, Edirne, Turkey
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16
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Gaál Z, Szűcs Z, Kántor I, Luczay A, Tóth-Heyn P, Benn O, Felszeghy E, Karádi Z, Madar L, Balogh I. A Comprehensive Analysis of Hungarian MODY Patients-Part I: Gene Panel Sequencing Reveals Pathogenic Mutations in HNF1A, HNF1B, HNF4A, ABCC8 and INS Genes. Life (Basel) 2021; 11:life11080755. [PMID: 34440499 PMCID: PMC8399091 DOI: 10.3390/life11080755] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/20/2021] [Accepted: 07/24/2021] [Indexed: 12/13/2022] Open
Abstract
Maturity-onset diabetes of the young (MODY) has about a dozen known causal genes to date, the most common ones being HNF1A, HNF4A, HNF1B and GCK. The phenotype of this clinically and genetically heterogeneous form of diabetes depends on the gene in which the patient has the mutation. We have tested 450 Hungarian index patients with suspected MODY diagnosis with Sanger sequencing and next-generation sequencing and found a roughly 30% positivity rate. More than 70% of disease-causing mutations were found in the GCK gene, about 20% in the HNF1A gene and less than 10% in other MODY-causing genes. We found 8 pathogenic and 9 likely pathogenic mutations in the HNF1A gene in a total of 48 patients and family members. In the case of HNF1A-MODY, the recommended first-line treatment is low dose sulfonylurea but according to our data, the majority of our patients had been on unnecessary insulin therapy at the time of requesting their genetic testing. Our data highlights the importance of genetic testing in the diagnosis of MODY and the establishment of the MODY subtype in order to choose the most appropriate treatment.
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Affiliation(s)
- Zsolt Gaál
- 4th Department of Medicine, Jósa András Teaching Hospital, 4400 Nyíregyháza, Hungary;
| | - Zsuzsanna Szűcs
- Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (Z.S.); (L.M.)
| | - Irén Kántor
- Department of Pediatrics, Jósa András Teaching Hospital, 4400 Nyíregyháza, Hungary;
| | - Andrea Luczay
- 1st Department of Pediatrics, Semmelweis University, 1085 Budapest, Hungary; (A.L.); (P.T.-H.)
| | - Péter Tóth-Heyn
- 1st Department of Pediatrics, Semmelweis University, 1085 Budapest, Hungary; (A.L.); (P.T.-H.)
| | - Orsolya Benn
- Department of Pediatrics, Szent György Hospital of Fejér County, 8000 Székesfehérvár, Hungary; (O.B.); (Z.K.)
| | - Enikő Felszeghy
- Department of Pediatrics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
| | - Zsuzsanna Karádi
- Department of Pediatrics, Szent György Hospital of Fejér County, 8000 Székesfehérvár, Hungary; (O.B.); (Z.K.)
| | - László Madar
- Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (Z.S.); (L.M.)
| | - István Balogh
- Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (Z.S.); (L.M.)
- Correspondence:
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17
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Patouni K, Cinek O, Pruhova S, Elblova L, Xatzipsalti M, Sertedaki A, Vazeou A. A case of digenic maturity onset diabetes of the young with heterozygous variants in both HNF1Α and HNF1Β genes. Eur J Med Genet 2021; 64:104264. [PMID: 34161864 DOI: 10.1016/j.ejmg.2021.104264] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 05/27/2021] [Accepted: 06/18/2021] [Indexed: 12/23/2022]
Abstract
BACKGROUND Maturity onset diabetes of the young (MODY) is the most commonly reported form of monogenic diabetes in the pediatric population. Only a few cases of digenic MODY have been reported up to now. CASE REPORT A female patient was diagnosed with diabetes at the age of 7 years and was treated with insulin. A strong family history of diabetes was present in the maternal side of the family. The patient also presented hypomagnesemia, glomerulocystic kidney disease and a bicornuate uterus. Genetic testing of the patient revealed that she was a double heterozygous carrier of HNF1A gene variant c.685C > T; (p.Arg229Ter) and a whole gene deletion of the HNF1B gene. Her mother was a carrier of the same HNF1A variant. CONCLUSION Digenic inheritance of MODY pathogenic variants is probably more common than currently reported in literature. The use of Next Generation Sequencing panels in testing strategies for MODY could unmask such cases that would otherwise remain undiagnosed.
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Affiliation(s)
- Konstantina Patouni
- Diabetes Center, First Department of Paediatrics, "P. & A. Kyriakou" Children's Hospital, Athens, Greece.
| | - Ondrej Cinek
- Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic
| | - Stepanka Pruhova
- Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic
| | - Lenka Elblova
- Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic
| | - Maria Xatzipsalti
- Diabetes Center, First Department of Paediatrics, "P. & A. Kyriakou" Children's Hospital, Athens, Greece
| | - Amalia Sertedaki
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - Andriani Vazeou
- Diabetes Center, First Department of Paediatrics, "P. & A. Kyriakou" Children's Hospital, Athens, Greece
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Yahaya TO, Yusuf AB, Danjuma JK, Usman BM, Ishiaku YM. Mechanistic links between vitamin deficiencies and diabetes mellitus: a review. EGYPTIAN JOURNAL OF BASIC AND APPLIED SCIENCES 2021; 8:189-202. [DOI: 10.1080/2314808x.2021.1945395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 06/16/2021] [Indexed: 02/08/2023]
Affiliation(s)
- Tajudeen O. Yahaya
- Department of Biology, Federal University Birnin Kebbi, Birnin Kebbi, Nigeria
| | - AbdulRahman B. Yusuf
- Department of Biochemistry and Molecular Biology, Federal University Birnin Kebbi, Birnin Kebbi, Nigeria
| | - Jamilu K. Danjuma
- Department of Biology, Federal University Birnin Kebbi, Birnin Kebbi Nigeria
| | - Bello M. Usman
- Department of Biology, Federal University Birnin Kebbi, Birnin Kebbi Nigeria
| | - Yahaya M. Ishiaku
- Department of Biochemistry and Molecular Biology, Federal University Dutsinma, Katsina, Nigeria
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Braverman-Gross C, Benvenisty N. Modeling Maturity Onset Diabetes of the Young in Pluripotent Stem Cells: Challenges and Achievements. Front Endocrinol (Lausanne) 2021; 12:622940. [PMID: 33692757 PMCID: PMC7937923 DOI: 10.3389/fendo.2021.622940] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 01/06/2021] [Indexed: 12/17/2022] Open
Abstract
Maturity onset diabetes of the young (MODY), is a group of monogenic diabetes disorders. Rodent models for MODY do not fully recapitulate the human phenotypes, calling for models generated in human cells. Human pluripotent stem cells (hPSCs), capable of differentiation towards pancreatic cells, possess a great opportunity to model MODY disorders in vitro. Here, we review the models for MODY diseases in hPSCs to date and the molecular lessons learnt from them. We also discuss the limitations and challenges that these types of models are still facing.
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