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Cobry EC, Steck AK. Review of Monogenic Diabetes: Clinical Features and Precision Medicine in Genetic Forms of Diabetes. Diabetes Technol Ther 2025. [PMID: 40176772 DOI: 10.1089/dia.2024.0602] [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] [Indexed: 04/04/2025]
Abstract
Monogenic diabetes is a group of diseases that encompasses a growing number of genetic abnormalities affecting pancreatic function/development leading to glycemic dysregulation. This includes conditions that have historically been referred to as maturity onset diabetes of the young or MODY in addition to neonatal diabetes mellitus. While recognition of a genetic or inherited form of diabetes has been known for decades, advances in molecular genetic testing have resulted in identification of specific forms of monogenic diabetes. Despite this, these genetic forms of diabetes remain widely underreported. It is important to be able to identify genetic forms of diabetes as treatment, monitoring for microvascular and macrovascular complications, and overall management varies for the different forms of monogenic diabetes. Furthermore, the identification of a specific monogenic form of diabetes can significantly impact the person's quality of life and other family members, as well as health care costs. This article highlights the identification, treatment, and management for various forms of monogenic diabetes and addresses some unmet needs in caring for people with monogenic forms of diabetes.
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Affiliation(s)
- Erin C Cobry
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora CO, USA
| | - Andrea K Steck
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora CO, USA
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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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Franks PW, Rich SS, Linder B, Zaghloul NA, Cefalu WT. A Research Roadmap to Address the Heterogeneity of Diabetes and Advance Precision Medicine. J Clin Endocrinol Metab 2025; 110:601-610. [PMID: 39657245 PMCID: PMC12063085 DOI: 10.1210/clinem/dgae844] [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: 09/12/2024] [Revised: 11/23/2024] [Accepted: 12/05/2024] [Indexed: 12/17/2024]
Abstract
The current classification of diabetes had its genesis over 85 years ago, when individuals with diabetes were first subclassified into insulin sensitive and insulin insensitive states based on the response to an oral glucose tolerance test. About 35 years later, the contemporary classifications of type 1 and type 2 diabetes were coined. Today's evidence, however, suggests that multiple etiologic and pathogenic processes lead to both type 1 and type 2 diabetes, reflecting significant heterogeneity in factors associated with initiation, progression, and clinical presentation of each disorder of glucose homeostasis. Further, the current classification fails to recognize what is currently defined as "atypical" diabetes. Heterogeneity of diabetes continues through the life-course of an individual, with modification of prognosis risk (eg, diabetic complications) altered by genetics, life experience, comorbidities, and therapy. Understanding the sources of heterogeneity in diabetes will likely improve diagnosis, prevention, treatment, and prediction of complications in both the medical and public health settings. Such knowledge will help inform progress in the emerging era of precision diabetes medicine. This article presents NIDDK's Heterogeneity of Diabetes Initiative and a corresponding roadmap for future research in type 2 diabetes heterogeneity.
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Affiliation(s)
- Paul W Franks
- Department of Clinical Sciences, Lund University, Helsingborg Hospital, Helsingborg 251 87, Sweden
| | - Stephen S Rich
- Department of Genome Sciences, University of Virginia, Charlottesville, VA 22908, USA
| | - Barbara Linder
- Division of Diabetes, Endocrinology & Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - Norann A Zaghloul
- Division of Diabetes, Endocrinology & Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
| | - William T Cefalu
- Division of Diabetes, Endocrinology & Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Dzhemileva LU, Zakharova EN, Goncharenko AO, Vorontsova MV, Rumyantsev SA, Mokrysheva NG, Loguinova MY, Chekhonin VP. Current views on etiology, diagnosis, epidemiology and gene therapy of maturity onset diabetes in the young. Front Endocrinol (Lausanne) 2025; 15:1497298. [PMID: 39902162 PMCID: PMC11788143 DOI: 10.3389/fendo.2024.1497298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 12/27/2024] [Indexed: 02/05/2025] Open
Abstract
MODY, or maturity-onset diabetes of the young, is a group of monogenic diseases characterized by autosomal dominant inheritance of a non-insulin-dependent form of diabetes that classically manifests in adolescence or in young adults under 25 years of age. MODY is a rare cause of diabetes, accounting for 1% of all cases, and is often misdiagnosed as type 1 or type 2 diabetes. It is of great importance to accurately diagnose MODY, as this allows for the most appropriate treatment of patients and facilitates early diagnosis for them and their families. This disease has a high degree of phenotypic and genetic polymorphism. The most prevalent forms of the disease are attributed to mutations in three genes: GCK (MODY 2) and (HNF)1A/4A (MODY 3 and MODY 1). The remaining MODY subtypes, which are less prevalent, have been identified by next generation sequencing (NGS) in the last decade. Mutations in the GCK gene result in asymptomatic, stable fasting hyperglycemia, which does not require specific treatment. Mutations in the HNF1A and HNF4A genes result in pancreatic β-cell dysfunction, which in turn causes hyperglycemia. This often leads to diabetic angiopathy. The most commonly prescribed drugs for the treatment of hyperglycemia are sulfonylurea derivatives. Nevertheless, with advancing age, some patients may require insulin therapy due to the development of resistance to sulfonylurea drugs. The strategy of gene therapy for monogenic forms of MODY is still an experimental approach, and it is unlikely to be widely used in the clinic due to the peculiarities of MODY structure and the high genetic polymorphism and clinical variability even within the same form of the disease. Furthermore, there is a lack of clear gene-phenotypic correlations, and there is quite satisfactory curability in the majority of patients. This review presents the main clinical and genetic characteristics and mutation spectrum of common and rarer forms of MODY, with a detailed analysis of the field of application of AVV vectors in the correction of hyperglycemia and insulin resistance.
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Tosur M. Maturity-onset diabetes of the young: A proposal for updated nomenclature. J Diabetes Investig 2024; 15:1818-1819. [PMID: 39344197 PMCID: PMC11615688 DOI: 10.1111/jdi.14320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 09/09/2024] [Indexed: 10/01/2024] Open
Abstract
Given the contemporary understanding of diabetes genetics, the term "maturity-onset diabetes of the young (MODY)" warrants renaming. I propose adopting the term "monogenic diabetes" in conjunction with the specific gene name.
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Affiliation(s)
- Mustafa Tosur
- Division of Diabetes and Endocrinology, Department of PediatricsBaylor College of Medicine, Texas Children's HospitalHoustonTexasUSA
- Children's Nutrition Research CenterUSDA/ARSHoustonTexasUSA
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Lv X, Gao J, Yang J, Zou Y, Chen J, Sun Y, Song J, Liu Y, Wang L, Xia L, Yu S, Wei Z, Chen L, Hou X. Clinical and functional characterization of a novel KCNJ11 (c.101G > A, p.R34H) mutation associated with maturity-onset diabetes mellitus of the young type 13. Endocrine 2024; 86:515-527. [PMID: 38761346 DOI: 10.1007/s12020-024-03873-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 05/09/2024] [Indexed: 05/20/2024]
Abstract
PURPOSE This study aimed to describe the clinical features, diagnostic and therapeutic course of a patient with MODY13 caused by KCNJ11 (c.101G > A, p.R34H) and how it contributes to the pathogenesis of MODY13, and to explore new therapeutic targets. METHODS Whole-exome sequencing was used to screen prediagnosed individuals and family members with clinically suspected KCNJ11 mutations. Real-time fluorescence quantitative PCR, western blotting, thallium flux of potassium channels, glucose-stimulated insulin secretion (GSIS), and immunofluorescence assays were used to analyze the regulation of insulin secretion by the KCNJ11 mutant in MIN6 cells. Daily blood glucose levels were continuously monitored for 14 days in the proband using the ambulatory blood glucose meter (SIBIONICS). RESULTS Mutation screening of the entire exon of the gene identified a heterozygous KCNJ11 (c.101G > A, p.R34H) mutation in the proband and his mother. Cell-based GSIS assays after transfection of MIN6 using wild-type and mutant plasmids revealed that this mutation impaired insulin secretory function. Furthermore, we found that this impaired secretory function is associated with reduced functional activity of the mutant KCNJ11 protein and reduced expression of the insulin secretion-associated exocytosis proteins STXBP1 and SNAP25. CONCLUSION For the first time, we revealed the pathogenic mechanism of KCNJ11 (c.101G > A, p.R34H) associated with MODY13. This mutant can cause alterations in KATP channel activity, reduce sensitivity to glucose stimulation, and impair pancreatic β-cell secretory function by downregulating insulin secretion-associated exocytosis proteins. Therefore, oral sulfonylurea drugs can lower blood glucose levels through pro-insulinotropic effects and are more favorable for patients with this mutation.
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Affiliation(s)
- Xiaoyu Lv
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Jing Gao
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Jingwen Yang
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Ying Zou
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Jun Chen
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Yujing Sun
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Jia Song
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Yiran Liu
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Liming Wang
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Longqing Xia
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Shijia Yu
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Zichun Wei
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
| | - Li Chen
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, Shandong, China
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, China
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, Shandong, China
| | - Xinguo Hou
- Department of Endocrinology, Qilu Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
- Institute of Endocrine and Metabolic Diseases of Shandong University, Jinan, 250012, Shandong, China.
- Key Laboratory of Endocrine and Metabolic Diseases, Shandong Province Medicine & Health, Jinan, 250012, Shandong, China.
- Jinan Clinical Research Center for Endocrine and Metabolic Disease, Jinan, 250012, Shandong, China.
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Hasballa I, Maggi D. MODY Only Monogenic? A Narrative Review of the Novel Rare and Low-Penetrant Variants. Int J Mol Sci 2024; 25:8790. [PMID: 39201476 PMCID: PMC11354648 DOI: 10.3390/ijms25168790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 07/26/2024] [Accepted: 08/12/2024] [Indexed: 09/02/2024] Open
Abstract
Maturity-onset diabetes of the young (MODY) represents the most frequent form of monogenic diabetes mellitus (DM), currently classified in 14 distinct subtypes according to single gene mutations involved in the differentiation and function of pancreatic β-cells. A significant proportion of MODY has unknown etiology, suggesting that the genetic landscape is still to be explored. Recently, novel potentially MODY-causal genes, involved in the differentiation and function of β-cells, have been identified, such as RFX6, NKX2.2, NKX6.1, WFS1, PCBD1, MTOR, TBC1D4, CACNA1E, MNX1, AKT2, NEUROG3, EIF2AK3, GLIS3, HADH, and PTF1A. Genetic and clinical features of MODY variants remain highly heterogeneous, with no direct genotype-phenotype correlation, especially in the low-penetrant subtypes. This is a narrative review of the literature aimed at describing the current state-of-the-art of the novel likely MODY-associated variants. For a deeper understanding of MODY complexity, we also report some related controversies concerning the etiological role of some of the well-known pathological genes and MODY inheritance pattern, as well as the rare association of MODY with autoimmune diabetes. Due to the limited data available, the assessment of MODY-related genes pathogenicity remains challenging, especially in the setting of rare and low-penetrant subtypes. In consideration of the crucial importance of an accurate diagnosis, prognosis and management of MODY, more studies are warranted to further investigate its genetic landscape and the genotype-phenotype correlation, as well as the pathogenetic contribution of the nongenetic modifiers in this cohort of patients.
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Affiliation(s)
- Iderina Hasballa
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, 16132 Genoa, Italy
| | - Davide Maggi
- Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, 16132 Genoa, Italy
- Diabetes Clinic, IRCCS Ospedale Policlinico San Martino Genoa, 16132 Genoa, Italy
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Müssig K. Diabetic Ketoacidosis in Patients with Maturity-Onset Diabetes of the Young. Exp Clin Endocrinol Diabetes 2024; 132:463-468. [PMID: 38838736 DOI: 10.1055/a-2338-8136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/07/2024]
Abstract
Maturity-onset diabetes of the young (MODY) is the most frequent monogenetic diabetes form. It is caused by mutations in genes important for the development and function of pancreatic beta-cells, resulting in impaired insulin secretion capacity. Up to now, 14 different types have been described. The inheritance pattern is autosomal dominant, leading to a strong family history with more than three affected generations. Young age at diagnosis and lack of pancreatic autoantibodies are further characteristics of MODY. The presence of diabetic ketoacidosis (DKA) was long regarded as an exclusion criterion for MODY. However, in recent years, several case reports on MODY patients presenting with DKA have been published. The present study aimed to give an overview of the current knowledge of DKA in MODY patients, with a collection of published case studies as a prerequisite for this review.
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Affiliation(s)
- Karsten Müssig
- Department of Internal Medicine, Gastroenterology and Diabetology, Niels Stensen Hospitals, Franziskus Hospital Harderberg, Georgsmarienhütte, Germany
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Li WX, Xu LL, Liu CF, Dong BZ, Wang YY. Analysis of an adult diabetes mellitus caused by a rare mutation of the gene: A case report. World J Clin Cases 2024; 12:3942-3949. [PMID: 38994305 PMCID: PMC11235441 DOI: 10.12998/wjcc.v12.i19.3942] [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: 02/22/2024] [Revised: 04/24/2024] [Accepted: 05/11/2024] [Indexed: 06/29/2024] Open
Abstract
BACKGROUND This study presents the clinical and genetic mutation characteristics of an unusual case of adult-onset diabetes mellitus occurring in adolescence, featuring a unique mutation in the peroxisome proliferator-activated receptor gamma (PPARG) gene. Data Access Statement: Research data supporting this publication are available from the NN repository at www.NNN.org/download/. CASE SUMMARY The methodology employed entailed meticulous collection of comprehensive clinical data from the probands and their respective family members. Additionally, high-throughput sequencing was conducted to analyze the PPARG genes of the patient, her siblings, and their offspring. The results of this investigation revealed that the patient initially exhibited elevated blood glucose levels during pregnancy, accompanied by insulin resistance and hypertriglyceridemia. Furthermore, these strains displayed increased susceptibility to diabetic kidney disease without any discernible aggregation patterns. The results from the gene detection process demonstrated a heterozygous mutation of guanine (G) at position 284 in the coding region of exon 2 of PPARG, which replaced the base adenine (A) (exon2c.284A>Gp.Tyr95Cys). This missense mutation resulted in the substitution of tyrosine with cysteine at the 95th position of the translated protein. Notably, both of her siblings harbored a nucleotide heterozygous variation at the same site, and both were diagnosed with diabetes. CONCLUSION The PPARG gene mutation, particularly the p.Tyr95Cys mutation, may represent a newly identified subtype of maturity-onset diabetes of the young. This subtype is characterized by insulin resistance and lipid metabolism disorders.
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Affiliation(s)
- Wen-Xuan Li
- Department of Endocrine and Metabolic Diseases, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Li-Li Xu
- Department of Endocrine and Metabolic Diseases, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Chuan-Feng Liu
- Department of Endocrine and Metabolic Diseases, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Bing-Zi Dong
- Department of Endocrine and Metabolic Diseases, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
| | - Yun-Yang Wang
- Department of Endocrine and Metabolic Diseases, The Affiliated Hospital of Qingdao University, Qingdao 266003, Shandong Province, China
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Annicchiarico A, Barile B, Buccoliero C, Nicchia GP, Brunetti G. Alternative therapeutic strategies in diabetes management. World J Diabetes 2024; 15:1142-1161. [PMID: 38983831 PMCID: PMC11229975 DOI: 10.4239/wjd.v15.i6.1142] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 02/17/2024] [Accepted: 04/12/2024] [Indexed: 06/11/2024] Open
Abstract
Diabetes is a heterogeneous metabolic disease characterized by elevated blood glucose levels resulting from the destruction or malfunction of pancreatic β cells, insulin resistance in peripheral tissues, or both, and results in a non-sufficient production of insulin. To adjust blood glucose levels, diabetic patients need exogenous insulin administration together with medical nutrition therapy and physical activity. With the aim of improving insulin availability in diabetic patients as well as ameliorating diabetes comorbidities, different strategies have been investigated. The first approaches included enhancing endogenous β cell activity or transplanting new islets. The protocol for this kind of intervention has recently been optimized, leading to standardized procedures. It is indicated for diabetic patients with severe hypoglycemia, complicated by impaired hypoglycemia awareness or exacerbated glycemic lability. Transplantation has been associated with improvement in all comorbidities associated with diabetes, quality of life, and survival. However, different trials are ongoing to further improve the beneficial effects of transplantation. Furthermore, to overcome some limitations associated with the availability of islets/pancreas, alternative therapeutic strategies are under evaluation, such as the use of mesenchymal stem cells (MSCs) or induced pluripotent stem cells for transplantation. The cotransplantation of MSCs with islets has been successful, thus providing protection against proinflammatory cytokines and hypoxia through different mechanisms, including exosome release. The use of induced pluripotent stem cells is recent and requires further investigation. The advantages of MSC implantation have also included the improvement of diabetes-related comorbidities, such as wound healing. Despite the number of advantages of the direct injection of MSCs, new strategies involving biomaterials and scaffolds have been developed to improve the efficacy of mesenchymal cell delivery with promising results. In conclusion, this paper offered an overview of new alternative strategies for diabetes management while highlighting some limitations that will need to be overcome by future approaches.
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Affiliation(s)
- Alessia Annicchiarico
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Barbara Barile
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Cinzia Buccoliero
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Grazia Paola Nicchia
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
| | - Giacomina Brunetti
- Department of Biosciences, Biotechnologies and Environment, University of Bari Aldo Moro, Bari 70125, Italy
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Chen C, Piao Y, Sang Y. A synonymous KCNJ11 variant leading to MODY13: A case report and literature review. Mol Genet Metab Rep 2024; 38:101043. [PMID: 38226203 PMCID: PMC10788303 DOI: 10.1016/j.ymgmr.2023.101043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 12/19/2023] [Accepted: 12/19/2023] [Indexed: 01/17/2024] Open
Abstract
Background Maturity-onset diabetes of the young, type 13 (MODY13) is a specific subclass of monogenic diabetes mellitus that does not exhibit the typical clinical manifestations of diabetes, necessitating the use of genetic testing for accurate diagnosis. With the progression of monogenic diabetes and MODY, the number of reported MODY13 cases has reached a minimum of 22. Nevertheless, there remains a dearth of information regarding patients diagnosed with MODY13 presenting synonymous variants. Case presentation This study presents a description of the clinical and genetic features of a 9-year-old male patient diagnosed with MODY13. A noteworthy finding in this case was the occurrence of a "separation phenomenon" between C-peptide and insulin during the standard meal test. Whole exome sequencing (WES) identified a KCNJ11 c.843C > T (p.L281=) mutation in exon 1, which contradicted the previously reported phenotype. Following the onset of ketosis, the patient underwent insulin therapy for a duration of one month, during which the insulin dosage was gradually modified based on blood glucose levels. In order to maintain normoglycemia, he adhered to a diabetic dietary regimen and participated in 1-2 h of moderate exercise daily. Conclusion The study implies that patient with KCNJ11 variant shows a "separation phenomenon" between C-peptide and insulin in standard meal test. Our report also enriched the genotype and phenotype spectrums of MODY13 and highlighted the importance of genetic testing in patients without characteristic clinical symptoms of diabetes.
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Affiliation(s)
- Congli Chen
- Department of Pediatric Endocrinology, Genetic, and Metabolism, National Center for Children's Health, Beijing Children's Hospital of Capital Medical University, Beijing, China
| | - Yurong Piao
- Department of Immunology, National Center for Children's Health, Beijing Children's Hospital of Capital Medical University, Beijing, China
| | - Yanmei Sang
- Department of Pediatric Endocrinology, Genetic, and Metabolism, National Center for Children's Health, Beijing Children's Hospital of Capital Medical University, Beijing, China
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Kumar A, Kumar A, Samadarshi S, Manrai M, Tevatia MS, Dawra S. Unknown presentation of a rare genetic disorder: Monogenic diabetes in young type 4 presenting with hepatic cysts and procoagulant state. Med J Armed Forces India 2023; 79:S297-S300. [PMID: 38144640 PMCID: PMC10746807 DOI: 10.1016/j.mjafi.2021.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 11/06/2021] [Indexed: 11/23/2022] Open
Abstract
Maturity onset diabetes in young (MODY) is the most common form of monogenic diabetes, which characteristically presents in adolescents and young adults. Till date, pathogenic variations involving 14 different genes have been causally implicated with the development of MODY. Maturity onset diabetes in young type 4 (MODY-4) is a very rare form of MODY. We present here case of 28-year-old nonobese male patient with distinct family history of diabetes spanning two generations, incidentally, detected to have a rare form of diabetes on genetic analysis when he presented with recurrent thromboembolic manifestations: deep vein thrombosis and pulmonary thromboembolism. Our case highlights a previously unknown disease association of a rare genetic disorder. Increasing awareness about this genetic disorder and early identification of such cases will enhance our understanding of hitherto unknown disease associations and the pathophysiological role of genetic mutations. This may contribute to the improved treatment and prevention of debilitating diseases such as diabetes.
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Affiliation(s)
- Anupam Kumar
- Senior Advisor (Endocrinology), Command Hospital (Southern Command), Pune, India
| | - Ankit Kumar
- Resident (Medicine), Command Hospital (Southern Command), Pune, India
| | - Samir Samadarshi
- Resident (Medicine), Command Hospital (Southern Command), Pune, India
| | - Manish Manrai
- Professor, Department of Internal Medicine, Armed Forces Medical College, Pune, India
| | | | - Saurabh Dawra
- Classified Specialist (Gastroenterology), Command Hospital (Southern Command), Pune, India
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Aarthy R, Aston-Mourney K, Amutha A, Mikocka-Walus A, Anjana RM, Unnikrishnan R, Jebarani S, Venkatesan U, Gopi S, Radha V, Mohan V. Identification of appropriate biochemical parameters and cut points to detect Maturity Onset Diabetes of Young (MODY) in Asian Indians in a clinic setting. Sci Rep 2023; 13:11408. [PMID: 37452084 PMCID: PMC10349068 DOI: 10.1038/s41598-023-37766-x] [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: 01/30/2023] [Accepted: 06/27/2023] [Indexed: 07/18/2023] Open
Abstract
Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes which is detected by genetic testing. We looked at clinical and biochemcial variables that could help detect possible MODY among Asian Indians with youth-onset diabetes. From the diabetes electronic medical records of a diabetes care centre in Chennai in southern India, demographic, anthropometric, and biochemical details of 34 genetically confirmed MODY participants were extracted. They were compared with patients with type 1 diabetes (T1D) (n = 1011) and type 2 diabetes (T2D) (n = 1605), diagnosed below 30 years of age. Clinical and biochemical variables including body mass index (BMI), glycated hemoglobin, HDL cholesterol, and C-peptide (fasting and stimulated) were analyzed to determine whether cut points could be derived to identify individuals who could be sent for genetic testing to diagnose or rule out MODY in this ethnic group. The age at diagnosis was higher for T2D (26.5 ± 4.0 years) compared to T1D (18.2 ± 6.1 years) and MODY (17.8 ± 6.0 years). Individuals with MODY had BMI, glycated hemoglobin, total cholesterol, triglycerides, HDL cholesterol, and C-peptide levels which were intermediate between T1D and T2D. The identified probable parameters and their cut points to identify cases for MODY genetic screening were BMI 21.2-22.7 kg/m2, glycated hemoglobin 7.2-10%, HDL cholesterol 43-45 mg/dl, fasting C -peptide, 1.2-2.1 ng/ml and stimulated C-peptide, 2.1-4.5 ng/ml. Asian Indians with MODY have clinical features that are intermediate between T1D and T2D and selected biochemical parameters, especially stimulated C peptide cut points were the most useful to diagnose MODY.
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Affiliation(s)
- Ramasamy Aarthy
- Madras Diabetes Research Foundation (ICMR Centre for Advanced Research on Diabetes), Chennai, India
- School of Medicine, IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, Deakin University Geelong, Geelong, Australia
| | - Kathryn Aston-Mourney
- School of Medicine, IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, Deakin University Geelong, Geelong, Australia
| | - Anandakumar Amutha
- Madras Diabetes Research Foundation (ICMR Centre for Advanced Research on Diabetes), Chennai, India
| | | | - Ranjit Mohan Anjana
- Madras Diabetes Research Foundation (ICMR Centre for Advanced Research on Diabetes), Chennai, India
- Dr. Mohan's Diabetes Specialties Centre (IDF Centre of Excellence in Diabetes Care), No 4, Conran Smith Road, Gopalapuram, Chennai, 600086, India
| | - Ranjit Unnikrishnan
- Madras Diabetes Research Foundation (ICMR Centre for Advanced Research on Diabetes), Chennai, India
- Dr. Mohan's Diabetes Specialties Centre (IDF Centre of Excellence in Diabetes Care), No 4, Conran Smith Road, Gopalapuram, Chennai, 600086, India
| | - Saravanan Jebarani
- Madras Diabetes Research Foundation (ICMR Centre for Advanced Research on Diabetes), Chennai, India
| | - Ulagamathesan Venkatesan
- Madras Diabetes Research Foundation (ICMR Centre for Advanced Research on Diabetes), Chennai, India
| | - Sundaramoorthy Gopi
- Madras Diabetes Research Foundation (ICMR Centre for Advanced Research on Diabetes), Chennai, India
| | - Venkatesan Radha
- Madras Diabetes Research Foundation (ICMR Centre for Advanced Research on Diabetes), Chennai, India
| | - Viswanathan Mohan
- Madras Diabetes Research Foundation (ICMR Centre for Advanced Research on Diabetes), Chennai, India.
- Dr. Mohan's Diabetes Specialties Centre (IDF Centre of Excellence in Diabetes Care), No 4, Conran Smith Road, Gopalapuram, Chennai, 600086, India.
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Aarthy R, Aston-Mourney K, Amutha A, Mikocka-Walus A, Anjana RM, Unnikrishnan R, Jebarani S, Venkatesan U, Gopi S, Radha V, Mohan V. Prevalence, clinical features and complications of common forms of Maturity Onset Diabetes of the Young (MODY) seen at a tertiary diabetes centre in south India. Prim Care Diabetes 2023:S1751-9918(23)00071-2. [PMID: 37055265 DOI: 10.1016/j.pcd.2023.04.004] [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: 09/30/2022] [Revised: 03/17/2023] [Accepted: 04/07/2023] [Indexed: 04/15/2023]
Abstract
BACKGROUND Maturity Onset Diabetes of the Young (MODY) is a form of monogenic diabetes caused by mutations in single genes, affecting adolescents or young adults. MODY is frequently misdiagnosed as type 1 diabetes (T1). Though several studies from India have reported on the genetic aspects of MODY, the clinical profile, complications and treatments given have not been reported so far, nor compared with T1D and type 2 diabetes (T2D). AIM To determine the prevalence, clinical features, and complications of common forms of genetically proven MODY seen at a tertiary diabetes centre in South India and compare them with matched individuals with T1D and T2D. METHODS Five hundred and thirty individuals identified as 'possible MODY' based on clinical criteria, underwent genetic testing for MODY. Diagnosis of MODY was confirmed based on pathogenic or likely pathogenic variants found using Genome Aggregation Database (gnomAD) and American College of Medical Genetics (ACMG) criteria. The clinical profile of MODY was compared with individuals with type 1 (T1D) and type 2 (T2D) diabetes, matched for duration of diabetes. Retinopathy was diagnosed by retinal photography; nephropathy by urinary albumin excretion > 30 µg/mg of creatinine and neuropathy by vibration perception threshold > 20 v on biothesiometry. RESULTS Fifty-eight patients were confirmed to have MODY (10.9%). HNF1A-MODY (n = 25) was the most common subtype followed by HNF4A-MODY (n = 11), ABCC8-MODY (n = 11), GCK-MODY (n = 6) and HNF1B-MODY (n = 5). For comparison of clinical profile, only the three 'actionable' subtypes - defined as those who may respond to sulphonylureas, namely, HNF1A, HNF4A and ABCC8-MODY, were included. Age at onset of diabetes was lower among HNF4A-MODY and HNF1A-MODY than ABCC8-MODY, T1D and T2D. Prevalence of retinopathy and nephropathy was higher among the three MODY subtypes taken together (n = 47) as compared to T1D (n = 86) and T2D (n = 86). CONCLUSION This is one of the first reports of MODY subtypes from India based on ACMG and gnomAD criteria. The high prevalence of retinopathy and nephropathy in MODY points to the need for earlier diagnosis and better control of diabetes in individuals with MODY.
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Affiliation(s)
- Ramasamy Aarthy
- Madras Diabetes Research Foundation, Chennai, India; Deakin University, School of Medicine, IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, Geelong, Australia
| | - Kathryn Aston-Mourney
- Deakin University, School of Medicine, IMPACT, Institute for Innovation in Physical and Mental Health and Clinical Translation, Geelong, Australia
| | | | | | - Ranjit Mohan Anjana
- Madras Diabetes Research Foundation, Chennai, India; Dr. Mohan's Diabetes Specialties Centre, Chennai, India
| | - Ranjit Unnikrishnan
- Madras Diabetes Research Foundation, Chennai, India; Dr. Mohan's Diabetes Specialties Centre, Chennai, India
| | | | | | | | | | - Viswanathan Mohan
- Madras Diabetes Research Foundation, Chennai, India; Dr. Mohan's Diabetes Specialties Centre, Chennai, India.
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15
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Abstract
Monogenic diabetes includes several clinical conditions generally characterized by early-onset diabetes, such as neonatal diabetes, maturity-onset diabetes of the young (MODY) and various diabetes-associated syndromes. However, patients with apparent type 2 diabetes mellitus may actually have monogenic diabetes. Indeed, the same monogenic diabetes gene can contribute to different forms of diabetes with early or late onset, depending on the functional impact of the variant, and the same pathogenic variant can produce variable diabetes phenotypes, even in the same family. Monogenic diabetes is mostly caused by impaired function or development of pancreatic islets, with defective insulin secretion in the absence of obesity. The most prevalent form of monogenic diabetes is MODY, which may account for 0.5-5% of patients diagnosed with non-autoimmune diabetes but is probably underdiagnosed owing to insufficient genetic testing. Most patients with neonatal diabetes or MODY have autosomal dominant diabetes. More than 40 subtypes of monogenic diabetes have been identified to date, the most prevalent being deficiencies of GCK and HNF1A. Precision medicine approaches (including specific treatments for hyperglycaemia, monitoring associated extra-pancreatic phenotypes and/or following up clinical trajectories, especially during pregnancy) are available for some forms of monogenic diabetes (including GCK- and HNF1A-diabetes) and increase patients' quality of life. Next-generation sequencing has made genetic diagnosis affordable, enabling effective genomic medicine in monogenic diabetes.
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16
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Zhang N, Zhao H, Li C, Zhang FZ. Novel gene mutation in maturity-onset diabetes of the young: A case report. World J Clin Cases 2023; 11:1099-1105. [PMID: 36874436 PMCID: PMC9979303 DOI: 10.12998/wjcc.v11.i5.1099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2022] [Revised: 12/20/2022] [Accepted: 01/19/2023] [Indexed: 02/14/2023] Open
Abstract
BACKGROUND Maturity-onset diabetes of the young (MODY) is the most common monogenic type of diabetes. Recently, 14 gene mutations have been found to be associated with MODY. In addition, the KLF11 gene mutation is the pathogenic gene of MODY7. To date, the clinical and functional characteristics of the novel KLF11 mutation c. G31A have not yet been reported.
CASE SUMMARY We report of a 30-year-old male patient with a one-year history of nonketosis-prone diabetes and a 3-generation family history of diabetes. The patient was found to carry a KLF11 gene mutation. Therefore, the clinical data of family members were collected and investigated. A total of four members of the family were found to have heterozygous mutations in the KLF11 gene c. G31A, which resulted in a change in the corresponding amino acid p.D11N. Three patients had diabetes mellitus, and one patient had impaired glucose tolerance.
CONCLUSION The heterozygous mutation of the KLF11 gene c.G31A (p. D11N) is a new mutation site of MODY7. Subsequently, the main treatment included dietary interventions and oral drugs.
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Affiliation(s)
- Na Zhang
- Department of Endocrinology, Liaocheng Third People's Hospital, Liaocheng 252000, Shandong Province, China
| | - Hui Zhao
- Department of Endocrinology, Binzhou Central Hospital, Binzhou 251700, Shandong Province, China
| | - Cui Li
- Department of Endocrinology, Liaocheng Third People's Hospital, Liaocheng 252000, Shandong Province, China
| | - Feng-Zhi Zhang
- Department of Endocrinology, Liaocheng Third People's Hospital, Liaocheng 252000, Shandong Province, China
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Greeley SAW, Polak M, Njølstad PR, Barbetti F, Williams R, Castano L, Raile K, Chi DV, Habeb A, Hattersley AT, Codner E. ISPAD Clinical Practice Consensus Guidelines 2022: The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes 2022; 23:1188-1211. [PMID: 36537518 PMCID: PMC10107883 DOI: 10.1111/pedi.13426] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 09/30/2022] [Indexed: 12/24/2022] Open
Affiliation(s)
- Siri Atma W. Greeley
- Section of Pediatric and Adult Endocrinology, Diabetes and Metabolism, Kovler Diabetes Center and Comer Children's HospitalUniversity of Chicago MedicineChicagoIllinoisUSA
| | - Michel Polak
- Hôpital Universitaire Necker‐Enfants MaladesUniversité de Paris Cité, INSERM U1016, Institut IMAGINEParisFrance
| | - Pål R. Njølstad
- Department of Clinical ScienceUniversity of Bergen, and Children and Youth Clinic, Hauk eland University HospitalBergenNorway
| | - Fabrizio Barbetti
- Clinical Laboratory UnitBambino Gesù Children's Hospital, IRCCSRomeItaly
| | - Rachel Williams
- National Severe Insulin Resistance ServiceCambridge University Hospitals NHS TrustCambridgeUK
| | - Luis Castano
- Endocrinology and Diabetes Research Group, Biocruces Bizkaia Health Research InstituteCruces University Hospital, CIBERDEM, CIBERER, Endo‐ERN, UPV/EHUBarakaldoSpain
| | - Klemens Raile
- Department of Paediatric Endocrinology and DiabetologyCharité – UniversitätsmedizinBerlinGermany
| | - Dung Vu Chi
- Center for Endocrinology, Metabolism, Genetics and Molecular Therapy, Departement of Pediatric Endocrinology and DiabetesVietnam National Children's HospitalHanoiVietnam
- Department of Pediatrics and Department of Biology and Medical GeneticsHanoi Medical UniversityHanoiVietnam
| | - Abdelhadi Habeb
- Department of PediatricsPrince Mohamed bin Abdulaziz Hopsital, National Guard Health AffairsMadinahSaudi Arabia
| | - Andrew T. Hattersley
- Institute of Biomedical and Clinical SciencesUniversity of Exeter Medical SchoolExeterUK
| | - Ethel Codner
- Institute of Maternal and Child ResearchSchool of Medicine, University of ChileSantiagoChile
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18
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Libman I, Haynes A, Lyons S, Pradeep P, Rwagasor E, Tung JYL, Jefferies CA, Oram RA, Dabelea D, Craig ME. ISPAD Clinical Practice Consensus Guidelines 2022: Definition, epidemiology, and classification of diabetes in children and adolescents. Pediatr Diabetes 2022; 23:1160-1174. [PMID: 36537527 DOI: 10.1111/pedi.13454] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/09/2022] [Indexed: 12/24/2022] Open
Affiliation(s)
- Ingrid Libman
- Division of Pediatric Endocrinology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Aveni Haynes
- Children's Diabetes Centre, Telethon Kids Institute, Perth, Western Australia, Australia
| | - Sarah Lyons
- Pediatric Diabetes and Endocrinology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | - Praveen Pradeep
- Department of Endocrinology, All India Institute of Medical Sciences, New Delhi, India
| | - Edson Rwagasor
- Rwanda Biomedical Center, Rwanda Ministry of Health, Kigali, Rwanda
| | - Joanna Yuet-Ling Tung
- Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong, Hong Kong
| | - Craig A Jefferies
- Starship Children's Health, Te Whatu Ora Health New Zealand, Auckland, New Zealand
| | - Richard A Oram
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Dana Dabelea
- Department of Epidemiology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Maria E Craig
- The Children's Hospital at Westmead, Sydney, New South Wales (NSW), Australia.,University of Sydney Children's Hospital Westmead Clinical School, Sydney, NEW, Australia.,Discipline of Paediatrics & Child Health, School of Clinical Medicine, University of NSW Medicine & Health, Sydney, NSW, Australia
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Bonner C, Saponaro C. Where to for precision treatment of HNF1A-MODY? Diabetologia 2022; 65:1825-1829. [PMID: 35412067 DOI: 10.1007/s00125-022-05696-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 02/16/2022] [Indexed: 11/03/2022]
Affiliation(s)
- Caroline Bonner
- Inserm, CHU Lille, Institut Pasteur de Lille, University of Lille, Lille, France.
| | - Chiara Saponaro
- Inserm, CHU Lille, Institut Pasteur de Lille, University of Lille, Lille, France
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20
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Tosur M, Philipson LH. Precision diabetes: Lessons learned from maturity-onset diabetes of the young (MODY). J Diabetes Investig 2022; 13:1465-1471. [PMID: 35638342 PMCID: PMC9434589 DOI: 10.1111/jdi.13860] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/20/2022] [Accepted: 05/27/2022] [Indexed: 11/28/2022] Open
Abstract
Maturity-onset of diabetes of the young (MODY) are monogenic forms of diabetes characterized by early onset diabetes with autosomal dominant inheritance. Since its first description about six decades ago, there have been significant advancements in our understanding of MODY from clinical presentations to molecular diagnostics and therapeutic responses. The prevalence of MODY is estimated as at least 1.1-6.5% of the pediatric diabetes population with a high degree of geographic variability that might arise from several factors in the criteria used to ascertain cases. GCK-MODY, HNF1A-MODY, and HNF4A-MODY account for >90% of MODY cases. While some MODY forms do not require treatment (i.e., GCK-MODY), some others are highly responsive to oral agents (i.e., HNF1A-MODY). The risk of micro- and macro-vascular complications of diabetes also differ significantly between MODY forms. Despite its high clinical impact, 50-90% of MODY cases are estimated to be misdiagnosed as type 1 or type 2 diabetes. Although there are many clinical features suggestive of MODY diagnosis, there is no single clinical criterion. An online MODY Risk Calculator can be a useful tool for clinicians in the decision-making process for MODY genetic testing in some situations. Molecular genetic tests with a commercial gene panel should be performed in cases with a suspicion of MODY. Unresolved atypical cases can be further studied by exome or genome sequencing in a clinical or research setting, as available.
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Affiliation(s)
- Mustafa Tosur
- The Division of Diabetes and Endocrinology, Department of Pediatrics, Baylor College of MedicineTexas Children's HospitalHoustonTexasUSA
| | - Louis H Philipson
- Departments of Medicine and Pediatrics, Kovler Diabetes CenterUniversity of ChicagoChicagoIllinoisUSA
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21
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Srinivasan S, Todd J. The Genetics of Type 2 Diabetes in Youth: Where We Are and the Road Ahead. J Pediatr 2022; 247:17-21. [PMID: 35660490 PMCID: PMC9833991 DOI: 10.1016/j.jpeds.2022.05.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 05/24/2022] [Accepted: 05/27/2022] [Indexed: 01/13/2023]
Affiliation(s)
- Shylaja Srinivasan
- Department of Pediatrics, University of California San Francisco, San Francisco, CA.
| | - Jennifer Todd
- Department of Pediatrics, University of Vermont, Burlington, VT
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22
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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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23
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Sampathkumar G, Valiyaparambil PP, Kumar H, Bhavani N, Nair V, Menon U, Menon A, Abraham N, Chapla A, Thomas N. Low genetic confirmation rate in South Indian subjects with a clinical diagnosis of maturity-onset diabetes of the young (MODY) who underwent targeted next-generation sequencing for 13 genes. J Endocrinol Invest 2022; 45:607-615. [PMID: 34741762 DOI: 10.1007/s40618-021-01698-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 10/29/2021] [Indexed: 12/29/2022]
Abstract
PURPOSE To screen for maturity-onset diabetes of the young (MODY) variants in subjects with an early age of onset and positive family history of diabetes mellitus. METHODS 60 subjects with onset of diabetes between 3 and 30 years of age and parental history (onset < 35 years) of diabetes were recruited after excluding autoimmune, pancreatic and syndromic forms of diabetes. Detailed pedigree chart and clinical data were recorded. MODY genetic testing (MODY 1-13) was performed and variant classification was done adhering to the ACMG guidelines. RESULTS Baseline characteristics of subjects were as follows: mean age of onset of diabetes 19.9 ± 7 years, mean duration of diabetes 6.3 ± 6.8 years, BMI 23.3 ± 3 kg/m2 and C-peptide 1.56 ± 1.06 nmol/l. Four out of sixty (6.6%) were positive for variants classifiable as pathogenic/likely pathogenic: one patient with HNF4Ac.691C > T, (p.Arg231Trp), two with HNF 1A c.746C > A(p.Ser249Ter) and c.1340C > T(p.Pro447Leu), and one with ABCC8 c.4544C > T (p.Thr1515Met). MODY 1 and MODY 3 variants were documented in the paediatric age group (< 18 years). CONCLUSION A genetic diagnosis of MODY could be confirmed in only 6.6% (4/60) of patients clinically classifiable as MODY. This is less than that reported in clinically diagnosed MODY subjects of European descent. Newly published population data and more stringent criteria for assessment of pathogenicity and younger age of onset of type 2 diabetes in Indians could have contributed to the lower genetic confirmation rate. Apart from variants in the classical genes (HNF1A, HNF4A), a likely pathogenic variant in a non-classical gene (ABCC8) was noted in this study.
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Affiliation(s)
- G Sampathkumar
- Department of Endocrinology, Amrita Institute of Medical Sciences, Amrita University, Ponnekara P.O, Cochin, 682041, Kerala, India
| | - P P Valiyaparambil
- Department of Endocrinology, Amrita Institute of Medical Sciences, Amrita University, Ponnekara P.O, Cochin, 682041, Kerala, India.
| | - H Kumar
- Department of Endocrinology, Amrita Institute of Medical Sciences, Amrita University, Ponnekara P.O, Cochin, 682041, Kerala, India
| | - N Bhavani
- Department of Endocrinology, Amrita Institute of Medical Sciences, Amrita University, Ponnekara P.O, Cochin, 682041, Kerala, India
| | - V Nair
- Department of Endocrinology, Amrita Institute of Medical Sciences, Amrita University, Ponnekara P.O, Cochin, 682041, Kerala, India
| | - U Menon
- Department of Endocrinology, Amrita Institute of Medical Sciences, Amrita University, Ponnekara P.O, Cochin, 682041, Kerala, India
| | - A Menon
- Department of Endocrinology, Amrita Institute of Medical Sciences, Amrita University, Ponnekara P.O, Cochin, 682041, Kerala, India
| | - N Abraham
- Department of Endocrinology, Amrita Institute of Medical Sciences, Amrita University, Ponnekara P.O, Cochin, 682041, Kerala, India
| | - A Chapla
- Department of Endocrinology, Christian Medical College, Vellore, Tamil Nadu, India
| | - N Thomas
- Department of Endocrinology, Christian Medical College, Vellore, Tamil Nadu, India
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24
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Role of Actionable Genes in Pursuing a True Approach of Precision Medicine in Monogenic Diabetes. Genes (Basel) 2022; 13:genes13010117. [PMID: 35052457 PMCID: PMC8774614 DOI: 10.3390/genes13010117] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/04/2022] [Accepted: 01/05/2022] [Indexed: 12/16/2022] Open
Abstract
Monogenic diabetes is a genetic disorder caused by one or more variations in a single gene. It encompasses a broad spectrum of heterogeneous conditions, including neonatal diabetes, maturity onset diabetes of the young (MODY) and syndromic diabetes, affecting 1-5% of patients with diabetes. Some of these variants are harbored by genes whose altered function can be tackled by specific actions ("actionable genes"). In suspected patients, molecular diagnosis allows the implementation of effective approaches of precision medicine so as to allow individual interventions aimed to prevent, mitigate or delay clinical outcomes. This review will almost exclusively concentrate on the clinical strategy that can be specifically pursued in carriers of mutations in "actionable genes", including ABCC8, KCNJ11, GCK, HNF1A, HNF4A, HNF1B, PPARG, GATA4 and GATA6. For each of them we will provide a short background on what is known about gene function and dysfunction. Then, we will discuss how the identification of their mutations in individuals with this form of diabetes, can be used in daily clinical practice to implement specific monitoring and treatments. We hope this article will help clinical diabetologists carefully consider who of their patients deserves timely genetic testing for monogenic diabetes.
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25
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Karakilic E, Saygili ES, Silan F, Onduc GG, Agcaoglu U. New results for monogenic diabetes with analysis of causative genes using next-generation sequencing: a tertiary centre experience from Turkey. Int J Diabetes Dev Ctries 2021. [DOI: 10.1007/s13410-021-01027-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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26
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Gaál Z, Szűcs Z, Kántor I, Luczay A, Tóth-Heyn P, Benn O, Felszeghy E, Karádi Z, Madar L, Balogh I. A Comprehensive Analysis of Hungarian MODY Patients-Part I: Gene Panel Sequencing Reveals Pathogenic Mutations in HNF1A, HNF1B, HNF4A, ABCC8 and INS Genes. Life (Basel) 2021; 11:life11080755. [PMID: 34440499 PMCID: PMC8399091 DOI: 10.3390/life11080755] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/20/2021] [Accepted: 07/24/2021] [Indexed: 12/13/2022] Open
Abstract
Maturity-onset diabetes of the young (MODY) has about a dozen known causal genes to date, the most common ones being HNF1A, HNF4A, HNF1B and GCK. The phenotype of this clinically and genetically heterogeneous form of diabetes depends on the gene in which the patient has the mutation. We have tested 450 Hungarian index patients with suspected MODY diagnosis with Sanger sequencing and next-generation sequencing and found a roughly 30% positivity rate. More than 70% of disease-causing mutations were found in the GCK gene, about 20% in the HNF1A gene and less than 10% in other MODY-causing genes. We found 8 pathogenic and 9 likely pathogenic mutations in the HNF1A gene in a total of 48 patients and family members. In the case of HNF1A-MODY, the recommended first-line treatment is low dose sulfonylurea but according to our data, the majority of our patients had been on unnecessary insulin therapy at the time of requesting their genetic testing. Our data highlights the importance of genetic testing in the diagnosis of MODY and the establishment of the MODY subtype in order to choose the most appropriate treatment.
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Affiliation(s)
- Zsolt Gaál
- 4th Department of Medicine, Jósa András Teaching Hospital, 4400 Nyíregyháza, Hungary;
| | - Zsuzsanna Szűcs
- Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (Z.S.); (L.M.)
| | - Irén Kántor
- Department of Pediatrics, Jósa András Teaching Hospital, 4400 Nyíregyháza, Hungary;
| | - Andrea Luczay
- 1st Department of Pediatrics, Semmelweis University, 1085 Budapest, Hungary; (A.L.); (P.T.-H.)
| | - Péter Tóth-Heyn
- 1st Department of Pediatrics, Semmelweis University, 1085 Budapest, Hungary; (A.L.); (P.T.-H.)
| | - Orsolya Benn
- Department of Pediatrics, Szent György Hospital of Fejér County, 8000 Székesfehérvár, Hungary; (O.B.); (Z.K.)
| | - Enikő Felszeghy
- Department of Pediatrics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary;
| | - Zsuzsanna Karádi
- Department of Pediatrics, Szent György Hospital of Fejér County, 8000 Székesfehérvár, Hungary; (O.B.); (Z.K.)
| | - László Madar
- Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (Z.S.); (L.M.)
| | - István Balogh
- Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (Z.S.); (L.M.)
- Correspondence:
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Quilichini E, Fabre M, Nord C, Dirami T, Le Marec A, Cereghini S, Pasek RC, Gannon M, Ahlgren U, Haumaitre C. Insights into the etiology and physiopathology of MODY5/HNF1B pancreatic phenotype with a mouse model of the human disease. J Pathol 2021; 254:31-45. [PMID: 33527355 PMCID: PMC8251562 DOI: 10.1002/path.5629] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Revised: 12/18/2020] [Accepted: 01/19/2021] [Indexed: 12/12/2022]
Abstract
Maturity-onset diabetes of the young type 5 (MODY5) is due to heterozygous mutations or deletion of HNF1B. No mouse models are currently available to recapitulate the human MODY5 disease. Here, we investigate the pancreatic phenotype of a unique MODY5 mouse model generated by heterozygous insertion of a human HNF1B splicing mutation at the intron-2 splice donor site in the mouse genome. This Hnf1bsp2/+ model generated with targeted mutation of Hnf1b mimicking the c.544+1G>T (T) mutation identified in humans, results in alternative transcripts and a 38% decrease of native Hnf1b transcript levels. As a clinical feature of MODY5 patients, the hypomorphic mouse model Hnf1bsp2/+ displays glucose intolerance. Whereas Hnf1bsp2/+ isolated islets showed no altered insulin secretion, we found a 65% decrease in pancreatic insulin content associated with a 30% decrease in total large islet volume and a 20% decrease in total β-cell volume. These defects were associated with a 30% decrease in expression of the pro-endocrine gene Neurog3 that we previously identified as a direct target of Hnf1b, showing a developmental etiology. As another clinical feature of MODY5 patients, the Hnf1bsp2/+ pancreases display exocrine dysfunction with hypoplasia. We observed chronic pancreatitis with loss of acinar cells, acinar-to-ductal metaplasia, and lipomatosis, with upregulation of signaling pathways and impaired acinar cell regeneration. This was associated with ductal cell deficiency characterized by shortened primary cilia. Importantly, the Hnf1bsp2/+ mouse model reproduces the pancreatic features of the human MODY5/HNF1B disease, providing a unique in vivo tool for molecular studies of the endocrine and exocrine defects and to advance basic and translational research. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Evans Quilichini
- Centre National de la Recherche Scientifique (CNRS)UMR7622, Institut de Biologie Paris‐Seine (IBPS)ParisFrance
| | - Mélanie Fabre
- Centre National de la Recherche Scientifique (CNRS)UMR7622, Institut de Biologie Paris‐Seine (IBPS)ParisFrance
| | | | - Thassadite Dirami
- Centre National de la Recherche Scientifique (CNRS)UMR7622, Institut de Biologie Paris‐Seine (IBPS)ParisFrance
- Sorbonne UniversitéUMR7622‐IBPSParisFrance
| | - Axelle Le Marec
- Centre National de la Recherche Scientifique (CNRS)UMR7622, Institut de Biologie Paris‐Seine (IBPS)ParisFrance
- Sorbonne UniversitéUMR7622‐IBPSParisFrance
| | - Silvia Cereghini
- Centre National de la Recherche Scientifique (CNRS)UMR7622, Institut de Biologie Paris‐Seine (IBPS)ParisFrance
- Sorbonne UniversitéUMR7622‐IBPSParisFrance
| | - Raymond C Pasek
- Department of MedicineVanderbilt University Medical CenterNashvilleTNUSA
| | - Maureen Gannon
- Department of MedicineVanderbilt University Medical CenterNashvilleTNUSA
| | - Ulf Ahlgren
- Umeå Centre for Molecular MedicineUmeå UniversityUmeåSweden
| | - Cécile Haumaitre
- Centre National de la Recherche Scientifique (CNRS)UMR7622, Institut de Biologie Paris‐Seine (IBPS)ParisFrance
- Sorbonne UniversitéUMR7622‐IBPSParisFrance
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Unnikrishnan R, Radha V, Mohan V. Challenges Involved in Incorporating Personalised Treatment Plan as Routine Care of Patients with Diabetes. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2021; 14:327-333. [PMID: 33758531 PMCID: PMC7981142 DOI: 10.2147/pgpm.s271582] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/24/2020] [Accepted: 02/22/2021] [Indexed: 11/26/2022]
Abstract
Diabetes is a heterogenous disorder, and patients with this disorder vary considerably in their clinical presentation, response to therapy and risk of complications. Expanding knowledge about the pathophysiology of various forms of diabetes has raised the possibility that diagnostic and therapeutic modalities can be tailored to the individual patient in a personalized manner. The recent publication of a Consensus Statement on precision diabetes care underlines the major strides made in this field in the recent past. However, while personalized diabetes care has the potential to significantly improve outcomes in patients with diabetes in a safe and cost-effective manner, its wider application presents several challenges, especially in resource-strained settings. These challenges pertain equally to precision diagnostics, precision therapeutics and precision monitoring. This article discusses some of the important challenges that care providers are likely to face in applying the personalized approach in caring for their patients with diabetes, in the context of diagnosis and management of type 1 diabetes, type 2 diabetes and monogenic forms of diabetes. Suggestions are also presented for overcoming some of these challenges.
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Affiliation(s)
- Ranjit Unnikrishnan
- Department of Diabetology, Dr. Mohan's Diabetes Specialities Centre and Madras Diabetes Research Foundation, Chennai, India
| | - Venkatesan Radha
- Department of Molecular Genetics, Madras Diabetes Research Foundation, Chennai, India
| | - Viswanathan Mohan
- Department of Diabetology, Dr. Mohan's Diabetes Specialities Centre and Madras Diabetes Research Foundation, Chennai, India
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Pollin TI, Taylor SI. YIPF5 mutations cause neonatal diabetes and microcephaly: progress for precision medicine and mechanistic understanding. J Clin Invest 2021; 130:6228-6231. [PMID: 33164987 DOI: 10.1172/jci142364] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Identifying genes that result in monogenic diabetes can provide insights that can build a scientific foundation for precision medicine. At present, nearly 20% of neonatal diabetes cases have unknown causes. In this issue of the JCI, De Franco and Lytrivi et al. sequenced the genome of two probands with a rare neonatal diabetes subtype that also associated with microcephaly and epilepsy. The authors revealed mutations in the YIPF5 gene. YIPF5 resides in the Golgi apparatus and is thought to play a critical role in vesicular trafficking. Notably, disrupting YIPF5 in β cell-based models induced ER stress signaling and resulted in the accumulation of intracellular proinsulin. We believe that utilizing registries and biobanks to reveal other monogenic atypical forms of diabetes is an important approach to gaining insight and suggest that an insulin sensitizer may alleviate ER stress associated with YIPF5 disruption by decreasing the demand for insulin secretion.
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Motyka R, Kołbuc M, Wierzchołowski W, Beck BB, Towpik IE, Zaniew M. Four Cases of Maturity Onset Diabetes of the Young (MODY) Type 5 Associated with Mutations in the Hepatocyte Nuclear Factor 1 Beta (HNF1B) Gene Presenting in a 13-Year-Old Boy and in Adult Men Aged 33, 34, and 35 Years in Poland. AMERICAN JOURNAL OF CASE REPORTS 2021; 22:e928994. [PMID: 33526762 PMCID: PMC7869582 DOI: 10.12659/ajcr.928994] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Case series Patients: Male, 13-year-old • Male, 33-year-old • Male, 34-year-old • Male, 35-year-old Final Diagnosis: HNF1B nephropathy • HNF1B-MODY type 5 Symptoms: Diabetic ketoacidosis • elevated liver enzymes • hyperglycemia • hyperuricemia • hypomagnesemia • positive family history • renal cysts • renal magnesium wasting • weigh loss Medication:— Clinical Procedure: Genetic analysis • islet autoantibodies Specialty: Endocrinology and Metabolic • Nephrology
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Affiliation(s)
- Rafał Motyka
- University of Zielona Góra, Zielona Góra, Poland
| | - Marcin Kołbuc
- Department of Pediatrics, University of Zielona Góra, Zielona Góra, Poland
| | | | - Bodo B Beck
- Institute of Human Genetics and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany
| | - Iwona Ewa Towpik
- Department of Internal Medicine, Univiersity of Zielona Góra, Zielona Góra, Poland
| | - Marcin Zaniew
- Department of Pediatrics, Univiersity of Zielona Góra, Zielona Góra, Poland
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Aarthy R, Aston-Mourney K, Mikocka-Walus A, Radha V, Amutha A, Anjana RM, Unnikrishnan R, Mohan V. Clinical features, complications and treatment of rarer forms of maturity-onset diabetes of the young (MODY) - A review. J Diabetes Complications 2021; 35:107640. [PMID: 32763092 DOI: 10.1016/j.jdiacomp.2020.107640] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/21/2020] [Accepted: 05/21/2020] [Indexed: 12/15/2022]
Abstract
Maturity onset diabetes of the young (MODY) is the most common form of monogenic diabetes and is currently believed to have 14 subtypes. While much is known about the common subtypes of MODY (MODY-1, 2, 3 and 5) little is known about its rare subtypes (MODY4, 6-14). With the advent of next-generation sequencing (NGS) there are several reports of the rarer subtypes of MODY emerging from across the world. Therefore, a greater understanding on these rarer subtypes is needed. A search strategy was created, and common databases were searched, and 51 articles finally selected. INS-(MODY10) and ABCC8-(MODY12) mutations were reported in relatively large numbers compared to the other rare subtypes. The clinical characteristics of the rare MODY subtypes exhibited heterogeneity between families reported with the same mutation. Obesity and diabetic ketoacidosis (DKA) were also reported among rarer MODY subtypes which presents as a challenge as these are not part of the original description of MODY by Tattersal and Fajans. The treatment modalities of the rarer subtypes included oral drugs, predominantly sulfonylureas, insulin but also diet alone. Newer drugs like DPP-4 and SGLT2 inhibitors have also been tried as new modes of treatment. The microvascular and macrovascular complications among the patients with various MODY subtypes are less commonly reported. Recently, there is a view that not all the 14 forms of 'MODY' are true MODY and the very existence of some of these rarer subtypes as MODY has been questioned. This scoping review aims to report on the clinical characteristics, treatment and complications of the rarer MODY subtypes published in the literature.
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Affiliation(s)
- Ramasamy Aarthy
- School of Medicine, Deakin University, Australia; Madras Diabetes Research Foundation, Chennai, India
| | | | | | | | | | - Ranjit Mohan Anjana
- Dr Mohan's Diabetes Specialities Centre, Madras Diabetes Research Foundation, Chennai, India
| | - Ranjit Unnikrishnan
- Dr Mohan's Diabetes Specialities Centre, Madras Diabetes Research Foundation, Chennai, India
| | - Viswanathan Mohan
- Dr Mohan's Diabetes Specialities Centre, Madras Diabetes Research Foundation, Chennai, India.
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Moalla M, Safi W, Babiker Mansour M, Hadj Kacem M, Mahfood M, Abid M, Kammoun T, Hachicha M, Mnif-Feki M, Hadj Kacem F, Hadj Kacem H. Tunisian Maturity-Onset Diabetes of the Young: A Short Review and a New Molecular and Clinical Investigation. Front Endocrinol (Lausanne) 2021; 12:684018. [PMID: 34393998 PMCID: PMC8358796 DOI: 10.3389/fendo.2021.684018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 07/05/2021] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION/AIMS Maturity-Onset Diabetes of the Young (MODY) is a monogenic non-autoimmune diabetes with 14 different genetic forms. MODY-related mutations are rarely found in the Tunisian population. Here, we explored MODY related genes sequences among seventeen unrelated Tunisian probands qualifying the MODY clinical criteria. MATERIALS AND METHODS The GCK and HNF1A genes were systematically analyzed by direct sequencing in all probands. Then, clinical exome sequencing of 4,813 genes was performed on three unrelated patients. Among them, 130 genes have been reported to be involved in the regulation of glucose metabolism, β-cell development, differentiation and function. All identified variants were analyzed according to their frequencies in the GnomAD database and validated by direct sequencing. RESULTS We identified the previously reported GCK mutation (rs1085307455) in one patient. The clinical features of the MODY2 proband were similar to previous reports. In this study, we revealed rare and novel alterations in GCK (rs780806456) and ABCC8 (rs201499958) genes with uncertain significance. We also found two likely benign alterations in HNF1A (rs1800574) and KLF11 (rs35927125) genes with minor allele frequencies similar to those depicted in public databases. No pathogenic variants have been identified through clinical exome analysis. CONCLUSIONS The most appropriate patients were selected, following a strict clinical screening approach, for genetic testing. However, the known MODY1-13 genes could not explain most of the Tunisian MODY cases, suggesting the involvement of unidentified genes in the majority of Tunisian affected families.
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Affiliation(s)
- Mariam Moalla
- Laboratory of Molecular and Cellular Screening Processes, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
| | - Wajdi Safi
- Endocrinology Department, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Maab Babiker Mansour
- Department of Applied Biology, College of Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Mohamed Hadj Kacem
- Laboratory of Molecular and Cellular Screening Processes, Center of Biotechnology of Sfax, University of Sfax, Sfax, Tunisia
| | - Mona Mahfood
- Department of Applied Biology, College of Sciences, University of Sharjah, Sharjah, United Arab Emirates
| | - Mohamed Abid
- Endocrinology Department, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Thouraya Kammoun
- Pediatric Department, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Mongia Hachicha
- Pediatric Department, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Mouna Mnif-Feki
- Endocrinology Department, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Faten Hadj Kacem
- Endocrinology Department, Hedi Chaker University Hospital, Sfax, Tunisia
| | - Hassen Hadj Kacem
- Department of Applied Biology, College of Sciences, University of Sharjah, Sharjah, United Arab Emirates
- *Correspondence: Hassen Hadj Kacem,
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Keskinler MV, Erbakan AN, Oguz A. MODY Probability Ratios in Patients Diagnosed with Type 2 Diabetes Mellitus at a Young Age. Medeni Med J 2020; 35:290-294. [PMID: 33717620 PMCID: PMC7945726 DOI: 10.5222/mmj.2020.56805] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Accepted: 12/07/2020] [Indexed: 11/22/2022] Open
Abstract
Objective Maturity-onset diabetes of the young (MODY) is a non-rare group of monogenic inherited diabetes which is commonly confused with type 1 and type 2 diabetes. Due to high costs of genetic tests that provide a definitive diagnosis, some screening scales are used to identify the high-risk patients. In this study, we aimed to evaluate whether (MODY Probability Calculator [MPC]) which is one of the screening tests will be helpful in identifying our high-risk patients among young patients with type 2 diabetes Method The patients received the diagnosis of type 2 diabetes aged <35 years were included in the study. The anthropometric characteristics of the patients, the treatments they received at the time of diagnosis, and the current treatments were recorded by retrospectively scanning patient files.The patients with the diagnosis of type 1 diabetes having autoantibodies to the pancreas were excluded from the study. The probability of MODY was calculated using MPC.. Results The mean age of 72 patients (40% female) was 41.5±7.2 years. Eighteen of the patients (25%) were using insulin at the time of diagnosis. The mean HbA1c was 8.6±2.2% and C-peptide was 2.35±1.52 ng/ml. The mean MODY positive predictive score calculated by MPC for risk of MODY was 11.23 percent. There were 61 patients (84.7%) with a risk of ≤20%, 9 patients (12.5%) with a risk of 20-50%, and 2 patients (2.8%) with ≥50%. In the group with MODY PPV score >20%, the age of onset of diabetes and the body mass index was significantly lower than the others (p<0.05, for both). There was no significant difference between current treatments of both groups. Conclusion It has been reported that MODY risk calculated by MPC may yield different results in different populations. The results of this study showed that 15% of our young-onset diabetes patients had an MPC score above 20 percent. Requesting MODY genetic tests in this 15% of the patient group can be presented as a practical suggestion.
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Affiliation(s)
- Mirac Vural Keskinler
- Istanbul Medeniyet University, Faculty of Medicine, Department of Internal Medicine, Istanbul, Turkey
| | - Ayse Naciye Erbakan
- Istanbul Medeniyet University, Faculty of Medicine, Department of Internal Medicine, Istanbul, Turkey
| | - Aytekin Oguz
- Istanbul Medeniyet University, Faculty of Medicine, Department of Internal Medicine, Istanbul, Turkey
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Trischitta V, Prudente S, Doria A. Disentangling the heterogeneity of adulthood-onset non-autoimmune diabetes: a little closer but lot more to do. Curr Opin Pharmacol 2020; 55:157-164. [PMID: 33271410 DOI: 10.1016/j.coph.2020.10.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 10/13/2020] [Accepted: 10/26/2020] [Indexed: 12/13/2022]
Abstract
Diabetes diagnosed in adults is a highly heterogeneous disorder. It mostly consists of what is referred to as type 2 diabetes but also comprises other entities (i.e. different diseases), including latent autoimmune diabetes, late onset forms of monogenic diabetes and familial diabetes of the adulthood, which has recently been the source of new diabetogenes discovery. Notably, type 2 diabetes is itself heterogeneous as it includes subtypes with onset at the extremes of age and/or weight distributions characterized by different degree of hyperglycemia and cardiovascular risk as compared to common forms of type 2 diabetes occurring in middle-aged, overweight/obese individuals. Understanding whether these are different presentations of one, highly heterogeneous disease or separate nosological entities with different clinical trajectories and requiring different treatments is essential to effectively pursue the path of precision medicine.
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Affiliation(s)
- Vincenzo Trischitta
- Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy; Department of Experimental Medicine, Sapienza University, Rome, Italy.
| | - Sabrina Prudente
- Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Alessandro Doria
- Research Division, Joslin Diabetes Center, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA.
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The epidemiology, molecular pathogenesis, diagnosis, and treatment of maturity-onset diabetes of the young (MODY). Clin Diabetes Endocrinol 2020; 6:20. [PMID: 33292863 PMCID: PMC7640483 DOI: 10.1186/s40842-020-00112-5] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 10/26/2020] [Indexed: 12/18/2022] Open
Abstract
Background The most common type of monogenic diabetes is maturity-onset diabetes of the young (MODY), a clinically and genetically heterogeneous group of endocrine disorders that affect 1–5% of all patients with diabetes mellitus. MODY is characterized by autosomal dominant inheritance but de novo mutations have been reported. Clinical features of MODY include young-onset hyperglycemia, evidence of residual pancreatic function, and lack of beta cell autoimmunity or insulin resistance. Glucose-lowering medications are the main treatment options for MODY. The growing recognition of the clinical and public health significance of MODY by clinicians, researchers, and governments may lead to improved screening and diagnostic practices. Consequently, this review article aims to discuss the epidemiology, pathogenesis, diagnosis, and treatment of MODY based on relevant literature published from 1975 to 2020. Main body The estimated prevalence of MODY from European cohorts is 1 per 10,000 in adults and 1 per 23,000 in children. Since little is known about the prevalence of MODY in African, Asian, South American, and Middle Eastern populations, further research in non-European cohorts is needed to help elucidate MODY’s exact prevalence. Currently, 14 distinct subtypes of MODY can be diagnosed through clinical assessment and genetic analysis. Various genetic mutations and disease mechanisms contribute to the pathogenesis of MODY. Management of MODY is subtype-specific and includes diet, oral antidiabetic drugs, or insulin. Conclusions Incidence and prevalence estimates for MODY are derived from epidemiologic studies of young people with diabetes who live in Europe, Australia, and North America. Mechanisms involved in the pathogenesis of MODY include defective transcriptional regulation, abnormal metabolic enzymes, protein misfolding, dysfunctional ion channels, or impaired signal transduction. Clinicians should understand the epidemiology and pathogenesis of MODY because such knowledge is crucial for accurate diagnosis, individualized patient management, and screening of family members.
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Ang SF, Tan CSH, Chan LWT, Goh LX, Kon WYC, Lian JX, Subramanium T, Sum CF, Lim SC. Clinical experience from a regional monogenic diabetes referral centre in Singapore. Diabetes Res Clin Pract 2020; 168:108390. [PMID: 32858097 DOI: 10.1016/j.diabres.2020.108390] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 07/06/2020] [Accepted: 08/19/2020] [Indexed: 11/30/2022]
Abstract
AIMS Monogenic diabetes (also known as maturity-onset diabetes of the young or MODY) affects a subset of individuals with young-onset diabetes. We report our diagnostic work-up experience for such individuals. METHODS Serving as a regional secondary-care diabetes centre in a multi-ethnic population, we receive referrals to evaluate MODY from endocrinologists in both public and private practice. Key criteria for consideration of genetic-testing are onset age ≤ 35, negative GAD antibody, no history of diabetic ketoacidosis, strong family history of diabetes and BMI < 32.5 kg/m2. A monogenic diabetes registry was set up since 2017 to study their disease trajectories. RESULTS We identified 30 out of 175 (17.1%) individuals with likely pathogenic/pathogenic variants. Importantly, 29 out of 30 (96.7%) occurred in clinically actionable genes. A continuous scale combining BMI, hs-CRP and HDL provided 80% (P < 0.001) diagnostic accuracy for MODY in our cohort, achieving a negative predictive value of 0.93 and sensitivity at 0.76. Subtyping MODY prior to genetic testing (if desired) will require specialist domain knowledge and additional biomarkers due to its genetic heterogeneity. CONCLUSIONS Through systematic and structured evaluation, the prevalence of MODY is non-trivial (17.1%) in a referral centre. Diagnostic algorithm combining clinical criteria and readily available biomarkers can support clinical decision for MODY genetic testing.
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Affiliation(s)
- Su Fen Ang
- Clinical Research Unit, Khoo Teck Puat Hospital (KTPH), Singapore
| | - Clara S H Tan
- Clinical Research Unit, Khoo Teck Puat Hospital (KTPH), Singapore
| | - Lovynn W T Chan
- Clinical Research Unit, Khoo Teck Puat Hospital (KTPH), Singapore
| | - Li Xian Goh
- Clinical Research Unit, Khoo Teck Puat Hospital (KTPH), Singapore
| | - Winston Y C Kon
- Department of Endocrinology, Tan Tock Seng Hospital (TTSH), Singapore
| | - Joyce X Lian
- Department of Endocrinology, Tan Tock Seng Hospital (TTSH), Singapore
| | | | - Chee Fang Sum
- Diabetes Centre, Admiralty Medical Centre (AdMC), Singapore
| | - Su Chi Lim
- Clinical Research Unit, Khoo Teck Puat Hospital (KTPH), Singapore; Diabetes Centre, Admiralty Medical Centre (AdMC), Singapore; Saw Swee Hock School of Public Health, National University of Singapore (NUS), Singapore.
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Khunti K, Hassanein M, Lee MK, Mohan V, Amod A. Role of Gliclazide MR in the Management of Type 2 Diabetes: Report of a Symposium on Real-World Evidence and New Perspectives. Diabetes Ther 2020; 11:33-48. [PMID: 32440835 PMCID: PMC7415040 DOI: 10.1007/s13300-020-00833-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Indexed: 12/12/2022] Open
Abstract
In patients with type 2 diabetes mellitus (T2DM) who require additional glucose-lowering on top of first-line metformin monotherapy, sulfonylureas are the most common choice for second-line therapy followed by dipeptidyl peptidase inhibitors (DPP-4i). This article summarises presentations at a symposium entitled "Real-World Evidence and New Perspectives with Gliclazide MR" held at the International Diabetes Federation Congress in Busan, South Korea on 4 December 2019. Although guideline recommendations vary between countries, the guidelines with the highest quality ratings include sulfonylureas as one of the preferred choices as second-line therapy for T2DM. Data from randomised controlled trials (RCTs) have consistently demonstrated that sulfonylureas are effective glucose-lowering agents and that the risk of severe hypoglycaemia with these agents is low. In addition, both RCTs and real-world observational studies have shown no increased risk of mortality or cardiovascular disease with the use of newer-generation sulfonylureas compared with other classes of glucose-lowering treatments. However, differences between sulfonylureas do exist, with gliclazide being associated with a significantly lower risk of mortality or cardiovascular mortality compared with glibenclamide, as well as the lowest incidence of severe hypoglycaemia compared with other agents in this class. Recent real-world studies into the effectiveness and safety of gliclazide appear to confirm these findings, and publication of new data from these studies in patients with T2DM in the UK, and in Muslim patients who are fasting during Ramadan, are awaited with interest. Another study being undertaken with gliclazide is a pan-India study in patients with maturity-onset diabetes of the young (MODY) subtypes 1, 3 and 12. Patients with these MODY subtypes respond particularly well to sulfonylurea treatment, and sulfonylureas are the first-line agents of choice in these patients. These new and ongoing studies will add to the cumulative data on the efficacy and safety of certain sulfonylureas in patients with diabetes.
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Affiliation(s)
- Kamlesh Khunti
- Diabetes Research Centre, University of Leicester, Leicester, UK
| | - Mohamed Hassanein
- Department of Endocrinology, Dubai Hospital, Dubai, United Arab Emirates
| | - Moon-Kyu Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Soonchunhyang University Gumi Hospital-Soonchunhyang University School of Medicine, Gumi, Kyungsangbuk-do, 39371, South Korea
| | | | - Aslam Amod
- Life Chatsmed Garden Hospital and Nelson R. Mandela School of Medicine, Durban, South Africa
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Sarmadi A, Mohammadi A, Tabatabaei F, Nouri Z, Chaleshtori MH, Tabatabaiefar MA. Molecular Genetic Study in a Cohort of Iranian Families Suspected to Maturity-Onset Diabetes of the Young, Reveals a Recurrent Mutation and a High-Risk Variant in the CEL Gene. Adv Biomed Res 2020; 9:25. [PMID: 33072637 PMCID: PMC7532821 DOI: 10.4103/abr.abr_18_20] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 03/01/2020] [Accepted: 04/07/2020] [Indexed: 01/14/2023] Open
Abstract
Background Diabetes mellitus (DM) is a group of metabolic disorders in the body, accompanied with increasing blood sugar levels. Diabetes is classified into three groups: Type 1 DM (T1DM), Type 2 DM (T2DM), and monogenic diabetes. Maturity-onset diabetes of the young (MODY) is a monogenic diabetes that is frequently mistaken for T1D or T2D. The aim of this study was to diagnose MODY and its subtype frequency in a diabetic population in Iran. Materials and Methods In this study among ten diabetic families that were highly suspected to MODY by nongenetic biomarkers and without any pathogenic mutation in GCK and HNF1A genes, two patients from two unrelated families were examined via whole-exome sequencing (WES) in order to detect the causative gene of diabetes. Co-segregation analysis of the identified variant was performed using Sanger sequencing. Results In this study, no pathogenic variant was found in GCK and HNF1A genes (MODY2 and MODY3), while these two types of MODY were introduced as the most frequent in other studies. By using WES, a pathogenic variant (p.I488T) was found in one of the patients in CEL gene causing MODY8 that its frequency is very rare in other studied populations. A high-risk variant associated with diabetes was found in another patient. Conclusion WES was applied in this study to reveal the cause of MODY in 1 family. This pathogenic mutation was previously reported as a disease causing mutation.
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Affiliation(s)
- Akram Sarmadi
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Aliasgar Mohammadi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fatemeh Tabatabaei
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Science, Isfahan, Iran
| | - Zahra Nouri
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Morteza Hashemzadeh Chaleshtori
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mohammad Amin Tabatabaiefar
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.,Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
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Arslanian S, El ghormli L, Haymond MH, Chan CL, Chernausek SD, Gandica RG, Gubitosi-Klug R, Levitsky LL, Siska M, Willi SM. Beta cell function and insulin sensitivity in obese youth with maturity onset diabetes of youth mutations vs type 2 diabetes in TODAY: Longitudinal observations and glycemic failure. Pediatr Diabetes 2020; 21:575-585. [PMID: 32064729 PMCID: PMC7654712 DOI: 10.1111/pedi.12998] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 01/22/2020] [Accepted: 01/29/2020] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE In treatment options for type 2 diabetes in adolescents and youth (TODAY), 4.5% of obese youth clinically diagnosed with type 2 diabetes (T2D) had genetic variants consistent with maturity onset diabetes of youth (MODY) diagnosis. The course of IS and β-cell function in obese youth with MODY remains unknown. In this secondary analysis, we examined IS and β-cell function in MODY vs. non-MODY obese youth at randomization and over time. METHODS Genetic data in TODAY included 426 non-MODY (T2D) and 22 MODY youth (7 glucokinase MODY mutation positive [GCK-MODY], 12 hepatocyte nuclear factor MODY mutation positive [HNF-MODY], 2 Insulin gene mutation [insulin (INS)-MODY], and 1 Kruppel-like factor 11 [KLF11-MODY]). Oral glucose tolerance test (OGTT)-derived IS, C-peptide index, and β-cell function relative to IS oral disposition index (oDI) was measured at randomization, and over 24 months in addition to total and high-molecular-weight adiponectin (HMWA). RESULTS At randomization, IS, total adiponectin, and HMWA were significantly higher in the two MODY groups than in non-MODY. β-cell function measured by C-peptide oDI was 3-fold higher in GCK-MODY than in HNF-MODY and 1.5-fold higher than non-MODY (P for both <.05). Glycemic failure rate was 75.0% in HNF-MODY, 46.9% in non-MODY, and zero in GCK-MODY youth. While the changes in IS and oDI were not different among the three groups in the first 6 months, IS improved from 6 to 24 months in HNF-MODY vs GCK-MODY youth. CONCLUSIONS In TODAY, β-cell function at randomization was worse in obese HNF-MODY youth compared with GCK-MODY youth, while insulin sensitivity was worse in non-MODY compared with the other two MODY groups. Over time, IS showed the greatest improvement in HNF-MODY youth. This raises the possibility that TODAY therapeutic modalities of insulin sensitization in these obese HNF-MODY youth may have played a beneficial role.
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Affiliation(s)
- Silva Arslanian
- UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Laure El ghormli
- George Washington University Biostatistics Center, Rockville, Maryland
| | | | | | | | | | | | | | | | - Steven M. Willi
- Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
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DSM-III criteria for affective disorders and schizophrenia : A preliminary appraisal using family interview findings. ACTA ACUST UNITED AC 2020. [DOI: 10.1017/s0767399x00001723] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
SummaryWe performed a blind family interview study of 226 first-degree relatives of 63 probands meeting DSM-III criteria for schizophrenia, schizoaffective disorder, and bipolar disorder, as diagnosed by the National Institute ot Mental Health Diagnostic Interview Schedule (DIS). A small test-retest reliability study demonstrated good agreement between the proband interviewer and the principal family interviewer for the major diagnostic categories of psychotic disorders. Excellent compliance was obtained, with 85% of living relatives interviewed personally.Three principal findings emerged front the study. First, as expected, bipolar disorder, as defined by DSM-III, displayed a strong familial comportent, comparable to that found by many studies using criteria other than those of DSM-III. Second, patients meeting DSM-III criteria for schizophrenia and schizoaffective disorder displayed a low familial prevalence of schizophrenia. Although initially suprising, this finding is in agreement with the results of several other recent lantily studies of schizophrenia. Upon comparing our results with those of other recent family studies of schizophrenia, it appears that the familial component in schizophrenia tnay be less than was estimated by earlier studies using older and “broader” definitions of schizophrenia.Third, we found that patients meeting DSM-III criteria for schizophrenia appeared genetically heterogeneous. Those who had displayed a superimposed full affective syndrome at some tinte in the course of their illness, together with those probands meeting DSM-III criteria for schizoaffective disorder, displayed a high familial prevalence of major affective disorder, similar to that found in the families of the bipolar probands. On the other hand, “pure” DSM-III schizophrenie probands, who had never experienced a superimposed full affective syndrome, displayed a low familial prevalence of major affective disorder, similar to that found in the general population. These findings favor the possibility that probands meeting DSM-III criteria for schizophrenia, but displaying a superimposed full affective syndrome, may in sonie cases have a disorder genetically relatcd to major affective disorder.Further prospective family interview studies, using DSM-III criteria and larger samples, will be necessary to test these preliminary impressions.
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Malikova J, Kaci A, Dusatkova P, Aukrust I, Torsvik J, Vesela K, Kankova PD, Njølstad PR, Pruhova S, Bjørkhaug L. Functional Analyses of HNF1A-MODY Variants Refine the Interpretation of Identified Sequence Variants. J Clin Endocrinol Metab 2020; 105:5722353. [PMID: 32017842 DOI: 10.1210/clinem/dgaa051] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2020] [Accepted: 02/03/2020] [Indexed: 12/14/2022]
Abstract
CONTEXT While rare variants of the hepatocyte nuclear factor-1 alpha (HNF1A) gene can cause maturity-onset diabetes of the young (HNF1A-MODY), other variants can be risk factors for the development of type 2 diabetes. As has been suggested by the American College of Medical Genetics (ACMG) guidelines for variant interpretation, functional studies provide strong evidence to classify a variant as pathogenic. OBJECTIVE We hypothesized that a functional evaluation can improve the interpretation of the HNF1A variants in our Czech MODY Registry. DESIGN, SETTINGS, AND PARTICIPANTS We studied 17 HNF1A variants that were identified in 48 individuals (33 female/15 male) from 20 Czech families with diabetes, using bioinformatics in silico tools and functional protein analyses (transactivation, protein expression, DNA binding, and nuclear localization). RESULTS Of the 17 variants, 12 variants (p.Lys120Glu, p.Gln130Glu, p.Arg131Pro, p.Leu139Pro, p.Met154Ile, p.Gln170Ter, p.Glu187SerfsTer40, p.Phe215SerfsTer18, p.Gly253Arg, p.Leu383ArgfsTer3, p.Gly437Val, and p.Thr563HisfsTer85) exhibited significantly reduced transcriptional activity or DNA binding (< 40%) and were classified as (likely) pathogenic, 2/17 variants were (likely) benign and 3/17 remained of uncertain significance. Functional analyses allowed for the reclassification of 10/17 variants (59%). Diabetes treatment was improved in 20/29 (69%) carriers of (likely) pathogenic HNF1A variants. CONCLUSION Functional evaluation of the HNF1A variants is necessary to better predict the pathogenic effects and to improve the diagnostic interpretation and treatment, particularly in cases where the cosegregation or family history data are not available or where the phenotype is more diverse and overlaps with other types of diabetes.
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Affiliation(s)
- Jana Malikova
- Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
| | - Alba Kaci
- KG Jebsen Center for Diabetes Research, Department of Clinical Science, Bergen, Norway
- Department of Pediatrics and Adolescents, Haukeland University Hospital, Bergen, Norway
| | - Petra Dusatkova
- Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
| | - Ingvild Aukrust
- KG Jebsen Center for Diabetes Research, Department of Clinical Science, Bergen, Norway
- Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
| | - Janniche Torsvik
- KG Jebsen Center for Diabetes Research, Department of Clinical Science, Bergen, Norway
- Department of Pediatrics and Adolescents, Haukeland University Hospital, Bergen, Norway
| | - Klara Vesela
- Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
| | - Pavla Dvorakova Kankova
- Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
| | - Pål R Njølstad
- KG Jebsen Center for Diabetes Research, Department of Clinical Science, Bergen, Norway
- Department of Pediatrics and Adolescents, Haukeland University Hospital, Bergen, Norway
| | - Stepanka Pruhova
- Department of Pediatrics, Charles University in Prague, Second Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
| | - Lise Bjørkhaug
- Department of Safety, Chemistry and Biomedical Laboratory Sciences, Western Norway University of Applied Sciences, Bergen, Norway
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Human Physiology of Genetic Defects Causing Beta-cell Dysfunction. J Mol Biol 2020; 432:1579-1598. [PMID: 31953147 DOI: 10.1016/j.jmb.2019.12.038] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 12/17/2019] [Accepted: 12/18/2019] [Indexed: 02/07/2023]
Abstract
The last decade has revealed hundreds of genetic variants associated with type 2 diabetes, many especially with insulin secretion. However, the evidence for their single or combined effect on beta-cell function relies mostly on genetic association of the variants or genetic risk scores with simple traits, and few have been functionally fully characterized even in cell or animal models. Translating the measured traits into human physiology is not straightforward: none of the various indices for beta-cell function or insulin sensitivity recapitulates the dynamic interplay between glucose sensing, endogenous glucose production, insulin production and secretion, insulin clearance, insulin resistance-to name just a few factors. Because insulin sensitivity is a major determinant of physiological need of insulin, insulin secretion should be evaluated in parallel with insulin sensitivity. On the other hand, multiple physiological or pathogenic processes can either mask or unmask subtle defects in beta-cell function. Even in monogenic diabetes, a clearly pathogenic genetic variant can result in different phenotypic characteristics-or no phenotype at all. In this review, we evaluate the methods available for studying beta-cell function in humans, critically examine the evidence linking some identified variants to a specific beta-cell phenotype, and highlight areas requiring further study.
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Rengaraj S, Thiyagalingam S, Kathirvel V, Delhikumar CG. Raised blood glucose due to heterozygous glucokinase gene mutation (GCK-MODY) diagnosed for the first time in pregnancy: The dilemmas and successful management - Case report and review of literature. Obstet Med 2020; 14:53-56. [PMID: 33995576 DOI: 10.1177/1753495x19874573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2019] [Revised: 07/12/2019] [Accepted: 08/15/2019] [Indexed: 11/16/2022] Open
Abstract
Glucokinase mutation (GCK-MODY) is frequently misdiagnosed as either type I or type II diabetes mellitus, especially if presented for the first time during pregnancy. Generally GCK-MODY affects 1-2% of individuals with a diagnosis of diabetes. The defect in the glucose sensing mechanism in GCK-MODY results in a higher set point for maintenance of glucose homeostasis. Treatment is not recommended outside the pregnancy; however, in pregnancy, fetal abdominal circumference helps to decide about the likelihood of the fetus having inherited the condition and therefore whether insulin is required in pregnancy. We present a case in which GCK-MODY was diagnosed for the first time after pregnancy; the subsequent pregnancy was uneventful. Genetic testing is mandatory to establish the diagnosis. Here the implications of MODY and its subtypes, along with the pattern of inheritance and management aspects are discussed.
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Affiliation(s)
| | | | - Vimala Kathirvel
- Department of Obstetrics and Gynaecology, JIPMER, Puducherry, India
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Zhong L, Zhao Z, Hu Q, Li Y, Zhao W, Li C, Xu Y, Rong R, Zhang J, Zhang Z, Li N, Liu Z. Identification of Maturity-Onset Diabetes of the Young Caused by Mutation in FOXM1 via Whole-Exome Sequencing in Northern China. Front Endocrinol (Lausanne) 2020; 11:534362. [PMID: 33633681 PMCID: PMC7900535 DOI: 10.3389/fendo.2020.534362] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Accepted: 11/27/2020] [Indexed: 12/30/2022] Open
Abstract
Diabetes mellitus is a highly heterogeneous disorder encompassing different types with particular clinical manifestations, while maturity-onset diabetes of the young (MODY) is an early-onset monogenenic diabetes. Most genetic predisposition of MODY has been identified in European and American populations. A large number of Chinese individuals are misdiagnosed due to defects of unknown genes. In this study, we analyzed the genetic and clinical characteristics of the Northern China. A total of 200 diabetic patients, including 10 suspected MODY subjects, were enrolled, and the mutational analysis of monogenic genes was performed by whole-exome sequencing and confirmed by familial information and Sanger sequencing. We found that clinical features and genetic characteristics have varied widely between MODY and other diabetic subjects in Northern China. FOXM1, a key molecule in the proliferation of pancreatic β-cells, has a rare mutation rs535471991, which leads to instability within the phosphorylated domain that impairs its function. Our findings indicate that FOXM1 may play a critical role in MODY, which could reduce the misdiagnose rate and provide promising therapy for MODY patients.
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Affiliation(s)
- Liang Zhong
- The Shijiazhuang Second Hospital, Shijiazhuang, China
- Hebei Provincial Key Laboratory of Basic Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
- Shijiazhuang Technology Innovation Center of Precision Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
| | - Zengyi Zhao
- The Shijiazhuang Second Hospital, Shijiazhuang, China
- Hebei Provincial Key Laboratory of Basic Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
| | - Qingshan Hu
- The Shijiazhuang Second Hospital, Shijiazhuang, China
- Hebei Provincial Key Laboratory of Basic Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
| | - Yang Li
- The Shijiazhuang Second Hospital, Shijiazhuang, China
- Hebei Provincial Key Laboratory of Basic Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
- Shijiazhuang Technology Innovation Center of Precision Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
| | - Weili Zhao
- The Shijiazhuang Second Hospital, Shijiazhuang, China
- Hebei Provincial Key Laboratory of Basic Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
- Shijiazhuang Technology Innovation Center of Precision Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
| | - Chuang Li
- The Shijiazhuang Second Hospital, Shijiazhuang, China
- Hebei Provincial Key Laboratory of Basic Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
| | - Yunqiang Xu
- The Shijiazhuang Second Hospital, Shijiazhuang, China
| | - Ruijuan Rong
- The Shijiazhuang Second Hospital, Shijiazhuang, China
- Hebei Provincial Key Laboratory of Basic Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
- Shijiazhuang Technology Innovation Center of Precision Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
| | - Jing Zhang
- The Shijiazhuang Second Hospital, Shijiazhuang, China
- Hebei Provincial Key Laboratory of Basic Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
- Shijiazhuang Technology Innovation Center of Precision Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
| | - Zifeng Zhang
- The Shijiazhuang Second Hospital, Shijiazhuang, China
- Hebei Provincial Key Laboratory of Basic Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
- Shijiazhuang Technology Innovation Center of Precision Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
| | - Nan Li
- The Shijiazhuang Second Hospital, Shijiazhuang, China
- Hebei Provincial Key Laboratory of Basic Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
- Shijiazhuang Technology Innovation Center of Precision Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
| | - Zanchao Liu
- The Shijiazhuang Second Hospital, Shijiazhuang, China
- Hebei Provincial Key Laboratory of Basic Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
- Shijiazhuang Technology Innovation Center of Precision Medicine for Diabetes, The Shijiazhuang Second Hospital, Shijiazhuang, China
- *Correspondence: Zanchao Liu,
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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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GoodSmith MS, Skandari MR, Huang ES, Naylor RN. The Impact of Biomarker Screening and Cascade Genetic Testing on the Cost-Effectiveness of MODY Genetic Testing. Diabetes Care 2019; 42:2247-2255. [PMID: 31558549 PMCID: PMC6868460 DOI: 10.2337/dc19-0486] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2019] [Accepted: 09/10/2019] [Indexed: 02/03/2023]
Abstract
OBJECTIVE In the U.S., genetic testing for maturity-onset diabetes of the young (MODY) is frequently delayed because of difficulty with insurance coverage. Understanding the economic implications of clinical genetic testing is imperative to advance precision medicine for diabetes. The objective of this article is to assess the cost-effectiveness of genetic testing, preceded by biomarker screening and followed by cascade genetic testing of first-degree relatives, for subtypes of MODY in U.S. pediatric patients with diabetes. RESEARCH DESIGN AND METHODS We used simulation models of distinct forms of diabetes to forecast the clinical and economic consequences of a systematic genetic testing strategy compared with usual care over a 30-year time horizon. In the genetic testing arm, patients with MODY received treatment changes (sulfonylureas for HNF1A- and HNF4A-MODY associated with a 1.0% reduction in HbA1c; no treatment for GCK-MODY). Study outcomes included costs, life expectancy (LE), and quality-adjusted life years (QALY). RESULTS The strategy of biomarker screening and genetic testing was cost-saving as it increased average quality of life (+0.0052 QALY) and decreased costs (-$191) per simulated patient relative to the control arm. Adding cascade genetic testing increased quality-of-life benefits (+0.0081 QALY) and lowered costs further (-$735). CONCLUSIONS A combined strategy of biomarker screening and genetic testing for MODY in the U.S. pediatric diabetes population is cost-saving compared with usual care, and the addition of cascade genetic testing accentuates the strategy's benefits. Widespread implementation of this strategy could improve the lives of patients with MODY while saving the health system money, illustrating the potential population health benefits of personalized medicine.
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Affiliation(s)
| | - M Reza Skandari
- Imperial College Business School, Imperial College London, London, U.K
| | - Elbert S Huang
- Section of General Internal Medicine, University of Chicago, Chicago, IL
| | - Rochelle N Naylor
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, IL
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Glotov OS, Serebryakova EA, Turkunova ME, Efimova OA, Glotov AS, Barbitoff YA, Nasykhova YA, Predeus AV, Polev DE, Fedyakov MA, Polyakova IV, Ivashchenko TE, Shved NY, Shabanova ES, Tiselko AV, Romanova OV, Sarana AM, Pendina AA, Scherbak SG, Musina EV, Petrovskaia-Kaminskaia AV, Lonishin LR, Ditkovskaya LV, Zhelenina LА, Tyrtova LV, Berseneva OS, Skitchenko RK, Suspitsin EN, Bashnina EB, Baranov VS. Whole‑exome sequencing in Russian children with non‑type 1 diabetes mellitus reveals a wide spectrum of genetic variants in MODY‑related and unrelated genes. Mol Med Rep 2019; 20:4905-4914. [PMID: 31638168 PMCID: PMC6854535 DOI: 10.3892/mmr.2019.10751] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Accepted: 08/28/2019] [Indexed: 12/13/2022] Open
Abstract
The present study reports on the frequency and the spectrum of genetic variants causative of monogenic diabetes in Russian children with non-type 1 diabetes mellitus. The present study included 60 unrelated Russian children with non-type 1 diabetes mellitus diagnosed before the age of 18 years. Genetic variants were screened using whole-exome sequencing (WES) in a panel of 35 genes causative of maturity onset diabetes of the young (MODY) and transient or permanent neonatal diabetes. Verification of the WES results was performed using PCR-direct sequencing. A total of 38 genetic variants were identified in 33 out of 60 patients (55%). The majority of patients (27/33, 81.8%) had variants in MODY-related genes: GCK (n=19), HNF1A (n=2), PAX4 (n=1), ABCC8 (n=1), KCNJ11 (n=1), GCK+HNF1A (n=1), GCK+BLK (n=1) and GCK+BLK+WFS1 (n=1). A total of 6 patients (6/33, 18.2%) had variants in MODY-unrelated genes: GATA6 (n=1), WFS1 (n=3), EIF2AK3 (n=1) and SLC19A2 (n=1). A total of 15 out of 38 variants were novel, including GCK, HNF1A, BLK, WFS1, EIF2AK3 and SLC19A2. To summarize, the present study demonstrates a high frequency and a wide spectrum of genetic variants causative of monogenic diabetes in Russian children with non-type 1 diabetes mellitus. The spectrum includes previously known and novel variants in MODY-related and unrelated genes, with multiple variants in a number of patients. The prevalence of GCK variants indicates that diagnostics of monogenic diabetes in Russian children may begin with testing for MODY2. However, the remaining variants are present at low frequencies in 9 different genes, altogether amounting to ~50% of the cases and highlighting the efficiency of using WES in non-GCK-MODY cases.
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Affiliation(s)
- Oleg S Glotov
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 St. Petersburg, Russia
| | - Elena A Serebryakova
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 St. Petersburg, Russia
| | - Mariia E Turkunova
- St. Petersburg State Pediatric Medical University, 194100 St. Petersburg, Russia
| | - Olga A Efimova
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 St. Petersburg, Russia
| | - Andrey S Glotov
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 St. Petersburg, Russia
| | | | - Yulia A Nasykhova
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 St. Petersburg, Russia
| | | | - Dmitrii E Polev
- St. Petersburg State University, 199034 St. Petersburg, Russia
| | | | | | - Tatyana E Ivashchenko
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 St. Petersburg, Russia
| | - Natalia Y Shved
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 St. Petersburg, Russia
| | - Elena S Shabanova
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 St. Petersburg, Russia
| | - Alena V Tiselko
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 St. Petersburg, Russia
| | - Olga V Romanova
- City Hospital Number 40, Sestroretsk, 197706 St. Petersburg, Russia
| | - Andrey M Sarana
- St. Petersburg State University, 199034 St. Petersburg, Russia
| | - Anna A Pendina
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 St. Petersburg, Russia
| | | | - Ekaterina V Musina
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 St. Petersburg, Russia
| | | | | | - Liliya V Ditkovskaya
- St. Petersburg State Pediatric Medical University, 194100 St. Petersburg, Russia
| | - Liudmila А Zhelenina
- St. Petersburg State Pediatric Medical University, 194100 St. Petersburg, Russia
| | - Ludmila V Tyrtova
- St. Petersburg State Pediatric Medical University, 194100 St. Petersburg, Russia
| | - Olga S Berseneva
- St. Petersburg State Pediatric Medical University, 194100 St. Petersburg, Russia
| | | | - Evgenii N Suspitsin
- St. Petersburg State Pediatric Medical University, 194100 St. Petersburg, Russia
| | - Elena B Bashnina
- North‑Western State Medical University Named After I.I. Mechnikov, 191015 St. Petersburg, Russia
| | - Vladislav S Baranov
- D.O. Ott Research Institute of Obstetrics, Gynecology and Reproductology, 199034 St. Petersburg, Russia
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[Other specific types of diabetes and exocrine pancreatic insufficiency (Update 2019)]. Wien Klin Wochenschr 2019; 131:16-26. [PMID: 30980164 DOI: 10.1007/s00508-019-1454-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The heterogenous catagory "specific types of diabetes due to other causes" encompasses disturbances in glucose metabolism due to other endocrine disorders such as acromegaly or hypercortisolism, drug-induced diabetes (e. g. antipsychotic medications, glucocorticoids, immunosuppressive agents, highly active antiretroviral therapy (HAART)), genetic forms of diabetes (e. g. Maturity Onset Diabetes of the Young (MODY), neonatal diabetes, Down Syndrome, Klinefelter Syndrome, Turner Syndrome), pancreatogenic diabetes (e. g. postoperatively, pancreatitis, pancreatic cancer, haemochromatosis, cystic fibrosis), and some rare autoimmune or infectious forms of diabetes. Diagnosis of specific diabetes types might influence therapeutic considerations. Exocrine pancreatic insufficiency is not only found in patients with pancreatogenic diabetes but is also frequently seen in type 1 and long-standing type 2 diabetes.
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Affiliation(s)
- Simon R Heller
- Department of Oncology & Metabolism, University of Sheffield Medical School, Sheffield, U.K.
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Ozsu E, Cizmecioglu FM, Yesiltepe Mutlu G, Yuksel AB, Calıskan M, Yesilyurt A, Hatun S. Maturity Onset Diabetes of the Young due to Glucokinase, HNF1-A, HNF1-B, and HNF4-A Mutations in a Cohort of Turkish Children Diagnosed as Type 1 Diabetes Mellitus. Horm Res Paediatr 2019; 90:257-265. [PMID: 30481753 DOI: 10.1159/000494431] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 10/10/2018] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND/AIMS Maturity onset diabetes of the young (MODY) is a rare condition often misdiagnosed as type 1 diabetes (T1D). The purposes of this study were: to identify any patients followed in a large Turkish cohort as T1D, with an atypical natural history, who may in fact have MODY, and to define the criteria which would indicate patients with likely MODY as early as possible after presentation to allow prompt genetic testing. METHODS Urinary C-peptide/creatinine ratio (UCPCR) was studied in 152 patients having a diagnosis of T1D for at least 3 years. Those with a UCPCR ≥0.2 nmol/mmol were selected for genetic analysis of the Glucokinase (GCK), Hepatocyte nuclear factor 1a (HNF1A), Hepatocyte nuclear factor 4a (HNF4A), and Hepatocyte nuclear factor 1b (HNF1B) genes. This UCPCR cut-off was used because of the reported high sensitivity and specificity. Cases were also evaluated using a MODY probability calculator. RESULTS Twenty-three patients from 152 participants (15.1%) had a UCPCR indicating persistent insulin reserve. The mean age ± SD of the patients was 13.6 ± 3.6 years (range 8.30-21.6). Of these 23, two (8.7%) were found to have a mutation, one with HNF4A and one with HNF1B mutation. No mutations were detected in the GCK or HNF1A genes. CONCLUSION In Turkish children with a diagnosis of T1D but who have persistent insulin reserve 3 years after diagnosis, up to 9% may have a genetic mutation indicating a diagnosis of MODY.
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Affiliation(s)
- Elif Ozsu
- Samsun Obstetrics and Children Hospital, İlkadım, Turkey,
| | - Filiz Mine Cizmecioglu
- University of Kocaeli, School of Medicine, Department of Pediatric Endocrinology and Diabetes, Izmit, Turkey
| | - Gul Yesiltepe Mutlu
- University of Koc, School of Medicine, Department of Pediatric Endocrinology and Diabetes, İstanbul, Turkey
| | - Aysegul Bute Yuksel
- Derince Research and Training Hospital, Pediatric Endocrinology, Kocaeli, Turkey
| | - Mursel Calıskan
- Department of Genetics, Dıskapı Yildirim Beyazit Education and Research Hospital, Ankara, Turkey
| | - Ahmet Yesilyurt
- Department of Genetics, Dıskapı Yildirim Beyazit Education and Research Hospital, Ankara, Turkey
| | - Sukru Hatun
- University of Koc, School of Medicine, Department of Pediatric Endocrinology and Diabetes, İstanbul, Turkey
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