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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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Magavern EF, Deshmukh H, Asselin G, Theusch E, Trompet S, Li X, Noordam R, Chen YDI, Seeman TE, Taylor KD, Post WS, Tardif JC, Paul DS, Benjamin EJ, Heard-Costa NL, Vasan RS, Rotter JI, Krauss RM, Jukema JW, Ridker PM, Munroe PB, Caulfield MJ, Chasman DI, Dubé MP, Hitman GA, Warren HR. GWAS of CRP response to statins further supports the role of APOE in statin response: A GIST consortium study. Pharmacol Res 2025; 212:107575. [PMID: 39798939 DOI: 10.1016/j.phrs.2024.107575] [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: 10/15/2024] [Revised: 12/30/2024] [Accepted: 12/31/2024] [Indexed: 01/15/2025]
Abstract
Statins are first-line treatments in the primary and secondary prevention of cardiovascular disease. Clinical studies show statins act independently of lipid-lowering mechanisms to decrease C-reactive protein (CRP), an inflammation marker. We aim to elucidate genetic loci associated with CRP statin response. CRP statin response is the change in log-CRP between off-treatment and on-treatment measurements. Cohort-level Genome-Wide Association Studies (GWAS) of CRP response were performed using 1000 Genomes imputed data, testing ∼10 million common genetic variants. GWAS meta-analysis combined results from seven cohorts and clinical trials totalling 14,070 statin-treated individuals of European ancestry within the GIST consortium. Secondary analyses included statin-by-placebo interaction analyses, and lookups in African ancestry cohorts. Our GWAS identified two genome-wide significant (P < 5e-8) loci: APOE and HNF1A for CRP statin response corrected for baseline CRP. The missense lead variant rs429358 at APOE, contributing to the APOE-E4 haplotype, is a risk locus for dyslipidaemia, Alzheimer's and coronary artery disease (CAD). The HNF1A locus is associated with diabetes, cholesterol levels, and CAD. Both loci are also associated with baseline CRP levels, and neither locus achieved a significant (P < 0.05) result from the statin v. placebo interaction meta-analysis using randomized clinical trial data. However, the interaction result (P-int=0.09) for APOE was suggestive and possibly underpowered. The APOE-E4 signal may therefore be associated with both CRP and LDL-cholesterol statin response. Combined with suggestions in the literature that APOE also leads to differential statin benefit in Alzheimer's, the APOE locus warrants further investigation for potential genetic effects on healthcare with statin treatment.
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Affiliation(s)
- Emma F Magavern
- Centre of Clinical Pharmacology & Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK; NIHR Barts Biomedical Research Centre, Queen Mary University of London, London, UK
| | | | - Geraldine Asselin
- Faculty of Medicine, Université de Montréal, and the Montreal Heart Institute, Montreal, Canada
| | - Elizabeth Theusch
- Department of Pediatrics, University of California San Francisco, Oakland, CA, United States
| | - Stella Trompet
- Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands; Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
| | - Xiaohui Li
- Institute for Translational Genomics and Population Sciences, Department of Pediatrics and The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Raymond Noordam
- Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
| | - Y-D Ida Chen
- Institute for Translational Genomics and Population Sciences, Department of Pediatrics and The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Teresa E Seeman
- Division of Geriatrics, Dept of Medicine, University of California Los Angeles, Los Angeles, CA, USA
| | - Kent D Taylor
- Institute for Translational Genomics and Population Sciences, Department of Pediatrics and The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Wendy S Post
- Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Jean-Claude Tardif
- Faculty of Medicine, Université de Montréal, and the Montreal Heart Institute, Montreal, Canada
| | - Dirk S Paul
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK; Precision Medicine and Biosamples, Oncology R&D, AstraZeneca, Cambridge, UK
| | - Emelia J Benjamin
- Boston University Chobanian & Avedisian School of Medicine and School of Public Health, NHLBI and Boston University's Framingham Heart Study, Framingham, MA, United States
| | - Nancy L Heard-Costa
- Boston University Chobanian & Avedisian School of Medicine and School of Public Health, NHLBI and Boston University's Framingham Heart Study, Framingham, MA, United States
| | - Ramachandran S Vasan
- Boston University Chobanian & Avedisian School of Medicine and School of Public Health, NHLBI and Boston University's Framingham Heart Study, Framingham, MA, United States
| | - Jerome I Rotter
- Institute for Translational Genomics and Population Sciences, Department of Pediatrics and The Lundquist Institute at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Ronald M Krauss
- Department of Pediatrics, University of California San Francisco, Oakland, CA, United States
| | - J Wouter Jukema
- Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
| | - Paul M Ridker
- Division of Preventive Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, United States
| | - Patricia B Munroe
- Centre of Clinical Pharmacology & Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK; NIHR Barts Biomedical Research Centre, Queen Mary University of London, London, UK
| | - Mark J Caulfield
- Centre of Clinical Pharmacology & Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK; NIHR Barts Biomedical Research Centre, Queen Mary University of London, London, UK
| | - Daniel I Chasman
- Division of Preventive Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, United States
| | - Marie-Pierre Dubé
- Faculty of Medicine, Université de Montréal, and the Montreal Heart Institute, Montreal, Canada
| | - Graham A Hitman
- Centre of Genomic Medicine and Child Health, Blizard Institute, Queen Mary University of London, London, UK
| | - Helen R Warren
- Centre of Clinical Pharmacology & Precision Medicine, William Harvey Research Institute, Queen Mary University of London, London, UK; NIHR Barts Biomedical Research Centre, Queen Mary University of London, London, UK.
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Yang C, Ji L, Han X. Low C-Reactive Protein Alleles in Hepatocyte Nuclear Factor 1A Are Associated With an Increased Risk of Cardiovascular Disease. J Clin Endocrinol Metab 2025; 110:592-600. [PMID: 39210612 DOI: 10.1210/clinem/dgae602] [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: 05/04/2024] [Revised: 07/10/2024] [Accepted: 08/29/2024] [Indexed: 09/04/2024]
Abstract
CONTEXT Rare variants in HNF1A cause both maturity onset diabetes of the young 3 (HNF1A-MODY) and reduced serum C-reactive protein (CRP) levels. Common variants of HNF1A are associated with serum CRP and type 2 diabetes mellitus (T2DM), but inconsistently with cardiovascular disease (CVD). OBJECTIVE Our study aimed to investigate the association of low CRP alleles in HNF1A with CVD and indirectly evaluate the CVD risk of HNF1A-MODY patients because of unavailability of enough cases to study their clinical outcomes. METHODS A literature search was performed using PubMed, Embase, and Cochrane Library databases from inception to December 2023. All relevant studies concerning the association of HNF1A with CRP, CVD, lipids, and T2DM were included. Odds ratios (ORs), 95% CIs, and study characteristics were extracted. RESULTS Three common coding variants of HNF1A (rs1169288, rs2464196, and rs1169289) were examined. The minor alleles of these variants correlated with low CRP levels (OR 0.89; 95% CI, 0.86-0.91; OR 0.89; 95% CI, 0.88-0.91; OR 0.89; 95% CI, 0.88-0.91, respectively). Their low CRP alleles were associated with increased risk of CVD (OR 1.03; 95% CI, 1.03-1.04), higher low-density lipoprotein cholesterol levels (OR 1.07; 95% CI, 1.04-1.10), and elevated risk of T2DM (OR 1.04; 95%, CI 1.01-1.08). CONCLUSION Our study revealed an association between low CRP alleles in HNF1A and a high CVD risk, which indicated that antidiabetic drugs with CV benefits such as glucagon-like peptide-1 receptor agonists should be recommended as a first-line choice for HNF1A-MODY.
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Affiliation(s)
- Chaochao Yang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing 100044, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing 100044, China
| | - Xueyao Han
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing 100044, China
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Horikawa Y, Hosomichi K, Yabe D. Monogenic diabetes. Diabetol Int 2024; 15:679-687. [PMID: 39469542 PMCID: PMC11512936 DOI: 10.1007/s13340-024-00698-6] [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: 01/16/2024] [Accepted: 01/25/2024] [Indexed: 10/30/2024]
Abstract
Diseases in which genetic factors contribute to nearly 100% of the causation by single-gene mutations are referred to as monogenic disorders or Mendelian genetic diseases. These include neonatal diabetes mellitus (NDM), presenting within the first six months of life, maturity-onset diabetes of the young (MODY), developing later in childhood or adolescence, mitochondrial diabetes (MIDD), and insulin-resistant disorders, etc. On the other hand, common lifestyle-related diseases such as type 2 diabetes (T2DM), hypertension and dyslipidemia are multifactorial, emerging through complex interplay of genetic and environmental factors. The identification of causative genes for diabetes resulting from single-gene abnormalities not only unveils previously unknown mechanisms of insulin secretion and sensitivity at the molecular level but also reveals novel targets for drug development. Moreover, monogenic diabetes in which insulin secretion is impaired serve to clarify the pathophysiology and suggest therapeutic targets for the common multifactorial type 2 diabetes mellitus prevalent in the Japanese population, which is characterized by impaired insulin secretion. In this study, we characterize the various monogenic subtypes of diabetes so far identified.
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Affiliation(s)
- Yukio Horikawa
- Department of Diabetes, Endocrinology and Metabolism, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, Japan
- Clinical Genetics Center, Gifu University Hospital, Gifu, Japan
- Center for Patient Flow Management, Gifu University Hospital, Gifu, Japan
| | - Kazuyoshi Hosomichi
- Laboratory of Computational Genomics, School of Life Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, 192-0392 Japan
| | - Daisuke Yabe
- Department of Diabetes, Endocrinology and Metabolism, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu, Japan
- Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Osaka, 553-0003 Japan
- Center for One Medicine Innovative Translational Research, Gifu University, Gifu, 501-1194 Japan
- Center for Research, Education and Development for Healthcare Life Design, Gifu University, Gifu, 501-1194 Japan
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Serbis A, Kantza E, Siomou E, Galli-Tsinopoulou A, Kanaka-Gantenbein C, Tigas S. Monogenic Defects of Beta Cell Function: From Clinical Suspicion to Genetic Diagnosis and Management of Rare Types of Diabetes. Int J Mol Sci 2024; 25:10501. [PMID: 39408828 PMCID: PMC11476815 DOI: 10.3390/ijms251910501] [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: 08/26/2024] [Revised: 09/25/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Monogenic defects of beta cell function refer to a group of rare disorders that are characterized by early-onset diabetes mellitus due to a single gene mutation affecting insulin secretion. It accounts for up to 5% of all pediatric diabetes cases and includes transient or permanent neonatal diabetes, maturity-onset diabetes of the young (MODY), and various syndromes associated with diabetes. Causative mutations have been identified in genes regulating the development or function of the pancreatic beta cells responsible for normal insulin production and/or release. To date, more than 40 monogenic diabetes subtypes have been described, with those caused by mutations in HNF1A and GCK genes being the most prevalent. Despite being caused by a single gene mutation, each type of monogenic diabetes, especially MODY, can appear with various clinical phenotypes, even among members of the same family. This clinical heterogeneity, its rarity, and the fact that it shares some features with more common types of diabetes, can make the clinical diagnosis of monogenic diabetes rather challenging. Indeed, several cases of MODY or syndromic diabetes are accurately diagnosed in adulthood, after having been mislabeled as type 1 or type 2 diabetes. The recent widespread use of more reliable sequencing techniques has improved monogenic diabetes diagnosis, which is important to guide appropriate treatment and genetic counselling. The current review aims to summarize the latest knowledge on the clinical presentation, genetic confirmation, and therapeutic approach of the various forms of monogenic defects of beta cell function, using three imaginary clinical scenarios and highlighting clinical and laboratory features that can guide the clinician in reaching the correct diagnosis.
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Affiliation(s)
- Anastasios Serbis
- Department of Pediatrics, University of Ioannina, 45110 Ioannina, Greece; (E.K.); (E.S.)
- Department of Endocrinology & Diabetes Center, University of Ioannina, 45110 Ioannina, Greece;
- 2nd Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University General Hospital, 54636 Thessaloniki, Greece;
| | - Evanthia Kantza
- Department of Pediatrics, University of Ioannina, 45110 Ioannina, Greece; (E.K.); (E.S.)
| | - Ekaterini Siomou
- Department of Pediatrics, University of Ioannina, 45110 Ioannina, Greece; (E.K.); (E.S.)
| | - Assimina Galli-Tsinopoulou
- 2nd Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University General Hospital, 54636 Thessaloniki, Greece;
| | - Christina Kanaka-Gantenbein
- Division of Endocrinology, Diabetes and Metabolism and Aghia Sophia ENDO-ERN Center for Rare Pediatric Endocrine Disorders, First Department of Pediatrics, Medical School, Aghia Sophia Children’s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Stelios Tigas
- Department of Endocrinology & Diabetes Center, University of Ioannina, 45110 Ioannina, Greece;
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ElSayed NA, Aleppo G, Bannuru RR, Bruemmer D, Collins BS, Ekhlaspour L, Gaglia JL, Hilliard ME, Johnson EL, Khunti K, Lingvay I, Matfin G, McCoy RG, Perry ML, Pilla SJ, Polsky S, Prahalad P, Pratley RE, Segal AR, Seley JJ, Selvin E, Stanton RC, Gabbay RA. 2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes-2024. Diabetes Care 2024; 47:S20-S42. [PMID: 38078589 PMCID: PMC10725812 DOI: 10.2337/dc24-s002] [Citation(s) in RCA: 519] [Impact Index Per Article: 519.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2023]
Abstract
The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
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Murphy R, Colclough K, Pollin TI, Ikle JM, Svalastoga P, Maloney KA, Saint-Martin C, Molnes J, Misra S, Aukrust I, de Franco E, Flanagan SE, Njølstad PR, Billings LK, Owen KR, Gloyn AL. The use of precision diagnostics for monogenic diabetes: a systematic review and expert opinion. COMMUNICATIONS MEDICINE 2023; 3:136. [PMID: 37794142 PMCID: PMC10550998 DOI: 10.1038/s43856-023-00369-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 09/21/2023] [Indexed: 10/06/2023] Open
Abstract
BACKGROUND Monogenic diabetes presents opportunities for precision medicine but is underdiagnosed. This review systematically assessed the evidence for (1) clinical criteria and (2) methods for genetic testing for monogenic diabetes, summarized resources for (3) considering a gene or (4) variant as causal for monogenic diabetes, provided expert recommendations for (5) reporting of results; and reviewed (6) next steps after monogenic diabetes diagnosis and (7) challenges in precision medicine field. METHODS Pubmed and Embase databases were searched (1990-2022) using inclusion/exclusion criteria for studies that sequenced one or more monogenic diabetes genes in at least 100 probands (Question 1), evaluated a non-obsolete genetic testing method to diagnose monogenic diabetes (Question 2). The risk of bias was assessed using the revised QUADAS-2 tool. Existing guidelines were summarized for questions 3-5, and review of studies for questions 6-7, supplemented by expert recommendations. Results were summarized in tables and informed recommendations for clinical practice. RESULTS There are 100, 32, 36, and 14 studies included for questions 1, 2, 6, and 7 respectively. On this basis, four recommendations for who to test and five on how to test for monogenic diabetes are provided. Existing guidelines for variant curation and gene-disease validity curation are summarized. Reporting by gene names is recommended as an alternative to the term MODY. Key steps after making a genetic diagnosis and major gaps in our current knowledge are highlighted. CONCLUSIONS We provide a synthesis of current evidence and expert opinion on how to use precision diagnostics to identify individuals with monogenic diabetes.
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Affiliation(s)
- Rinki Murphy
- Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
- Auckland Diabetes Centre, Te Whatu Ora Health New Zealand, Te Tokai Tumai, Auckland, New Zealand.
| | - Kevin Colclough
- Exeter Genomics Laboratory, Royal Devon University Healthcare NHS Foundation Trust, Exeter, United Kingdom
| | - Toni I Pollin
- Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Jennifer M Ikle
- Department of Pediatrics, Division of Endocrinology & Diabetes, Stanford School of Medicine, Stanford, CA, USA
- Stanford Diabetes Research Center, Stanford School of Medicine, Stanford, CA, USA
| | - Pernille Svalastoga
- Children and Youth Clinic, Haukeland University Hospital, Bergen, Norway
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Kristin A Maloney
- Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Cécile Saint-Martin
- Department of Medical Genetics, AP-HP Pitié-Salpêtrière Hospital, Sorbonne University, Paris, France
| | - Janne Molnes
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
| | - Shivani Misra
- Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK
- Department of Diabetes and Endocrinology, Imperial College Healthcare NHS Trust, London, UK
| | - Ingvild Aukrust
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
| | - Elisa de Franco
- Department of Clinical and Biomedical Science, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK
| | - Sarah E Flanagan
- Department of Clinical and Biomedical Science, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK
| | - Pål R Njølstad
- Children and Youth Clinic, Haukeland University Hospital, Bergen, Norway
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Liana K Billings
- Division of Endocrinology, NorthShore University HealthSystem, Skokie, IL, USA
- Department of Medicine, Pritzker School of Medicine, University of Chicago, Chicago, IL, USA
| | - Katharine R Owen
- Oxford Center for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, UK
- NIHR Oxford Biomedical Research Centre, Oxford, UK
| | - Anna L Gloyn
- Department of Pediatrics, Division of Endocrinology & Diabetes, Stanford School of Medicine, Stanford, CA, USA.
- Stanford Diabetes Research Center, Stanford School of Medicine, Stanford, CA, USA.
- Department of Genetics, Stanford School of Medicine, Stanford, CA, USA.
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DeForest N, Kavitha B, Hu S, Isaac R, Krohn L, Wang M, Du X, De Arruda Saldanha C, Gylys J, Merli E, Abagyan R, Najmi L, Mohan V, Flannick J, Peloso GM, Gordts PL, Heinz S, Deaton AM, Khera AV, Olefsky J, Radha V, Majithia AR. Human gain-of-function variants in HNF1A confer protection from diabetes but independently increase hepatic secretion of atherogenic lipoproteins. CELL GENOMICS 2023; 3:100339. [PMID: 37492105 PMCID: PMC10363808 DOI: 10.1016/j.xgen.2023.100339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 02/08/2023] [Accepted: 05/03/2023] [Indexed: 07/27/2023]
Abstract
Loss-of-function mutations in hepatocyte nuclear factor 1A (HNF1A) are known to cause rare forms of diabetes and alter hepatic physiology through unclear mechanisms. In the general population, 1:100 individuals carry a rare, protein-coding HNF1A variant, most of unknown functional consequence. To characterize the full allelic series, we performed deep mutational scanning of 11,970 protein-coding HNF1A variants in human hepatocytes and clinical correlation with 553,246 exome-sequenced individuals. Surprisingly, we found that ∼1:5 rare protein-coding HNF1A variants in the general population cause molecular gain of function (GOF), increasing the transcriptional activity of HNF1A by up to 50% and conferring protection from type 2 diabetes (odds ratio [OR] = 0.77, p = 0.007). Increased hepatic expression of HNF1A promoted a pro-atherogenic serum profile mediated in part by enhanced transcription of risk genes including ANGPTL3 and PCSK9. In summary, ∼1:300 individuals carry a GOF variant in HNF1A that protects carriers from diabetes but enhances hepatic secretion of atherogenic lipoproteins.
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Affiliation(s)
- Natalie DeForest
- Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA
| | - Babu Kavitha
- Department of Molecular Genetics, Madras Diabetes Research Foundation, ICMR Centre for Advanced Research on Diabetes, Affiliated with University of Madras, Chennai, India
| | - Siqi Hu
- Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Roi Isaac
- Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | | | - Minxian Wang
- Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
| | - Xiaomi Du
- Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Camila De Arruda Saldanha
- Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Jenny Gylys
- Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Edoardo Merli
- Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Ruben Abagyan
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
| | - Laeya Najmi
- Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Diabetes Research, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway
| | - Viswanathan Mohan
- Department of Diabetology, Dr. Mohan’s Diabetes Specialties Centre (IDF Centre of Education) & Madras Diabetes Research Foundation (ICMR Centre for Advanced Research on Diabetes), Chennai, India
| | - Alnylam Human Genetics
- Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA
- Department of Molecular Genetics, Madras Diabetes Research Foundation, ICMR Centre for Advanced Research on Diabetes, Affiliated with University of Madras, Chennai, India
- Alnylam Pharmaceuticals, Cambridge, MA, USA
- Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
- Center for Diabetes Research, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway
- Department of Diabetology, Dr. Mohan’s Diabetes Specialties Centre (IDF Centre of Education) & Madras Diabetes Research Foundation (ICMR Centre for Advanced Research on Diabetes), Chennai, India
- Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
- Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - AMP-T2D Consortium
- Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, CA, USA
- Department of Molecular Genetics, Madras Diabetes Research Foundation, ICMR Centre for Advanced Research on Diabetes, Affiliated with University of Madras, Chennai, India
- Alnylam Pharmaceuticals, Cambridge, MA, USA
- Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
- Center for Diabetes Research, Department of Clinical Science, University of Bergen, 5020 Bergen, Norway
- Department of Diabetology, Dr. Mohan’s Diabetes Specialties Centre (IDF Centre of Education) & Madras Diabetes Research Foundation (ICMR Centre for Advanced Research on Diabetes), Chennai, India
- Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
- Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Jason Flannick
- Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
| | - Gina M. Peloso
- Department of Biostatistics, Boston University School of Public Health, Boston, MA, USA
| | - Philip L.S.M. Gordts
- Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
- Glycobiology Research and Training Center, University of California, San Diego, La Jolla, CA, USA
| | - Sven Heinz
- Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | | | - Amit V. Khera
- Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Jerrold Olefsky
- Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Venkatesan Radha
- Department of Molecular Genetics, Madras Diabetes Research Foundation, ICMR Centre for Advanced Research on Diabetes, Affiliated with University of Madras, Chennai, India
| | - Amit R. Majithia
- Division of Endocrinology, Department of Medicine, University of California San Diego, La Jolla, CA, USA
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10
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Santomauro AC, Magalhães ÁLF, Motta FT, de Santana LS, Franco PC, de Freitas SM, Sanchez JJD, Costa-Riquetto AD, Teles MG. The performance of the MODY calculator in a non-Caucasian, mixed-race population diagnosed with diabetes mellitus before 35 years of age. Diabetol Metab Syndr 2023; 15:15. [PMID: 36747290 PMCID: PMC9900997 DOI: 10.1186/s13098-023-00985-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Accepted: 01/21/2023] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND A maturity-onset diabetes of the young (MODY) calculator has been described and validated for use in European Caucasians. This study evaluated its performance in Brazilians diagnosed with diabetes mellitus (DM) before 35 years of age. METHODS The electronic records of 391 individuals were reviewed in 2020 at the diabetes clinic of a quaternary hospital in São Paulo were analyzed: 231 with type 1 DM (T1DM), 46 with type 2 (T2DM) and 114 with MODY. The MODY calculator was applied to the three groups. A receiver operating characteristic curve was calculated to obtain cut-off points for this population. RESULTS The principal differences between the MODY and the T1DM and T2DM groups were body mass index, a positive family history of diabetes and mean HbA1c level. Age at diagnosis in the MODY group was only significantly different compared to the T2DM group. Specificity and sensitivity were good for the cut-off points of 40%, 50% and 60%, with the accuracy of the model for any of these cut-off points being > 95%. CONCLUSION The capacity of the calculator to identify Brazilian patients with MODY was good. Values ≥ 60% proved useful for selecting candidates for MODY genetic testing, with good sensitivity and specificity.
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Affiliation(s)
- Augusto Cezar Santomauro
- 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
| | - Áurea Luiza Fernandes Magalhães
- 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
| | - Flávia Tedesco Motta
- 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
| | - Lucas Santos de Santana
- 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
| | - Pedro Campos Franco
- 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
| | - Silvia Maria de Freitas
- Department of Statistics and Applied Mathematics, Postgraduate Program in Modeling and Quantitative Methods, Science Center, Pici Campus, Federal University of Ceará (UFC), Fortaleza, CE 60440-900 Brazil
| | - Jeniffer Johana Duarte Sanchez
- Department of Statistics and Applied Mathematics, Postgraduate Program in Modeling and Quantitative Methods, Science Center, Pici Campus, Federal University of Ceará (UFC), Fortaleza, CE 60440-900 Brazil
| | - Aline Dantas Costa-Riquetto
- 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
| | - Milena G. Teles
- 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
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11
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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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12
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Miyachi Y, Miyazawa T, Ogawa Y. HNF1A Mutations and Beta Cell Dysfunction in Diabetes. Int J Mol Sci 2022; 23:ijms23063222. [PMID: 35328643 PMCID: PMC8948720 DOI: 10.3390/ijms23063222] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/14/2022] [Accepted: 03/16/2022] [Indexed: 12/26/2022] Open
Abstract
Understanding the genetic factors of diabetes is essential for addressing the global increase in type 2 diabetes. HNF1A mutations cause a monogenic form of diabetes called maturity-onset diabetes of the young (MODY), and HNF1A single-nucleotide polymorphisms are associated with the development of type 2 diabetes. Numerous studies have been conducted, mainly using genetically modified mice, to explore the molecular basis for the development of diabetes caused by HNF1A mutations, and to reveal the roles of HNF1A in multiple organs, including insulin secretion from pancreatic beta cells, lipid metabolism and protein synthesis in the liver, and urinary glucose reabsorption in the kidneys. Recent studies using human stem cells that mimic MODY have provided new insights into beta cell dysfunction. In this article, we discuss the involvement of HNF1A in beta cell dysfunction by reviewing previous studies using genetically modified mice and recent findings in human stem cell-derived beta cells.
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13
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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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14
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Maturity Onset Diabetes of the Young-New Approaches for Disease Modelling. Int J Mol Sci 2021; 22:ijms22147553. [PMID: 34299172 PMCID: PMC8303136 DOI: 10.3390/ijms22147553] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/04/2021] [Accepted: 07/09/2021] [Indexed: 02/08/2023] Open
Abstract
Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous group of monogenic endocrine disorders that is characterised by autosomal dominant inheritance and pancreatic β-cell dysfunction. These patients are commonly misdiagnosed with type 1 or type 2 diabetes, as the clinical symptoms largely overlap. Even though several biomarkers have been tested none of which could be used as single clinical discriminator. The correct diagnosis for individuals with MODY is of utmost importance, as the applied treatment depends on the gene mutation or is subtype-specific. Moreover, in patients with HNF1A-MODY, additional clinical monitoring can be included due to the high incidence of vascular complications observed in these patients. Finally, stratification of MODY patients will enable better and newer treatment options for MODY patients, once the disease pathology for each patient group is better understood. In the current review the clinical characteristics and the known disease-related abnormalities of the most common MODY subtypes are discussed, together with the up-to-date applied diagnostic criteria and treatment options. Additionally, the usage of pluripotent stem cells together with CRISPR/Cas9 gene editing for disease modelling with the possibility to reveal new pathophysiological mechanisms in MODY is discussed.
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15
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Liu Y, Xie Z, Sun X, Wang Y, Xiao Y, Luo S, Huang G, Li X, Xia Y, Zhou Z. A new screening strategy and whole-exome sequencing for the early diagnosis of maturity-onset diabetes of the young. Diabetes Metab Res Rev 2021; 37:e3381. [PMID: 32621647 DOI: 10.1002/dmrr.3381] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 06/01/2020] [Accepted: 06/30/2020] [Indexed: 12/13/2022]
Abstract
AIMS This study aimed to establish a systematic screening strategy to select candidates for genetic testing among patients with maturity-onset diabetes of the young (MODY) and to accomplish early diagnosis of MODY. MATERIALS AND METHODS We enrolled 1478 sporadic patients from the outpatient department of endocrinology. Out of the1478 patients, 1279 participants were successfully screened according to the "AACM" strategy, which includes the age of onset, autoantibody to islet antigen, C-peptide and metabolic syndrome. Another six probands and their families who fulfilled the common clinical criteria for MODY were also examined for causative gene mutations. Whole-exome sequencing (WES) was performed to examine the mutations. RESULTS A total of 24 out of 1279 sporadic patients with newly diagnosed diabetes were eligible for genetic testing. Mutations were found in 4/24 participants in the cohort, as well as in 2/6 pedigrees. A likely pathogenic alteration, a likely benign alteration and three alterations with uncertain significance were identified with WES. Most of the mutant genes recognised in our trial were not the most common causative genes of MODY, and all of the mutations were specifically reported in Asian patients only, suggesting a unique genetic background of MODY in different ethnicities. CONCLUSIONS In this systematic study of MODY in a new-onset diabetes cohort, MODY cases were incorrectly diagnosed as type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), suggesting that an observant clinician is necessary for early and correct MODY diagnosis. This systematic approach to screening is practical and specific enough to identify patients who are most appropriate for genetic testing.
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Affiliation(s)
- Yue Liu
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
- Foshan Women and Children Hospital, Foshan, Guangdong, China
| | - Zhiguo Xie
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Xiaoxiao Sun
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Yanfei Wang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Yang Xiao
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Shuoming Luo
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Gan Huang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Xia Li
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Ying Xia
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
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16
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Fu J, Ping F, Wang T, Liu Y, Wang X, Yu J, Deng M, Liu J, Zhang Q, Yu M, Li M, Li Y, Xiao X. A Clinical Prediction Model to Distinguish Maturity-Onset Diabetes of the Young From Type 1 and Type 2 Diabetes in the Chinese Population. Endocr Pract 2021; 27:776-782. [PMID: 33991656 DOI: 10.1016/j.eprac.2021.05.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 04/03/2021] [Accepted: 05/04/2021] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Genetic detection for the diagnosis of maturity-onset diabetes of the young (MODY) in China has low sensitivity and specificity. Better gene detection is urgently needed to distinguish testing subjects. We proposed to use numerous and weighted clinical traits as key indicators for reasonable genetic testing to predict the probability of MODY in the Chinese population. METHODS We created a prediction model based on data from 306 patients, including 140 patients with MODY, 84 patients with type 1 diabetes (T1D), and 82 patients with type 2 diabetes (T2D). This model was evaluated using receiver operating characteristic curves. RESULTS Compared with patients with T1D, patients with MODY had higher C-peptide levels and negative antibodies, and most patients with MODY had a family history of diabetes. Different from T2D, MODY was characterized by lower body mass index and younger diagnostic age. A clinical prediction model was established to define the comprehensive probability of MODY by a weighted consolidation of the most distinguishing features, and the model showed excellent discrimination (areas under the curve of 0.916 in MODY vs T1D and 0.942 in MODY vs T2D). Further, high-sensitivity C-reactive protein, glycated hemoglobin A1c, 2-h postprandial glucose, and triglyceride were used as indicators for glucokinase-MODY, while triglyceride, high-sensitivity C-reactive protein, and hepatocellular adenoma were used as indicators for hepatocyte nuclear factor 1-α MODY. CONCLUSION We developed a practical prediction model that could predict the probability of MODY and provide information to identify glucokinase-MODY and hepatocyte nuclear factor 1-α MODY. These results provide an advanced and more reasonable process to identify the most appropriate patients for genetic testing.
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Affiliation(s)
- Junling Fu
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China; Department of Endocrinology, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Fan Ping
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Tong Wang
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Yiwen Liu
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Xiaojing Wang
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Jie Yu
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Mingqun Deng
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Jieying Liu
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Qian Zhang
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Miao Yu
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Ming Li
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Yuxiu Li
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
| | - Xinhua Xiao
- Department of Endocrinology, Key Laboratory of Endocrinology of the Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China.
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17
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Rao G, Jensen ET. Type 2 Diabetes in Youth. Glob Pediatr Health 2021; 7:2333794X20981343. [PMID: 34036121 PMCID: PMC8126957 DOI: 10.1177/2333794x20981343] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 12/07/2020] [Accepted: 11/24/2020] [Indexed: 01/21/2023] Open
Abstract
The incidence of type 2 diabetes in children and adolescents in the United States
rose at an annual rate of 4.8% between 2002-2003 and 2014-2015. Type 2 diabetes
progresses more aggressively to complications than type 1 diabetes. For example,
in one large epidemiological study, proliferative retinopathy affected 5.6% and
9.1% of children with type 1 and type 2 diabetes, respectively. Screening begins
at age 10 or at onset of puberty, and is recommended among children with a BMI%
≥85 with risk factors such as a family history and belonging to a high risk
racial or ethnic or racial group. HbA1C% is preferred for screening as it does
not require fasting. As distinguishing between type 1 and type 2 diabetes is not
straightforward, all children with new onset disease should undergo autoantibody
testing. Results of lifestyle interventions for control of type 2 diabetes have
been disappointing, but are still recommended for their educational value and
the potential impact upon some participants. There is limited evidence for the
benefit of newer mediations. Liraglutide, a GLP-1 agonist, however, has been
shown to significantly reduce HbA1C% in one study and is now approved for
children. Liraglutide should be considered as second line therapy.
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Affiliation(s)
- Goutham Rao
- University Hospitals of Cleveland and Case Western Reserve University, Cleveland, OH, USA
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Kim JH, Lee Y, Choi Y, Kim GH, Yoo HW, Choi JH. Etiologic distribution and clinical characteristics of pediatric diabetes in 276 children and adolescents with diabetes at a single academic center. BMC Pediatr 2021; 21:108. [PMID: 33663443 PMCID: PMC7931559 DOI: 10.1186/s12887-021-02575-6] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 02/24/2021] [Indexed: 12/16/2022] Open
Abstract
Background The prevalence of monogenic diabetes is estimated to be 1.1–6.3% of patients with diabetes mellitus (DM) in Europe. The overlapping clinical features of various forms of diabetes make differential diagnosis challenging. Therefore, this study investigated the etiologic distribution and clinical characteristics of pediatric diabetes, including monogenic diabetes, who presented at a single tertiary center over the last 20 years. Methods This study included 276 consecutive patients with DM diagnosed before 18 years of age from January 2000 to December 2019 in Korea. Clinical features, biochemical findings, β-cell autoantibodies, and molecular characteristics were reviewed retrospectively. Results Of the 276 patients, 206 patients (74.6%), 49 patients (17.8%), and 21 patients (7.6%) were diagnosed with type 1 DM, type 2 DM, and clinically suspected monogenic diabetes, respectively. Among 21 patients suspected to have monogenic diabetes, 8 patients had clinical maturity-onset diabetes of the young (MODY), and the remaining 13 patients had other types of monogenic diabetes. Among them, genetic etiologies were identified in 14 patients (5.1%) from 13 families, which included MODY 5, transient neonatal DM, developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, Wolfram syndrome, Donohue syndrome, immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, Fanconi-Bickel syndrome, Wolcott-Rallison syndrome, cystic fibrosis-related diabetes, and maternally inherited diabetes and deafness. Conclusions Genetically confirmed monogenic diabetes accounted for 5.1% of patients evaluated at a single tertiary center over 20-year period. Based on the findings for our sample, the frequency of mutations in the major genes of MODY appears to be low among pediatric patients in Korea. It is critical to identify the genetic cause of DM to provide appropriate therapeutic options and genetic counseling. Supplementary Information The online version contains supplementary material available at 10.1186/s12887-021-02575-6.
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Affiliation(s)
- Ja Hye Kim
- Department of Pediatrics, Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Yena Lee
- Department of Pediatrics, Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Yunha Choi
- Department of Pediatrics, Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Gu-Hwan Kim
- Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Han-Wook Yoo
- Department of Pediatrics, Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Jin-Ho Choi
- Department of Pediatrics, Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea.
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Zhang H, Colclough K, Gloyn AL, Pollin TI. Monogenic diabetes: a gateway to precision medicine in diabetes. J Clin Invest 2021; 131:142244. [PMID: 33529164 PMCID: PMC7843214 DOI: 10.1172/jci142244] [Citation(s) in RCA: 96] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Monogenic diabetes refers to diabetes mellitus (DM) caused by a mutation in a single gene and accounts for approximately 1%-5% of diabetes. Correct diagnosis is clinically critical for certain types of monogenic diabetes, since the appropriate treatment is determined by the etiology of the disease (e.g., oral sulfonylurea treatment of HNF1A/HNF4A-diabetes vs. insulin injections in type 1 diabetes). However, achieving a correct diagnosis requires genetic testing, and the overlapping of the clinical features of monogenic diabetes with those of type 1 and type 2 diabetes has frequently led to misdiagnosis. Improvements in sequencing technology are increasing opportunities to diagnose monogenic diabetes, but challenges remain. In this Review, we describe the types of monogenic diabetes, including common and uncommon types of maturity-onset diabetes of the young, multiple causes of neonatal DM, and syndromic diabetes such as Wolfram syndrome and lipodystrophy. We also review methods of prioritizing patients undergoing genetic testing, and highlight existing challenges facing sequence data interpretation that can be addressed by forming collaborations of expertise and by pooling cases.
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Affiliation(s)
- Haichen Zhang
- University of Maryland School of Medicine, Department of Medicine, Baltimore, Maryland, USA
| | - Kevin Colclough
- Exeter Genomics Laboratory, Royal Devon and Exeter Hospital, Exeter, United Kingdom
| | - Anna L. Gloyn
- Department of Pediatrics, Division of Endocrinology, and,Stanford Diabetes Research Center, Stanford School of Medicine, Stanford, California, USA
| | - Toni I. Pollin
- University of Maryland School of Medicine, Department of Medicine, Baltimore, Maryland, USA
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20
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Broome DT, Pantalone KM, Kashyap SR, Philipson LH. Approach to the Patient with MODY-Monogenic Diabetes. J Clin Endocrinol Metab 2021; 106:237-250. [PMID: 33034350 PMCID: PMC7765647 DOI: 10.1210/clinem/dgaa710] [Citation(s) in RCA: 74] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 10/02/2020] [Indexed: 12/14/2022]
Abstract
UNLABELLED Maturity-onset diabetes of the young, or MODY-monogenic diabetes, is a not-so-rare collection of inherited disorders of non-autoimmune diabetes mellitus that remains insufficiently diagnosed despite increasing awareness. These cases are important to efficiently and accurately diagnose, given the clinical implications of syndromic features, cost-effective treatment regimen, and the potential impact on multiple family members. Proper recognition of the clinical manifestations, family history, and cost-effective lab and genetic testing provide the diagnosis. All patients must undergo a thorough history, physical examination, multigenerational family history, lab evaluation (glycated hemoglobin A1c [HbA1c], glutamic acid decarboxylase antibodies [GADA], islet antigen 2 antibodies [IA-2A], and zinc transporter 8 [ZnT8] antibodies). The presence of clinical features with 3 (or more) negative antibodies may be indicative of MODY-monogenic diabetes, and is followed by genetic testing. Molecular genetic testing should be performed before attempting specific treatments in most cases. Additional testing that is helpful in determining the risk of MODY-monogenic diabetes is the MODY clinical risk calculator (>25% post-test probability in patients not treated with insulin within 6 months of diagnosis should trigger genetic testing) and 2-hour postprandial (after largest meal of day) urinary C-peptide to creatinine ratio (with a ≥0.2 nmol/mmol to distinguish HNF1A- or 4A-MODY from type 1 diabetes). Treatment, as well as monitoring for microvascular and macrovascular complications, is determined by the specific variant that is identified. In addition to the diagnostic approach, this article will highlight recent therapeutic advancements when patients no longer respond to first-line therapy (historically sulfonylurea treatment in many variants). LEARNING OBJECTIVES Upon completion of this educational activity, participants should be able to. TARGET AUDIENCE This continuing medical education activity should be of substantial interest to endocrinologists and all health care professionals who care for people with diabetes mellitus.
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Affiliation(s)
- David T Broome
- Department of Endocrinology, Diabetes & Metabolism, Cleveland Clinic Foundation, Cleveland, Ohio
- Correspondence and Reprint Requests: David T. Broome, MD, Department of Endocrinology, Diabetes & Metabolism, Cleveland Clinic Foundation, 9500 Euclid Avenue, Mail code: F-20, Cleveland, OH 44195, USA. E-mail:
| | - Kevin M Pantalone
- Department of Endocrinology, Diabetes & Metabolism, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Sangeeta R Kashyap
- Department of Endocrinology, Diabetes & Metabolism, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Louis H Philipson
- Kovler Diabetes Center, Departments of Medicine and Pediatrics, University of Chicago, Chicago, Illinois
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Hulín J, Škopková M, Valkovičová T, Mikulajová S, Rosoľanková M, Papcun P, Gašperíková D, Staník J. Clinical implications of the glucokinase impaired function - GCK MODY today. Physiol Res 2020; 69:995-1011. [PMID: 33129248 DOI: 10.33549/physiolres.934487] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Heterozygous inactivating mutations of the glucokinase (GCK) gene are causing GCK-MODY, one of the most common forms of the Maturity Onset Diabetes of the Young (MODY). GCK-MODY is characterized by fasting hyperglycemia without apparent worsening with aging and low risk for chronic vascular complications. Despite the mild clinical course, GCK-MODY could be misdiagnosed as type 1 or type 2 diabetes. In the diagnostic process, the clinical suspicion is often based on the clinical diagnostic criteria for GCK-MODY and should be confirmed by DNA analysis. However, there are several issues in the clinical and also in genetic part that could complicate the diagnostic process. Most of the people with GCK-MODY do not require any pharmacotherapy. The exception are pregnant women with a fetus which did not inherit GCK mutation from the mother. Such a child has accelerated growth, and has increased risk for diabetic foetopathy. In this situation the mother should be treated with substitutional doses of insulin. Therefore, distinguishing GCK-MODY from gestational diabetes in pregnancy is very important. For this purpose, special clinical diagnostic criteria for clinical identification of GCK-MODY in pregnancy are used. This review updates information on GCK-MODY and discusses several currently not solved problems in the clinical diagnostic process, genetics, and treatment of this type of monogenic diabetes.
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Affiliation(s)
- J Hulín
- Department of Pediatrics, Medical Faculty of the Comenius University, Bratislava, Slovakia.
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22
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Abstract
Monogenic diabetes, including maturity-onset diabetes of the young, neonatal diabetes, and other rare forms of diabetes, results from a single gene mutation. It has been estimated to represent around 1% to 6% of all diabetes. With the advances in genome sequencing technology, it is possible to diagnose more monogenic diabetes cases than ever before. In Korea, 11 studies have identified several monogenic diabetes cases, using Sanger sequencing and whole exome sequencing since 2001. The recent largest study, using targeted exome panel sequencing, found a molecular diagnosis rate of 21.1% for monogenic diabetes in clinically suspected patients. Mutations in glucokinase (GCK), hepatocyte nuclear factor 1α (HNF1A), and HNF4A were most commonly found. Genetic diagnosis of monogenic diabetes is important as it determines the therapeutic approach required for patients and helps to identify affected family members. However, there are still many challenges, which include a lack of simple clinical criterion for selecting patients for genetic testing, difficulties in interpreting the genetic test results, and high costs for genetic testing. In this review, we will discuss the latest updates on monogenic diabetes in Korea, and suggest an algorithm to screen patients for genetic testing. The genetic tests and non-genetic markers for accurate diagnosis of monogenic diabetes will be also reviewed.
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Affiliation(s)
- Ye Seul Yang
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Uijeongbu St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea
| | - Soo Heon Kwak
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Kyong Soo Park
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University College of Medicine, Seoul, Korea
- Corresponding author: Kyong Soo Park Department of Internal Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea E-mail:
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Misra S, Hassanali N, Bennett AJ, Juszczak A, Caswell R, Colclough K, Valabhji J, Ellard S, Oliver NS, Gloyn AL. Homozygous Hypomorphic HNF1A Alleles Are a Novel Cause of Young-Onset Diabetes and Result in Sulfonylurea-Sensitive Diabetes. Diabetes Care 2020; 43:909-912. [PMID: 32001615 PMCID: PMC7102871 DOI: 10.2337/dc19-1843] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 01/07/2020] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Heterozygous loss-of-function mutations in HNF1A cause maturity-onset diabetes of the young (MODY). Affected individuals can be treated with low-dose sulfonylureas. Individuals with homozygous HNF1A mutations causing MODY have not been reported. RESEARCH DESIGN AND METHODS We phenotyped a kindred with young-onset diabetes and performed molecular genetic testing, a mixed meal tolerance test, a sulfonylurea challenge, and in vitro assays to assess variant protein function. RESULTS A homozygous HNF1A variant (p.A251T) was identified in three insulin-treated family members diagnosed with diabetes before 20 years of age. Those with the homozygous variant had low hs-CRP levels (0.2-0.8 mg/L), and those tested demonstrated sensitivity to sulfonylurea given at a low dose, completely transitioning off insulin. In silico modeling predicted a variant of unknown significance; however, in vitro studies supported a modest reduction in transactivation potential (79% of that for the wild type; P < 0.05) in the absence of endogenous HNF1A. CONCLUSIONS Homozygous hypomorphic HNF1A variants are a cause of HNF1A-MODY. We thus expand the allelic spectrum of variants in dominant genes causing diabetes.
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Affiliation(s)
- Shivani Misra
- Diabetes, Endocrinology and Metabolism, Imperial College London, London, U.K.
| | - Neelam Hassanali
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
| | - Amanda J Bennett
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
| | - Agata Juszczak
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K
| | - Richard Caswell
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K
| | - Kevin Colclough
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K
| | - Jonathan Valabhji
- Diabetes and Endocrinology, Imperial College Healthcare NHS Trust, London, U.K
| | - Sian Ellard
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, U.K
| | - Nicholas S Oliver
- Diabetes, Endocrinology and Metabolism, Imperial College London, London, U.K.,Diabetes and Endocrinology, Imperial College Healthcare NHS Trust, London, U.K
| | - Anna L Gloyn
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, U.K.,Wellcome Centre for Human Genetics, University of Oxford, Oxford, U.K.,Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, U.K
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24
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Ma Y, Gong S, Wang X, Cai X, Xiao X, Gu W, Yang J, Zhong L, Xiao J, Li M, Liu W, Zhang S, Zhou X, Li Y, Zhou L, Zhu Y, Luo Y, Ren Q, Huang X, Gao X, Zhang X, Zhang R, Chen L, Wang F, Wang Q, Hu M, Han X, Ji L. New clinical screening strategy to distinguish HNF1A variant-induced diabetes from young early-onset type 2 diabetes in a Chinese population. BMJ Open Diabetes Res Care 2020; 8:8/1/e000745. [PMID: 32238361 PMCID: PMC7170412 DOI: 10.1136/bmjdrc-2019-000745] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 02/11/2020] [Accepted: 03/09/2020] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE Maturity-onset diabetes of the young caused by hepatocyte nuclear factor-1 alpha (HNF1A) variants (HNF1A-MODY) is a common form of monogenetic diabetes. Although patients with HNF1A-MODY might specifically benefit from sulfonylurea treatment, available methods for screening this specific type of diabetes are not cost-effective. This study was designed to establish an optimized clinical strategy based on multiple biomarkers to distinguish patients with HNF1A-MODY from clinically diagnosed early-onset type 2 diabetes (EOD) for genetic testing in a Chinese population. RESEARCH DESIGN AND METHODS A case-control study including 125 non-related young patients with EOD and 15 probands with HNF1A-MODY (cohort 1) was conducted to evaluate reported biomarkers for HNF1A-MODY. A cut-off for the fasting insulin (Fins) level, the 97.5 percentile of 150 healthy subjects with normal components of metabolic syndrome (cohort 2), was used to filter out individuals with obvious insulin resistance (Fins <102 pmol/L). An optimized clinical screening strategy (HNF1A-CSS) was established, and its effectiveness was assessed in another group of 410 young patients with EOD (cohort 3). RESULTS In cohort 1, body mass index (BMI), serum high-density lipoprotein cholesterol (HDL-c) and high-sensitivity C reactive protein (hs-CRP) levels were confirmed to be useful for the differential diagnosis of HNF1A-MODY. In cohort 3, eight probands with HNF1A-MODY were identified. In cohort 3 and young relatives with HNF1A-MODY, meeting three of four criteria (BMI <28 kg/m2, hs-CRP <0.75 mg/L, Fins <102 pmol/L and HDL-c >1.12 mmol/L), the sensitivity and specificity of HNF1A-CSS were 100% and 69.3%, respectively. In the pooled analysis of all young patients, HNF1A-CSS displayed 90.5% sensitivity and 73.6% specificity for identifying patients with HNF1A-MODY among those with clinically diagnosed EOD. CONCLUSION Our HNF1A-CSS is useful for distinguishing patients with HNF1A-MODY from patients with EOD in a young Chinese population.
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Affiliation(s)
- Yumin Ma
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
| | - Siqian Gong
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
| | - Xirui Wang
- Department of Endocrinology and Metabolism, Beijing Airport Hospital, Beijing, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
| | - Xinhua Xiao
- Department of Endocrinology, Peking Union Medical College Hospital, Diabetes Research Center of Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Weijun Gu
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, China
| | - Jinkui Yang
- Department of Endocrinology, Beijing Tong Ren Hospital, Capital Medical University, Beijing, China
| | - Liyong Zhong
- Department of Endocrinology, Beijing Tian Tan Hospital, Capital Medical University, Beijing, China
| | - Jianzhong Xiao
- Department of Endocrinology and Metabolism, Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Meng Li
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
| | - Wei Liu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
| | - Simin Zhang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
| | - Xianghai Zhou
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
| | - Yufeng Li
- Department of Endocrinology and Metabolism, Beijing Pinggu Hospital, Beijing, China
| | - Lingli Zhou
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
| | - Yu Zhu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
| | - Yingying Luo
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
| | - Qian Ren
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
| | - Xiuting Huang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
| | - Xueying Gao
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
| | - Xiuying Zhang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
| | - Rui Zhang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
| | - Ling Chen
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
| | - Fang Wang
- Department of Endocrinology, Beijing Tian Tan Hospital, Capital Medical University, Beijing, China
| | - Qiuping Wang
- Department of Endocrinology, Beijing Liangxiang Hospital, Capital Medical University, Beijing, China
| | - Mengdie Hu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
| | - Xueyao Han
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Center, Beijing, China
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Abstract
MODY (Maturity Onset Diabetes of the Young) is a type of diabetes resulting from a pathogenic effect of gene mutations. Up to date, 13 MODY genes are known. Gene HNF1A is one of the most common causes of MODY diabetes (HNF1A-MODY; MODY3). This gene is polymorphic and more than 1200 pathogenic and non-pathogenic HNF1A variants were described in its UTRs, exons and introns. For HNF1A-MODY, not just gene but also phenotype heterogeneity is typical. Although there are some clinical instructions, HNF1A-MODY patients often do not meet every diagnostic criteria or they are still misdiagnosed as type 1 and type 2 diabetics. There is a constant effort to find suitable biomarkers to help with in distinguishing of MODY3 from Type 1 Diabetes (T1D) and Type 2 Diabetes (T2D). DNA sequencing is still necessary for unambiguous confirmation of clinical suspicion of MODY. NGS (Next Generation Sequencing) methods brought discoveries of multiple new gene variants and new instructions for their pathogenicity classification were required. The most actual problem is classification of variants with uncertain significance (VUS) which is a stumbling-block for clinical interpretation. Since MODY is a hereditary disease, DNA analysis of family members is helpful or even crucial. This review is updated summary about HNF1A-MODY genetics, pathophysiology, clinics functional studies and variant classification.
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Sousa M, Bruges-Armas J. Monogenic Diabetes: Genetics and Relevance on Diabetes Mellitus Personalized Medicine. Curr Diabetes Rev 2020; 16:807-819. [PMID: 31886753 DOI: 10.2174/1573399816666191230114352] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 11/11/2019] [Accepted: 12/12/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Diabetes mellitus (DM) is a complex disease with significant impression in today's world. Aside from the most common types recognized over the years, such as type 1 diabetes (T1DM) and type 2 diabetes (T2DM), recent studies have emphasized the crucial role of genetics in DM, allowing the distinction of monogenic diabetes. METHODS Authors did a literature search with the purpose of highlighting and clarifying the subtypes of monogenic diabetes, as well as the accredited genetic entities responsible for such phenotypes. RESULTS The following subtypes were included in this literature review: maturity-onset diabetes of the young (MODY), neonatal diabetes mellitus (NDM) and maternally inherited diabetes and deafness (MIDD). So far, 14 subtypes of MODY have been identified, while three subtypes have been identified in NDM - transient, permanent, and syndromic. DISCUSSION Despite being estimated to affect approximately 2% of all the T2DM patients in Europe, the exact prevalence of MODY is still unknown, accentuating the need for research focused on biomarkers. Consequently, due to its impact in the course of treatment, follow-up of associated complications, and genetic implications for siblings and offspring of affected individuals, it is imperative to diagnose the monogenic forms of DM accurately. CONCLUSION Currently, advances in the genetics field allowed the recognition of new DM subtypes, which until now, were considered slight variations of the typical forms. Thus, it is imperative to act in the close interaction between genetics and clinical manifestations, to facilitate diagnosis and individualize treatment.
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MESH Headings
- Deafness/classification
- Deafness/diagnosis
- Deafness/genetics
- Diabetes Mellitus, Type 1/diagnosis
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 2/classification
- Diabetes Mellitus, Type 2/diagnosis
- Diabetes Mellitus, Type 2/genetics
- Genetic Testing
- Genotype
- Humans
- Infant
- Infant, Newborn
- Infant, Newborn, Diseases/classification
- Infant, Newborn, Diseases/diagnosis
- Infant, Newborn, Diseases/genetics
- Mitochondrial Diseases/classification
- Mitochondrial Diseases/diagnosis
- Mitochondrial Diseases/genetics
- Mutation
- Phenotype
- Precision Medicine
- Syndrome
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Affiliation(s)
- Madalena Sousa
- Serviço Especializado de Epidemiologia e Biologia Molecular (SEEBMO), Hospital de Santo Espírito da Ilha Terceira (HSEIT), Angra do Heroísmo, Azores, Portugal
| | - Jácome Bruges-Armas
- Serviço Especializado de Epidemiologia e Biologia Molecular (SEEBMO), Hospital de Santo Espírito da Ilha Terceira (HSEIT), Angra do Heroísmo, Azores, Portugal
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Peixoto-Barbosa R, Reis AF, Giuffrida FMA. Update on clinical screening of maturity-onset diabetes of the young (MODY). Diabetol Metab Syndr 2020; 12:50. [PMID: 32528556 PMCID: PMC7282127 DOI: 10.1186/s13098-020-00557-9] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Accepted: 05/29/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Maturity-onset diabetes of the young (MODY) is the most common type of monogenic diabetes, being characterized by beta-cell disfunction, early onset, and autosomal dominant inheritance. Despite the rapid evolution of molecular diagnosis methods, many MODY cases are misdiagnosed as type 1 or type 2 diabetes. High costs of genetic testing and limited knowledge of MODY as a relevant clinical entity are some of the obstacles that hinder correct MODY diagnosis and treatment. We present a broad review of clinical syndromes related to most common MODY subtypes, emphasizing the role of biomarkers that can help improving the accuracy of clinical selection of candidates for molecular diagnosis. MAIN BODY To date, MODY-related mutations have been reported in at least 14 different genes. Mutations in glucokinase (GCK), hepatocyte nuclear factor-1 homeobox A (HNF1A), and hepatocyte nuclear factor-4 homeobox A (HNF4A) are the most common causes of MODY. Accurate etiological diagnosis can be challenging. Many biomarkers such as apolipoprotein-M (ApoM), aminoaciduria, complement components, and glycosuria have been tested, but have not translated into helpful diagnostic tools. High-sensitivity C-reactive protein (hs-CRP) levels are lower in HNF1A-MODY and have been tested in some studies to discriminate HNF1A-MODY from other types of diabetes, although more data are needed. Overall, presence of pancreatic residual function and absence of islet autoimmunity seem the most promising clinical instruments to select patients for further investigation. CONCLUSIONS The selection of diabetic patients for genetic testing is an ongoing challenge. Metabolic profiling, diabetes onset age, pancreatic antibodies, and C-peptide seem to be useful tools to better select patients for genetic testing. Further studies are needed to define cut-off values in different populations.
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Affiliation(s)
- Renata Peixoto-Barbosa
- Disciplina de Endocrinologia, Centro de Diabetes, Universidade Federal de São Paulo (UNIFESP), Rua Estado de Israel, 639–Vila Clementino, São Paulo, SP CEP: 04022-001 Brazil
- Departamento de Ciências da Vida, Universidade do Estado da Bahia (UNEB), Salvador, Brazil
| | - André F. Reis
- Disciplina de Endocrinologia, Centro de Diabetes, Universidade Federal de São Paulo (UNIFESP), Rua Estado de Israel, 639–Vila Clementino, São Paulo, SP CEP: 04022-001 Brazil
| | - Fernando M. A. Giuffrida
- Disciplina de Endocrinologia, Centro de Diabetes, Universidade Federal de São Paulo (UNIFESP), Rua Estado de Israel, 639–Vila Clementino, São Paulo, SP CEP: 04022-001 Brazil
- Departamento de Ciências da Vida, Universidade do Estado da Bahia (UNEB), Salvador, Brazil
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Oliveira SC, Neves JS, Pérez A, Carvalho D. Maturity-onset diabetes of the young: From a molecular basis perspective toward the clinical phenotype and proper management. ACTA ACUST UNITED AC 2019; 67:137-147. [PMID: 31718996 DOI: 10.1016/j.endinu.2019.07.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 07/04/2019] [Accepted: 07/09/2019] [Indexed: 12/28/2022]
Abstract
Maturity-onset diabetes of the young (MODY) comprises a heterogeneous group of monogenic disorders characterized by primary defect in pancreatic β-cell function, early onset and autosomal dominant inheritance, accounting for about 1-5% of all diabetes diagnoses. Mutations in 14 genes are responsible for the majority of all MODY cases described so far. The clinical phenotype relies on genetic defects, with important implications in the optimal treatment and prognosis definition. MODY's early diagnosis remains a challenge, since this group of inherited disorders comprises a large clinical spectrum and it usually overlaps with other types of diabetes, requiring a high index of suspicion even if the definitive statement demands a molecular genetic study. Recent advances on the genetic determinants and pathophysiology of MODY have allowed a better understanding of its underlying molecular mechanisms, providing a proper genetic counseling and early diagnosis. These new management insights will make possible to set up new therapeutic strategies, with drugs able to prevent, correct or at least delay the decline of pancreatic β-cell function, thus affording for a more personalized treatment and, ultimately, for a better patient care.
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Affiliation(s)
- Sofia Castro Oliveira
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal; Faculty of Medicine of the Universidade do Porto, Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
| | - João Sérgio Neves
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal; Faculty of Medicine of the Universidade do Porto, Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Antonio Pérez
- Department of Endocrinology and Nutrition, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; CIBER de Diabetes y Enfermidades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Davide Carvalho
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal; Faculty of Medicine of the Universidade do Porto, Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
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Urbanova J, Brunerova L, Broz J. How can maturity-onset diabetes of the young be identified among more common diabetes subtypes? Wien Klin Wochenschr 2019; 131:435-441. [PMID: 31493099 DOI: 10.1007/s00508-019-01543-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 08/13/2019] [Indexed: 12/27/2022]
Abstract
Maturity onset diabetes of the young (MODY) represents a diabetes type which has an enormous clinical impact. It significantly alters treatment, refines a patient's prognosis and enables early detection of diabetes in relatives. Nevertheless, when diabetes is manifested the vast majority of MODY patients are not correctly diagnosed, but mostly falsely included among patients with type 1 or type 2 diabetes, in many cases permanently. The aim of this article is to offer a simple and comprehensible guide for recognizing individuals with MODY hidden among adult patients with another type of long-term diabetes and in women with gestational diabetes.
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Affiliation(s)
- Jana Urbanova
- Diabetologic centre II. , Department of Medicine, Third Faculty of Medicine and Faculty Hospital Kralovske Vinohrady, Charles University, Šrobarova 50, 10034, Prague, Czech Republic
| | - Ludmila Brunerova
- Diabetologic centre II. , Department of Medicine, Third Faculty of Medicine and Faculty Hospital Kralovske Vinohrady, Charles University, Šrobarova 50, 10034, Prague, Czech Republic.
| | - Jan Broz
- Department of Medicine, Second Faculty of Medicine and Faculty Hospital Motol, Charles Univeristy, V Úvalu 84, 15006, Prague, Czech Republic
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Fu J, Wang T, Liu J, Wang X, Zhang Q, Li M, Xiao X. Using Clinical Indices to Distinguish MODY2 (GCK Mutation) and MODY3 (HNF1A Mutation) from Type 1 Diabetes in a Young Chinese Population. Diabetes Ther 2019; 10:1381-1390. [PMID: 31214998 PMCID: PMC6612336 DOI: 10.1007/s13300-019-0647-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Indexed: 12/21/2022] Open
Abstract
INTRODUCTION Accurate diagnosis of maturity-onset diabetes of the young (MODY) is required in order to select appropriate treatment options and to assess prognosis. The aim of this study was to explore potential clinical indicators that could be used to differentiate MODY2, MODY3, and type 1 diabetes (T1D) in young subjects. METHODS Twelve patients with MODY3 and 29 patients with MODY2 were characterized and compared to 26 patients with T1D. These three groups were matched for age and gender. Clinical profiles of the 67 patients were collected. Receiver operating characteristic (ROC) curves were used to identify the optimal cutoff values of clinical indicators. RESULTS Compared to patients with T1D, subjects with MODY3 had higher fasting C-peptide levels (1.34 ± 1.51 vs. 0.29 ± 0.22 ng/mL; P < 0.001) and lower high-sensitivity C-reactive protein (hsCRP) levels (0.18 ± 0.15 vs. 1.22 ± 1.49 mg/L, P = 0.004); patients with MODY2 had lower hsCRP (0.37 ± 0.39 vs. 1.22 ± 1.49 mg/L; P = 0.003), total cholesterol (4.12 ± 0.68 vs. 4.61 ± 0.81 mmol/L, P = 0.034), and low-density lipoprotein cholesterol (LDL-C) (2.24 ± 0.68 vs. 2.67 ± 0.79 ng/L, P = 0.002) levels and higher fasting C-peptide levels (0.96 ± 0.42 vs. 0.29 ± 0.22 ng/mL, P = 0.002). The ROC-derived hsCRP values for discriminating MODY2 from T1D, MODY3 from T1D, and MODY3 from MODY2 were 0.675, 0.833, and 0.763, respectively. The ROC-derived fasting C-peptide levels for discriminating MODY2 from T1D and MODY3 from T1D were 0.951 and 0.975, respectively. The ROC-derived total cholesterol and LDL-C values for discriminating MODY2 from T1D were 0.670 and 0.662, respectively; the ROC-derived triglyceride value for discriminating MODY3 from MODY2 was 0.756. Additionally, a combination of indicators permitted better discrimination of MODY subtypes than any single parameter. CONCLUSION Our findings suggest that fasting C-peptide, hsCRP, and lipid levels permit good discrimination among MODY2, MODY3, and T1D. These clinical indicators could be used as markers of MODY2 and MODY3 in young patients with diabetes.
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Affiliation(s)
- Junling Fu
- Peking Union Medical College Hospital, Beijing, China
| | - Tong Wang
- Peking Union Medical College Hospital, Beijing, China
| | - Jieying Liu
- Peking Union Medical College Hospital, Beijing, China
| | - Xiaojing Wang
- Peking Union Medical College Hospital, Beijing, China
| | - Qian Zhang
- Peking Union Medical College Hospital, Beijing, China
| | - Ming Li
- Peking Union Medical College Hospital, Beijing, China
| | - Xinhua Xiao
- Peking Union Medical College Hospital, Beijing, China.
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Urakami T. Maturity-onset diabetes of the young (MODY): current perspectives on diagnosis and treatment. Diabetes Metab Syndr Obes 2019; 12:1047-1056. [PMID: 31360071 PMCID: PMC6625604 DOI: 10.2147/dmso.s179793] [Citation(s) in RCA: 128] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Accepted: 05/22/2019] [Indexed: 12/11/2022] Open
Abstract
Maturity-onset diabetes of the young (MODY) is characterized by autosomal dominant inheritance, onset before 25 years of age, absence of β-cell autoimmunity, and sustained pancreatic β-cell function. To date, mutations have been identified in at least 14 different genes, including six genes encoding proteins that, respectively, correspond to MODY subtypes 1-6: hepatocyte nuclear factor (HNF) 4α (HNF4α), glucokinase (GCK), HNF1α (HNF1 α), pancreatic and duodenal homeobox 1 (PDX1), HNF1β (HNF1 β), and neurogenic differentiation 1 (NEUROD1). Diagnostic tools based on currently available genetic tests can facilitate the correct diagnosis and appropriate treatment of patients with MODY. Candidates for genetic testing include nonobese subjects with hyperglycemia, no evidence of β-cell autoimmunity, sustained β-cell function, and a strong family history of similar-type diabetes among first-degree relatives. Moreover, identification of the MODY subtype is important, given the subtype-related differences in the age of onset, clinical course and progression, type of hyperglycemia, and response to treatment. This review discusses the current perspectives on the diagnosis and treatment of MODY, particularly with regard to the six major subtypes (MODY 1-6).
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Affiliation(s)
- Tatsuhiko Urakami
- Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan
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Szopa M, Klupa T, Kapusta M, Matejko B, Ucieklak D, Glodzik W, Zapala B, Sani CM, Hohendorff J, Malecki MT, Skupien J. A decision algorithm to identify patients with high probability of monogenic diabetes due to HNF1A mutations. Endocrine 2019; 64:75-81. [PMID: 30778899 PMCID: PMC6453873 DOI: 10.1007/s12020-019-01863-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 02/05/2019] [Indexed: 11/09/2022]
Abstract
PURPOSE To investigate the utility of biomarkers of maturity-onset diabetes of the young (MODY), high-sensitivity C-reactive protein (hsCRP), and 1,5-anhydroglucitol (1,5-AG) in conjunction with other clinical and laboratory features to improve diagnostic accuracy and provide a diagnostic algorithm for HNF1A MODY. METHODS We examined 77 patients with HNF1A MODY, 88 with GCK MODY mutations, 99 with type 1 diabetes, and 92 with type 2 diabetes. In addition to 1,5-AG and hsCRP, we considered body mass index (BMI), fasting glucose, and fasting serum C-peptide as potential biomarkers. Logistic regression and receiver operating characteristic curves were used in marker evaluation. RESULTS Concentration of hsCRP was lowest in HNF1A MODY (0.51 mg/l) and highest in type 2 diabetes (1.33 mg/l). The level of 1,5-AG was lowest in type 1 diabetes and HNF1A MODY, 3.8 and 4.7 μg/ml, respectively, and highest (11.2 μg/ml) in GCK MODY. In the diagnostic algorithm, we first excluded patients with type 1 diabetes based on low C-peptide (C-statistic 0.98) before using high BMI and C-peptide to identify type 2 diabetes patients (C-statistic 0.92). Finally, 1,5-AG and hsCRP in conjunction yielded a C-statistic of 0.86 in discriminating HNF1A from GCK MODY. We correctly classified 92.9% of patients with type 1 diabetes, 84.8% with type 2 diabetes, 64.9% HNF1A MODY, and 52.3% GCK MODY patients. CONCLUSIONS Plasma 1,5-AG and serum hsCRP do not discriminate sufficiently HNF1A MODY from common diabetes types, but could be potentially useful in prioritizing Sanger sequencing of HNF1A gene.
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Affiliation(s)
- Magdalena Szopa
- Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland
| | - Tomasz Klupa
- Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland
| | - Maria Kapusta
- Department of Clinical Biochemistry, Jagiellonian University Medical College, Krakow, Poland
| | - Bartlomiej Matejko
- Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland
| | - Damian Ucieklak
- Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland
| | | | - Barbara Zapala
- Department of Clinical Biochemistry, Jagiellonian University Medical College, Krakow, Poland
| | - Cyrus Maurice Sani
- School of Medicine in English, Jagiellonian University Medical College, Krakow, Poland
| | - Jerzy Hohendorff
- Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland
| | - Maciej T Malecki
- Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland
| | - Jan Skupien
- Department of Metabolic Diseases, Jagiellonian University Medical College, Krakow, Poland.
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Wang X, Wang T, Yu M, Zhang H, Ping F, Zhang Q, Xu J, Feng K, Xiao X. Screening of HNF1A and HNF4A mutation and clinical phenotype analysis in a large cohort of Chinese patients with maturity-onset diabetes of the young. Acta Diabetol 2019; 56:281-288. [PMID: 30293189 DOI: 10.1007/s00592-018-1232-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Accepted: 09/21/2018] [Indexed: 12/17/2022]
Abstract
AIMS The study aimed to screen the HNF1A and HNF4A mutation in a large Chinese cohort of high clinical suspicion of maturity-onset diabetes of the young (MODY) patients and characterize the clinical features of those patients. The performance of hsCRP as a biomarker to differentiate MODY3 from early onset T2DM was also evaluated. METHODS A total of 74 patients with a strong clinical suspicion of MODY from 59 families and 33 newly diagnosed early-onset T2DM were included. HNF1A and HNF4A mutations were analyzed by Sanger sequencing. ROC curves were used to identify the optimal cutoff of hsCRP. RESULTS One novel (c.864_865insG) and six recurrent HNF1A mutations (R203H, R263H, P379T, L422P, P519L and c.873delC) in 17 patients from 8 families (13.6%), as well as one novel HNF4A (R331H) mutation were identified. Nonspecific clinical presentations were observed in MODYX compared to MODY3 patients. MODY3 subjects exhibited with younger, lower BMI, TG, fasting and postprandial C-peptide, higher HDL than T2DM. Particularly, we confirmed serum hsCRP was lower in MODY3 than T2DM. ROC curve showed a good discrimination with an AUC of 0.852 and identified a cutoff hsCRP of 0.79 (75% sensitivity and 83% specificity). Good glycemic control was observed in all identified patients after switching to glimepiride therapy. CONCLUSIONS The prevalence of HNF1A mutation was relatively lower in Mainland China and HNF4A mutation was rare. Serum hsCRP concentrations performed well in discriminating MODY3 from T2DM. Molecular diagnosis of MODY3/1 did transform management in clinical practice and facilitated the glycemic control.
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Affiliation(s)
- Xiaojing Wang
- Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Shuai fu yuan No.1, Dongcheng District, Beijing, China
| | - Tong Wang
- Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Shuai fu yuan No.1, Dongcheng District, Beijing, China
| | - Miao Yu
- Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Shuai fu yuan No.1, Dongcheng District, Beijing, China
| | - Huabing Zhang
- Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Shuai fu yuan No.1, Dongcheng District, Beijing, China
| | - Fan Ping
- Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Shuai fu yuan No.1, Dongcheng District, Beijing, China
| | - Qian Zhang
- Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Shuai fu yuan No.1, Dongcheng District, Beijing, China
| | - Jianping Xu
- Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Shuai fu yuan No.1, Dongcheng District, Beijing, China
| | - Kai Feng
- Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Shuai fu yuan No.1, Dongcheng District, Beijing, China
| | - Xinhua Xiao
- Key Laboratory of Endocrinology, Department of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College, Shuai fu yuan No.1, Dongcheng District, Beijing, China.
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Association between a Genetic Risk Score Based on Single Nucleotide Polymorphisms of Coronary Artery Disease-Related Genes and Left Main Coronary Artery Disease. BIOMED RESEARCH INTERNATIONAL 2019; 2018:8610368. [PMID: 30671475 PMCID: PMC6323456 DOI: 10.1155/2018/8610368] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Accepted: 12/11/2018] [Indexed: 12/13/2022]
Abstract
Coronary artery disease (CAD) is the leading cause of mortality and morbidity worldwide. Left main coronary artery disease (LMCAD) is a severe phenotype of CAD and has a genetic component. Previous studies identified 3 inflammation-related single nucleotide polymorphisms (SNPs) contributing to the development of LMCAD. We integrated these SNPs into a genetic risk score for the prediction of LMCAD. We enrolled 1544 patients with CAD between 2007 and 2011. The individual associations of the 3 SNPs with LMCAD were assessed. We then calculated the genetic risk score for each patient and stratified patients into low-risk, intermediate-risk, and high-risk categories of genetic risk. In univariable logistic regression analysis, the odds of LMCAD for the high-risk group were 2.81 (95% confidence interval [CI]: 1.72-4.60; P = 0.02) times those of the low-risk group. After adjustment for CAD-related clinical variables, the high-risk group (adjusted OR: 2.78; 95% CI: 1.69-4.58; P = 0.02) had increased odds of LMCAD when compared with the low-risk group. Comparison of model c-statistics showed greater predictive value with regard to LMCAD for the genetic risk score model than the models including single SNPs.
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Abstract
PURPOSE OF REVIEW Monogenic forms of diabetes have specific treatments that differ from the standard care provided for type 1 and type 2 diabetes, making the appropriate diagnosis essential. In this review, we discuss current clinical challenges that remain, including improving case-finding strategies, particularly those that have transethnic applicability, and understanding the interpretation of genetic variants as pathogenic, with clinically meaningful impacts. RECENT FINDINGS Biomarker approaches to the stratification for genetic testing now appear to be most effective in identifying cases of monogenic diabetes, and use of genetic risk scores may also prove useful. However, applicability in all ethnic groups is lacking. Challenges remain in the classification of genes as diabetes-causing and the interpretation of genetic variants at the clinical interface. Since the discovery that genetic defects can cause neonatal or young-onset diabetes, multiple causal genes have been identified and there have been many advances in strategies to detect genetic forms of diabetes and their treatments. Approaches learnt from monogenic diabetes are now being translated to polygenic diabetes.
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Affiliation(s)
- Shivani Misra
- Diabetes, Endocrinology & Metabolism, Imperial College London, Ground Floor Medical School, St Mary’s Campus, Norfolk Place, London, W2 1PG UK
| | - Katharine R. Owen
- Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, OX3 7LJ UK
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Rama Chandran S, Bhalshankar J, Farhad Vasanwala R, Zhao Y, Owen KR, Su-Lyn Gardner D. Traditional clinical criteria outperform high-sensitivity C-reactive protein for the screening of hepatic nuclear factor 1 alpha maturity-onset diabetes of the young among young Asians with diabetes. Ther Adv Endocrinol Metab 2018; 9:271-282. [PMID: 30181854 PMCID: PMC6116767 DOI: 10.1177/2042018818776167] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Accepted: 04/20/2018] [Indexed: 11/15/2022] Open
Abstract
BACKGROUND Young adults with diabetes in Asia represent a heterogeneous group. Using traditional clinical criteria to preselect individuals for testing for maturity-onset diabetes of the young (MODY) may exclude a large proportion from testing. High-sensitivity C-reactive protein (hs-CRP) has shown promise as a biomarker to differentiate hepatic nuclear factor 1 alpha (HNF1A)-MODY from type 2 diabetes. We aimed to compare the use of hs-CRP as a biomarker versus traditional criteria, to guide testing for HNF1A-MODY among a cohort of young adults with diabetes in Singapore. METHODS A total of 252 adults (age of onset ⩽45 years) and 20 children with diabetes were recruited. Using traditional criteria (family history of diabetes and onset of diabetes ⩽25 years) and an hs-CRP cut off of ⩽0.5 mg/l, 125 and 37 adults, respectively, were identified for HNF1A gene testing. All children underwent HNF1A gene testing. RESULTS Five adults (5/143, 3.5%) with HNF1A-MODY were identified. There were no HNF1A gene mutations among the children. Traditional criteria correctly identified all five HNF1A-MODY individuals (5/125, 4%), while applying an hs-CRP level of ⩽0.5 mg/l selected just 1 of these 5 for HNF1A gene testing (1/37, 2.7%). None of those with a positive GAD antibody or undetectable C-peptide level had HNF1A-MODY. CONCLUSION The use of hs-CRP to guide screening for HNF1A-MODY among Asian young adults with diabetes did not improve the diagnostic yield. Applying a combination of age of onset of diabetes under 25 years and a family history of diabetes alone could guide targeted HNF1A-MODY screening in Asians, with an expected yield of 4% diagnosed with HNF1A-MODY among those screened.
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Affiliation(s)
| | - Jaydutt Bhalshankar
- National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore
| | | | - Yi Zhao
- Division of Clinical Research, Singapore General Hospital, Singapore
| | - Katharine R. Owen
- Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, Oxford, UK Oxford National Institute for Health Research Biomedical Research Centre, The Churchill Hospital, Oxford, UK
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The E3 SUMO ligase PIASγ is a novel interaction partner regulating the activity of diabetes associated hepatocyte nuclear factor-1α. Sci Rep 2018; 8:12780. [PMID: 30143652 PMCID: PMC6109179 DOI: 10.1038/s41598-018-29448-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Accepted: 07/09/2018] [Indexed: 02/07/2023] Open
Abstract
The transcription factor hepatocyte nuclear factor-1α (HNF-1A) is involved in normal pancreas development and function. Rare variants in the HNF1A gene can cause monogenic diabetes, while common variants confer type 2 diabetes risk. The precise mechanisms for regulation of HNF-1A, including the role and function of post-translational modifications, are still largely unknown. Here, we present the first evidence for HNF-1A being a substrate of SUMOylation in cellulo and identify two lysine (K) residues (K205 and K273) as SUMOylation sites. Overexpression of protein inhibitor of activated STAT (PIASγ) represses the transcriptional activity of HNF-1A and is dependent on simultaneous HNF-1A SUMOylation at K205 and K273. Moreover, PIASγ is a novel HNF-1A interaction partner whose expression leads to translocation of HNF-1A to the nuclear periphery. Thus, our findings support that the E3 SUMO ligase PIASγ regulates HNF-1A SUMOylation with functional implications, representing new targets for drug development and precision medicine in diabetes.
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Barbetti F, D'Annunzio G. Genetic causes and treatment of neonatal diabetes and early childhood diabetes. Best Pract Res Clin Endocrinol Metab 2018; 32:575-591. [PMID: 30086875 DOI: 10.1016/j.beem.2018.06.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Diabetes mellitus and impaired fasting glucose associated with single gene mutations are less rare than previously thought and may account for more than 6% of patients attending a pediatric diabetes clinic. The number of loci involved in monogenic diabetes exceed 25, and appropriate genetic diagnosis is crucial to direct therapy, for genetic counseling and for prognosis of short- and long-term complications. Among patients with neonatal diabetes (i.e. with onset within first 6 months of life) and patients with Maturity Onset Diabetes of the Young (MODY; an autosomal dominant form of diabetes), those carrying mutations in KCNJ11, ABCC8, HNF1A and HNF4A genes usually respond to oral therapy with sulphonylurea, while those bearing GCK mutations do not necessitate any treatment. Sensor-augmented continuous subcutaneous insulin infusion has been successfully employed in neonatal diabetes, and long-lasting effectiveness of sulfonylurea in KCNJ11 mutation carriers with neonatal diabetes well documented.
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Affiliation(s)
- Fabrizio Barbetti
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 100133 Rome, Italy; S. Pietro Fatebenefratelli Hospital, 00189 Rome, Italy.
| | - Giuseppe D'Annunzio
- Pediatric Clinic, Regional Center for Pediatric Diabetes, IRCCS Istituto Giannina Gaslini, Via Gaslini 5, 16147, Genoa, Italy.
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Abstract
PURPOSE OF REVIEW We provide a review of monogenic diabetes in young children and adolescents with a focus on recognition, management, and pharmacological treatment. RECENT FINDINGS Monogenic forms of diabetes account for approximately 1-2% of diabetes in children and adolescents, and its incidence has increased in recent years due to greater awareness and wider availability of genetic testing. Monogenic diabetes is due to single gene defects that primarily affect beta cell function with more than 30 different genes reported. Children with antibody-negative, C-peptide-positive diabetes should be evaluated and genetically tested for monogenic diabetes. Accurate genetic diagnosis impacts treatment in the most common types of monogenic diabetes, including the use of sulfonylureas in place of insulin or other glucose-lowering agents or discontinuing pharmacologic treatment altogether. Diagnosis of monogenic diabetes can significantly improve patient care by enabling prediction of the disease course and guiding appropriate management and treatment.
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Affiliation(s)
- May Sanyoura
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, 5841 S. Maryland Ave., MC 1027, Chicago, IL, 60637, USA
| | - Louis H Philipson
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, 5841 S. Maryland Ave., MC 1027, Chicago, IL, 60637, USA
| | - Rochelle Naylor
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, 5841 S. Maryland Ave., MC 1027, Chicago, IL, 60637, USA.
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Owen KR. Monogenic diabetes in adults: what are the new developments? Curr Opin Genet Dev 2018; 50:103-110. [DOI: 10.1016/j.gde.2018.04.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 04/16/2018] [Accepted: 04/19/2018] [Indexed: 12/13/2022]
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Majidi S, Fouts A, Pyle L, Chambers C, Armstrong T, Wang Z, Batish SD, Klingensmith G, Steck AK. Can Biomarkers Help Target Maturity-Onset Diabetes of the Young Genetic Testing in Antibody-Negative Diabetes? Diabetes Technol Ther 2018; 20:106-112. [PMID: 29355436 PMCID: PMC6110120 DOI: 10.1089/dia.2017.0317] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND Maturity-onset diabetes of the young (MODY) is an antibody-negative, autosomal dominant form of diabetes. With the increasing prevalence of diabetes and the expense of MODY testing, markers to identify those who need further genetic testing would be beneficial. We investigated whether HLA genotypes, random C-peptide, and/or high-sensitivity C-reactive protein (hsCRP) levels could be helpful biomarkers for identifying MODY in antibody-negative diabetes. METHODS Subjects (N = 97) with diabetes onset ≤age 25, measurable C-peptide (≥0.1 ng/mL), and negative for all four diabetes autoantibodies were enrolled at a large academic center and tested for MODY 1-5 through Athena Diagnostics. A total of 22 subjects had a positive or very likely pathogenic mutation for MODY. RESULTS Random C-peptide levels were significantly different between MODY-positive and MODY-negative subjects (0.16 nmol/L vs. 0.02 nmol/L; P = 0.02). After adjusting for age and diabetes duration, hsCRP levels were significantly lower in MODY-positive subjects (0.37 mg/L vs. 0.87 mg/L; P = 0.02). Random C-peptide level ≥0.15 nmol/L obtained at ≥6 months after diagnosis had 83% sensitivity for diagnosis of MODY with a negative predictive value of 96%. Receiver operating characteristic curves showed that area under the curve for random C-peptide (0.75) was significantly better than hsCRP (0.54), high-risk HLA DR3/4-DQB1*0302 (0.59), and high-risk HLA/random C-peptide combined (0.54; P = 0.03). CONCLUSIONS Random C-peptide obtained at ≥6 months after diagnosis can be a useful biomarker to identify antibody-negative individuals who need further genetic testing for MODY, whereas hsCRP and HLA do not appear to improve this antibody/C-peptide-based approach.
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Affiliation(s)
- Shideh Majidi
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado
- Address correspondence to:Shideh Majidi, MDBarbara Davis Center for Childhood DiabetesUniversity of Colorado Denver1775 Aurora Ct, A140,Aurora, CO 80045
| | - Alexandra Fouts
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado
| | - Laura Pyle
- Department of Pediatrics, University of Colorado Denver, Aurora, Colorado
| | - Christina Chambers
- Department of Pediatrics, University of Colorado Denver, Aurora, Colorado
| | - Taylor Armstrong
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado
| | | | | | - Georgeanna Klingensmith
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado
| | - Andrea K. Steck
- Barbara Davis Center for Childhood Diabetes, University of Colorado Denver, Aurora, Colorado
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Hepatocyte nuclear factors as possible C-reactive protein transcriptional inducer in the liver and white adipose tissue of rats with experimental chronic renal failure. Mol Cell Biochem 2018; 446:11-23. [PMID: 29330688 PMCID: PMC6096500 DOI: 10.1007/s11010-018-3268-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2017] [Accepted: 01/04/2018] [Indexed: 12/11/2022]
Abstract
Inflammation related to chronic kidney disease (CKD) is an important clinical problem. We recently determined that hepatocyte nuclear factor 1α (HNF1α) was upregulated in the livers of chronic renal failure (CRF) rats—experimental model of CKD. Considering that the promoter region of gene encoding C-reactive protein (CRP) contains binding sites for HNF1α and that the loss-of-function mutation in the Hnfs1α leads to significant reduction in circulating CRP levels, we hypothesized that HNF1α can activate the Crp in CRF rats. Here, we found coordinated upregulation of genes encoding CRP, interleukin-6 (IL-6), HNF1α, and HNF4α in the livers and white adipose tissue (WAT) of CRF rats, as compared to the pair-fed and control animals. This was accompanied by elevated serum levels of CRP and IL-6. CRP and HNFs’ mRNA levels correlated positively with CRP and HNFs’ protein levels in the liver and WAT. Similar upregulation of the Crp, Il-6, and Hnfs in the liver and WAT and increased serum CRP and IL-6 concentrations were found in lipopolysaccharide (LPS)-induced systemic inflammation in rats. Moreover, silencing HNF1α in HepG2 cells by small interfering RNA led to decrease in CRP mRNA levels. Our results suggests that (a) HNFs act in concert with IL-6 in the upregulation of CRP production by the liver and WAT, leading to an increase in circulating CRP concentration in CRF rats and (b) CRF-related inflammation plays an important role in the upregulation of genes that encode HNFs and CRP in the liver and WAT of CRF rats.
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Grulich-Henn J, Klose D. Understanding childhood diabetes mellitus: new pathophysiological aspects. J Inherit Metab Dis 2018; 41:19-27. [PMID: 29247329 DOI: 10.1007/s10545-017-0120-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 11/28/2017] [Indexed: 12/16/2022]
Abstract
Diabetes mellitus (DM) is not a single disease, but several pathophysiological conditions where synthesis, release, and/or action of insulin are disturbed. A progressive autoimmune/autoinflammatory destruction of islet cells is still considered the main pathophysiological event in the development of T1DM, but there is evidence that T1DM itself is a heterogeneous disease. More than 50 gene regions are closely associated with T1DM and a variety of epigenetic factors and metabolic patterns have been characterized, which may play a role in the development of T1DM. The pathogenesis and genetics of type 2 DM (T2DM) are distinct from T1DM. Genes associated with T2DM are distinct from those in T1DM. Characteristic metabolic patterns, different from those in T1DM were reported in T2DM, and some children with T2DM also express islet-antibodies. Huge progress has been made in the characterization of other specific types of DM, which had been considered very rare before. The molecular clarification of maturity-onset diabetes of the young (MODY) has greatly improved our understanding of the pathophysiology of DM. There are genetic overlaps between T2DM and monogenetic DM. Neonatal DM has been shown to be monogenetic in most cases, and genetic elucidation leads to more precise and individualized therapies. Cystic fibrosis related DM (CFRDM) should be considered a genuine part of cystic fibrosis, and not a complication, since pancreatic fibrosis does not sufficiently explain the pathophysiology of CFRDM. Disturbances of cystic fibrosis transmembrane conductance regulator (CFTR) as well as autoimmunity are involved in the pathogenesis of CFRDM.
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MESH Headings
- Adolescent
- Age of Onset
- Autoantibodies/immunology
- Autoimmunity
- Blood Glucose/metabolism
- Child
- Child, Preschool
- Cystic Fibrosis/epidemiology
- Cystic Fibrosis/genetics
- Cystic Fibrosis/metabolism
- Cystic Fibrosis/physiopathology
- Cystic Fibrosis Transmembrane Conductance Regulator/genetics
- Cystic Fibrosis Transmembrane Conductance Regulator/metabolism
- Diabetes Mellitus, Type 1/blood
- Diabetes Mellitus, Type 1/epidemiology
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/physiopathology
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/epidemiology
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/physiopathology
- Energy Metabolism/genetics
- Genetic Predisposition to Disease
- Humans
- Infant
- Infant, Newborn
- Infant, Newborn, Diseases/blood
- Infant, Newborn, Diseases/epidemiology
- Infant, Newborn, Diseases/genetics
- Infant, Newborn, Diseases/physiopathology
- Insulin/blood
- Islets of Langerhans/immunology
- Islets of Langerhans/metabolism
- Islets of Langerhans/pathology
- Islets of Langerhans/physiopathology
- Risk Factors
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Affiliation(s)
- Juergen Grulich-Henn
- University Children´s Hospital, University of Heidelberg, Im Neuenheimer Feld 430, Heidelberg, D-69120, Germany.
| | - Daniela Klose
- University Children´s Hospital, University of Heidelberg, Im Neuenheimer Feld 430, Heidelberg, D-69120, Germany
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Johansson BB, Irgens HU, Molnes J, Sztromwasser P, Aukrust I, Juliusson PB, Søvik O, Levy S, Skrivarhaug T, Joner G, Molven A, Johansson S, Njølstad PR. Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry. Diabetologia 2017; 60:625-635. [PMID: 27913849 DOI: 10.1007/s00125-016-4167-1] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 11/09/2016] [Indexed: 12/18/2022]
Abstract
AIMS/HYPOTHESIS MODY can be wrongly diagnosed as type 1 diabetes in children. We aimed to find the prevalence of MODY in a nationwide population-based registry of childhood diabetes. METHODS Using next-generation sequencing, we screened the HNF1A, HNF4A, HNF1B, GCK and INS genes in all 469 children (12.1%) negative for both GAD and IA-2 autoantibodies and 469 antibody-positive matched controls selected from the Norwegian Childhood Diabetes Registry (3882 children). Variants were classified using clinical diagnostic criteria for pathogenicity ranging from class 1 (neutral) to class 5 (pathogenic). RESULTS We identified 58 rare exonic and splice variants in cases and controls. Among antibody-negative patients, 6.5% had genetic variants of classes 3-5 (vs 2.4% in controls; p = 0.002). For the stricter classification (classes 4 and 5), the corresponding number was 4.1% (vs 0.2% in controls; p = 1.6 × 10-5). HNF1A showed the strongest enrichment of class 3-5 variants, with 3.9% among antibody-negative patients (vs 0.4% in controls; p = 0.0002). Antibody-negative carriers of variants in class 3 had a similar phenotype to those carrying variants in classes 4 and 5. CONCLUSIONS/INTERPRETATION This is the first study screening for MODY in all antibody-negative children in a nationwide population-based registry. Our results suggest that the prevalence of MODY in antibody-negative childhood diabetes may reach 6.5%. One-third of these MODY cases had not been recognised by clinicians. Since a precise diagnosis is important for treatment and genetic counselling, molecular screening of all antibody-negative children should be considered in routine diagnostics.
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Affiliation(s)
- Bente B Johansson
- K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway
- Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
| | - Henrik U Irgens
- K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway
- Department of Paediatrics, Haukeland University Hospital, Bergen, Norway
| | - Janne Molnes
- K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway
- Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
| | - Paweł Sztromwasser
- Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
- Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Ingvild Aukrust
- K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway
- Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
| | - Petur B Juliusson
- Department of Paediatrics, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Oddmund Søvik
- K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway
- Department of Paediatrics, Haukeland University Hospital, Bergen, Norway
| | - Shawn Levy
- Hudson Alpha Institute for Biotechnology, Huntsville, AL, USA
| | - Torild Skrivarhaug
- Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
| | - Geir Joner
- Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Health and Society, University of Oslo, Oslo, Norway
| | - Anders Molven
- K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway
- Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen, Bergen, Norway
- Department of Pathology, Haukeland University Hospital, Bergen, Norway
| | - Stefan Johansson
- K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway
- Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway
| | - Pål R Njølstad
- K. G. Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, N-5020, Bergen, Norway.
- Department of Paediatrics, Haukeland University Hospital, Bergen, Norway.
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45
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Lachance CH. Practical Aspects of Monogenic Diabetes: A Clinical Point of View. Can J Diabetes 2016; 40:368-375. [PMID: 26897468 DOI: 10.1016/j.jcjd.2015.11.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2015] [Revised: 10/20/2015] [Accepted: 11/10/2015] [Indexed: 12/16/2022]
Affiliation(s)
- Carl-Hugo Lachance
- CHU de Québec-Hôpital Saint-François d'Assise, Québec City, Québec, Canada.
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46
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Althari S, Gloyn AL. When is it MODY? Challenges in the Interpretation of Sequence Variants in MODY Genes. Rev Diabet Stud 2016; 12:330-48. [PMID: 27111119 DOI: 10.1900/rds.2015.12.330] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
The genomics revolution has raised more questions than it has provided answers. Big data from large population-scale resequencing studies are increasingly deconstructing classic notions of Mendelian disease genetics, which support a simplistic correlation between mutational severity and phenotypic outcome. The boundaries are being blurred as the body of evidence showing monogenic disease-causing alleles in healthy genomes, and in the genomes of individu-als with increased common complex disease risk, continues to grow. In this review, we focus on the newly emerging challenges which pertain to the interpretation of sequence variants in genes implicated in the pathogenesis of maturity-onset diabetes of the young (MODY), a presumed mono-genic form of diabetes characterized by Mendelian inheritance. These challenges highlight the complexities surrounding the assignments of pathogenicity, in particular to rare protein-alerting variants, and bring to the forefront some profound clinical diagnostic implications. As MODY is both genetically and clinically heterogeneous, an accurate molecular diagnosis and cautious extrapolation of sequence data are critical to effective disease management and treatment. The biological and translational value of sequence information can only be attained by adopting a multitude of confirmatory analyses, which interrogate variant implication in disease from every possible angle. Indeed, studies which have effectively detected rare damaging variants in known MODY genes in normoglycemic individuals question the existence of a sin-gle gene mutation scenario: does monogenic diabetes exist when the genetic culprits of MODY have been systematical-ly identified in individuals without MODY?
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Affiliation(s)
- Sara Althari
- Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, UK
| | - Anna L Gloyn
- Oxford Centre for Diabetes Endocrinology and Metabolism, University of Oxford, UK
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47
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Kim SH. Maturity-Onset Diabetes of the Young: What Do Clinicians Need to Know? Diabetes Metab J 2015; 39:468-77. [PMID: 26706916 PMCID: PMC4696982 DOI: 10.4093/dmj.2015.39.6.468] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2015] [Accepted: 11/25/2015] [Indexed: 11/15/2022] Open
Abstract
Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes that is characterized by an early onset, autosomal dominant mode of inheritance and a primary defect in pancreatic β-cell function. MODY represents less than 2% of all diabetes cases and is commonly misdiagnosed as type 1 or type 2 diabetes mellitus. At least 13 MODY subtypes with distinct genetic etiologies have been identified to date. A correct genetic diagnosis is important as it often leads to personalized treatment for those with diabetes and enables predictive genetic testing for their asymptomatic relatives. Next-generation sequencing may provide an efficient method for screening mutations in this form of diabetes as well as identifying new MODY genes. In this review, I discuss a current update on MODY in the literatures and cover the studies that have been performed in Korea.
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Affiliation(s)
- Sung Hoon Kim
- Division of Endocrinology & Metabolism, Department of Medicine, Cheil General Hospital & Women's Healthcare Center, Dankook University College of Medicine, Seoul, Korea.
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48
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Abstract
Monogenic diabetes is frequently mistakenly diagnosed as either type 1 or type 2 diabetes, yet accounts for approximately 1-2% of diabetes. Identifying monogenic forms of diabetes has practical implications for specific therapy, screening of family members and genetic counselling. The most common forms of monogenic diabetes are due to glucokinase (GCK), hepatocyte nuclear factor (HNF)-1A and HNF-4A, HNF-1B, m.3243A>G gene defects. Practical aspects of their recognition, diagnosis and management are outlined, particularly as they relate to pregnancy. This knowledge is important for all physicians managing diabetes in pregnancy, given this is a time when previously unrecognised monogenic diabetes may be uncovered with careful attention to atypical features of diabetes misclassified as type 1, type 2, or gestational diabetes.
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Affiliation(s)
- Rinki Murphy
- Department of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
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49
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Bellanné-Chantelot C, Coste J, Ciangura C, Fonfrède M, Saint-Martin C, Bouché C, Sonnet E, Valéro R, Lévy DJ, Dubois-Laforgue D, Timsit J. High-sensitivity C-reactive protein does not improve the differential diagnosis of HNF1A-MODY and familial young-onset type 2 diabetes: A grey zone analysis. DIABETES & METABOLISM 2015; 42:33-7. [PMID: 25753245 DOI: 10.1016/j.diabet.2015.02.001] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Revised: 02/04/2015] [Accepted: 02/05/2015] [Indexed: 12/13/2022]
Abstract
AIM Low plasma levels of high-sensitivity C-reactive protein (hs-CRP) have been suggested to differentiate hepatocyte nuclear factor 1 alpha-maturity-onset diabetes of the young (HNF1A-MODY) from type 2 diabetes (T2D). Yet, differential diagnosis of HNF1A-MODY and familial young-onset type 2 diabetes (F-YT2D) remains a difficult challenge. Thus, this study assessed the added value of hs-CRP to distinguish between the two conditions. METHODS This prospective multicentre study included 143 HNF1A-MODY patients, 310 patients with a clinical history suggestive of HNF1A-MODY, but not confirmed genetically (F-YT2D), and 215 patients with T2D. The ability of models, including clinical characteristics and hs-CRP to predict HNF1A-MODY was analyzed, using the area of the receiver operating characteristic (AUROC) curve, and a grey zone approach was used to evaluate these models in clinical practice. RESULTS Median hs-CRP values were lower in HNF1A-MODY (0.25mg/L) than in F-YT2D (1.14mg/L) and T2D (1.70mg/L) patients. Clinical parameters were sufficient to differentiate HNF1A-MODY from classical T2D (AUROC: 0.99). AUROC analyses to distinguish HNF1A-MODY from F-YT2D were 0.82 for clinical features and 0.87 after including hs-CRP. For the grey zone analysis, the lower boundary was set to miss<1.5% of true positives in non-tested subjects, while the upper boundary was set to perform 50% of genetic tests in individuals with no HNF1A mutation. On comparing HNF1A-MODY with F-YT2D, 65% of patients were classified in between these categories - in the zone of diagnostic uncertainty - even after adding hs-CRP to clinical parameters. CONCLUSION hs-CRP does not improve the differential diagnosis of HNF1A-MODY and F-YT2D.
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Affiliation(s)
- C Bellanné-Chantelot
- Department of Genetics, AP-HP, Hôpital Pitié-Salpétrière, Université Pierre-et-Marie-Curie, 47-83, boulevard de l'Hôpital, 75013 Paris, France.
| | - J Coste
- Unit of Biostatistics and Epidemiology, AP-HP, Hôtel Dieu; Unit Research APEMAC, EA 4360, Université Paris-Descartes, Sorbonne Paris Cité, Lorraine Université, 75004 Paris, France
| | - C Ciangura
- Department of Diabetology, AP-HP, Hôpital Pitié-Salpétrière, Université Pierre-et-Marie-Curie, 75013 Paris, France
| | - M Fonfrède
- Department of Medical Biochemistry, AP-HP, Hôpital Pitié-Salpétrière, 75013 Paris, France
| | - C Saint-Martin
- Department of Genetics, AP-HP, Hôpital Pitié-Salpétrière, Université Pierre-et-Marie-Curie, 47-83, boulevard de l'Hôpital, 75013 Paris, France
| | - C Bouché
- Department of Diabetology, AP-HP, Hôpital Lariboisière, 75010 Paris, France
| | - E Sonnet
- Department of Endocrinology, CHU de Brest, 29609 Brest, France
| | - R Valéro
- Department of Nutrition, Metabolic diseases, Endocrinology, AP-HM, Hôpital de la Timone, Aix-Marseille Université, 13385 Marseille, France
| | - D-J Lévy
- Department of Diabetology, AP-HP, Hôpital Cochin, Université Paris-Descartes, 75014 Paris, France
| | - D Dubois-Laforgue
- Department of Diabetology, AP-HP, Hôpital Cochin, Université Paris-Descartes, 75014 Paris, France
| | - J Timsit
- Department of Diabetology, AP-HP, Hôpital Cochin, Université Paris-Descartes, 75014 Paris, France
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50
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Anık A, Çatlı G, Abacı A, Böber E. Maturity-onset diabetes of the young (MODY): an update. J Pediatr Endocrinol Metab 2015; 28:251-63. [PMID: 25581748 DOI: 10.1515/jpem-2014-0384] [Citation(s) in RCA: 102] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Accepted: 11/24/2014] [Indexed: 11/15/2022]
Abstract
Maturity-onset diabetes of the young (MODY) is a group of monogenic disorders characterized by autosomal dominantly inherited non-insulin dependent form of diabetes classically presenting in adolescence or young adults before the age of 25 years. MODY is a rare cause of diabetes (1% of all cases) and is frequently misdiagnosed as Type 1 diabetes (T1DM) or Type 2 diabetes (T2DM). A precise molecular diagnosis is essential because it leads to optimal treatment of the patients and allows early diagnosis for their asymptomatic family members. Mutations in the glucokinase (GCK) (MODY 2) and hepatocyte nuclear factor (HNF)1A/4A (MODY 3 and MODY 1) genes are the most common causes of MODY. GCK mutations cause a mild, asymptomatic, and stable fasting hyperglycemia usually requiring no specific treatment. However, mutations in the HNF1A and HNF4A cause a progressive pancreatic β-cell dysfunction and hyperglycemia that can result in microvascular complications. Sulfonylureas are effective in these patients by acting on adenosine triphosphate (ATP)-sensitive potassium channels, although insulin therapy may be required later in life. Mutations in the HNF1B (MODY 5) is associated with pancreatic agenesis, renal abnormalities, genital tract malformations, and liver dysfunction. Compared to MODY 1, 2, 3, and 5, the remaining subtypes of MODY have a much lower prevalence. In this review, we summarize the main clinical and laboratory characteristics of the common and rarer causes of MODY.
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