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Werner C, Schmidt S, Kellner C, Burghardt K, Reuken PA, Kloos C, Wolf G. [Striking manifestation and unexpected therapeutic course of diabetes mellitus in a 22-year-old male patient]. INNERE MEDIZIN (HEIDELBERG, GERMANY) 2025; 66:236-240. [PMID: 39342034 PMCID: PMC11799017 DOI: 10.1007/s00108-024-01797-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 09/04/2024] [Indexed: 10/01/2024]
Abstract
The case of a 22-year-old male patient who presented with acute on chronic hyperglycemia in known MODY ("maturity onset diabetes of the young") 12 (ABCC8 gene) after 11 months of treatment cessation is reported. To emphasize the importance of the awareness of this therapeutically important entity of diabetes, the essential facts of this inherited disease are summarized.
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Affiliation(s)
- Christoph Werner
- Klinik für Innere Medizin III, FB Endokrinologie und Stoffwechselerkrankungen, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland.
| | - Sebastian Schmidt
- Klinik für Innere Medizin III, FB Endokrinologie und Stoffwechselerkrankungen, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
| | - Christiane Kellner
- Klinik für Innere Medizin III, FB Endokrinologie und Stoffwechselerkrankungen, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
| | - Katharina Burghardt
- Praxis für Humangenetik, Zentrum für ambulante Medizin, Universitätsklinikum Jena, Jena, Deutschland
| | - Philipp A Reuken
- Klinik für Innere Medizin IV, Universitätsklinikum Jena, Jena, Deutschland
| | - Christof Kloos
- Klinik für Innere Medizin III, FB Endokrinologie und Stoffwechselerkrankungen, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
| | - Gunter Wolf
- Klinik für Innere Medizin III, FB Endokrinologie und Stoffwechselerkrankungen, Universitätsklinikum Jena, Am Klinikum 1, 07747, Jena, Deutschland
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Bonnefond A, Florez JC, Loos RJF, Froguel P. Dissection of type 2 diabetes: a genetic perspective. Lancet Diabetes Endocrinol 2025; 13:149-164. [PMID: 39818223 DOI: 10.1016/s2213-8587(24)00339-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 09/11/2024] [Accepted: 10/30/2024] [Indexed: 01/18/2025]
Abstract
Diabetes is a leading cause of global mortality and disability, and its economic burden is substantial. This Review focuses on type 2 diabetes, which makes up 90-95% of all diabetes cases. Type 2 diabetes involves a progressive loss of insulin secretion often alongside insulin resistance and metabolic syndrome. Although obesity and a sedentary lifestyle are considerable contributors, research over the last 25 years has shown that type 2 diabetes develops on a predisposing genetic background, with family and twin studies indicating considerable heritability (ie, 31-72%). This Review explores type 2 diabetes from a genetic perspective, highlighting insights into its pathophysiology and the implications for precision medicine. More specifically, the traditional understanding of type 2 diabetes genetics has focused on a dichotomy between monogenic and polygenic forms. However, emerging evidence suggests a continuum that includes monogenic, oligogenic, and polygenic contributions, revealing their complementary roles in type 2 diabetes pathophysiology. Recent genetic studies provide deeper insights into disease mechanisms and pave the way for precision medicine approaches that could transform type 2 diabetes management. Additionally, the effect of environmental factors on type 2 diabetes, particularly from epigenetic modifications, adds another layer of complexity to understanding and addressing this multifaceted disease.
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Affiliation(s)
- Amélie Bonnefond
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Department of Metabolism, Imperial College London, London, UK.
| | - Jose C Florez
- Center for Genomic Medicine and Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Programs in Metabolism and Medical and Population Genetics, Broad Institute, Cambridge, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Ruth J F Loos
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Philippe Froguel
- Université de Lille, Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Department of Metabolism, Imperial College London, London, UK.
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Schembri M, Formosa MM. Identification of osteoporosis genes using family studies. Front Endocrinol (Lausanne) 2024; 15:1455689. [PMID: 39502568 PMCID: PMC11534825 DOI: 10.3389/fendo.2024.1455689] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 09/29/2024] [Indexed: 11/08/2024] Open
Abstract
Osteoporosis is a multifactorial bone disease characterised by reduced bone mass and increased fracture risk. Family studies have made significant contribution in unravelling the genetics of osteoporosis. Yet, most of the underlying molecular and biological mechanisms remain unknown prompting the need for further studies. This review outlines the proper phenotyping and advanced genetic techniques in the form of high-throughput DNA sequencing used to identify genetic factors underlying monogenic osteoporosis in a family-based setting. The steps related to variant filtering prioritisation and curation are also described. From an evolutionary perspective, deleterious risk variants with higher penetrance tend to be rare as a result of negative selection. High-throughput sequencing (HTS) can identify rare variants with large effect sizes which are likely to be missed by candidate gene analysis or genome-wide association studies (GWAS) wherein common variants with small to moderate effect sizes are identified. We also describe the importance of replicating implicated genes, and possibly variants, identified following HTS to confirm their causality. Replication of the gene in other families, singletons or independent cohorts confirms that the shortlisted genes and/or variants are indeed causal. Furthermore, novel genes and/or variants implicated in monogenic osteoporosis require a thorough validation by means of in vitro and in vivo assessment. Therefore, analyses of families can continue to elucidate the genetic architecture of osteoporosis, paving the way for improved diagnostic and therapeutic strategies.
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Affiliation(s)
- Marichela Schembri
- Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, Malta
| | - Melissa M. Formosa
- Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, Malta
- Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta
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Ka M, Hawkins E, Pouponnot C, Duvillié B. Modelling human diabetes ex vivo: a glance at maturity onset diabetes of the young. Front Endocrinol (Lausanne) 2024; 15:1427413. [PMID: 39387055 PMCID: PMC11461259 DOI: 10.3389/fendo.2024.1427413] [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: 07/23/2024] [Accepted: 09/03/2024] [Indexed: 10/12/2024] Open
Abstract
Diabetes is a complex metabolic disease which most commonly has a polygenic origin; however, in rare cases, diabetes may be monogenic. This is indeed the case in both Maturity Onset Diabetes of the Young (MODY) and neonatal diabetes. These disease subtypes are believed to be simpler than Type 1 (T1D) and Type 2 Diabetes (T2D), which allows for more precise modelling. During the three last decades, many studies have focused on rodent models. These investigations provided a wealth of knowledge on both pancreas development and beta cell function. In particular, they allowed the establishment of a hierarchy of the transcription factors and highlighted the role of microenvironmental factors in the control of progenitor cell proliferation and differentiation. Transgenic mice also offered the possibility to decipher the mechanisms that define the functional identity of the pancreatic beta cells. Despite such interest in transgenic mice, recent data have also indicated that important differences exist between mice and human. To overcome these limitations, new human models are necessary. In the present review, we describe these ex vivo models, which are created using stem cells and organoids, and represent an important step toward islet cell therapy and drug discovery.
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Affiliation(s)
- Moustapha Ka
- Department of Signaling, Radiobiology and Cancer, Institut Curie, Orsay, France
- INSERM U1021, Centre Universitaire, Orsay, France
- CNRS UMR 3347, Centre Universitaire, Orsay, France
- Université Paris-Saclay, Orsay, France
- PSL Research University, Paris, France
- Equipe Labellisée par la Ligue contre le cancer, Orsay, France
| | - Eleanor Hawkins
- Department of Signaling, Radiobiology and Cancer, Institut Curie, Orsay, France
- INSERM U1021, Centre Universitaire, Orsay, France
- CNRS UMR 3347, Centre Universitaire, Orsay, France
- Université Paris-Saclay, Orsay, France
- PSL Research University, Paris, France
- Equipe Labellisée par la Ligue contre le cancer, Orsay, France
| | - Celio Pouponnot
- Department of Signaling, Radiobiology and Cancer, Institut Curie, Orsay, France
- INSERM U1021, Centre Universitaire, Orsay, France
- CNRS UMR 3347, Centre Universitaire, Orsay, France
- Université Paris-Saclay, Orsay, France
- PSL Research University, Paris, France
- Equipe Labellisée par la Ligue contre le cancer, Orsay, France
| | - Bertrand Duvillié
- Department of Signaling, Radiobiology and Cancer, Institut Curie, Orsay, France
- INSERM U1021, Centre Universitaire, Orsay, France
- CNRS UMR 3347, Centre Universitaire, Orsay, France
- Université Paris-Saclay, Orsay, France
- PSL Research University, Paris, France
- Equipe Labellisée par la Ligue contre le cancer, Orsay, France
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Kumar KK, Aburawi EH, Ljubisavljevic M, Leow MKS, Feng X, Ansari SA, Emerald BS. Exploring histone deacetylases in type 2 diabetes mellitus: pathophysiological insights and therapeutic avenues. Clin Epigenetics 2024; 16:78. [PMID: 38862980 PMCID: PMC11167878 DOI: 10.1186/s13148-024-01692-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 06/04/2024] [Indexed: 06/13/2024] Open
Abstract
Diabetes mellitus is a chronic disease that impairs metabolism, and its prevalence has reached an epidemic proportion globally. Most people affected are with type 2 diabetes mellitus (T2DM), which is caused by a decline in the numbers or functioning of pancreatic endocrine islet cells, specifically the β-cells that release insulin in sufficient quantity to overcome any insulin resistance of the metabolic tissues. Genetic and epigenetic factors have been implicated as the main contributors to the T2DM. Epigenetic modifiers, histone deacetylases (HDACs), are enzymes that remove acetyl groups from histones and play an important role in a variety of molecular processes, including pancreatic cell destiny, insulin release, insulin production, insulin signalling, and glucose metabolism. HDACs also govern other regulatory processes related to diabetes, such as oxidative stress, inflammation, apoptosis, and fibrosis, revealed by network and functional analysis. This review explains the current understanding of the function of HDACs in diabetic pathophysiology, the inhibitory role of various HDAC inhibitors (HDACi), and their functional importance as biomarkers and possible therapeutic targets for T2DM. While their role in T2DM is still emerging, a better understanding of the role of HDACi may be relevant in improving insulin sensitivity, protecting β-cells and reducing T2DM-associated complications, among others.
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Affiliation(s)
- Kukkala Kiran Kumar
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 15551, Al Ain, Abu Dhabi, United Arab Emirates
| | - Elhadi Husein Aburawi
- Department of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
| | - Milos Ljubisavljevic
- Department of Physiology, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
- Duke-NUS Medical School, Cardiovascular and Metabolic Disorders Program, Singapore, Singapore
| | - Melvin Khee Shing Leow
- LKC School of Medicine, Nanyang Technological University, Singapore, Singapore
- Dept of Endocrinology, Tan Tock Seng Hospital, Singapore, Singapore
- Duke-NUS Medical School, Cardiovascular and Metabolic Disorders Program, Singapore, Singapore
| | - Xu Feng
- Department of Biochemistry, YLL School of Medicine, National University of Singapore, Singapore, Singapore
| | - Suraiya Anjum Ansari
- Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, Abu Dhabi, United Arab Emirates
- Zayed Center for Health Sciences, United Arab Emirates University, Abu Dhabi, United Arab Emirates
- ASPIRE Precision Medicine Research Institute, Abu Dhabi, United Arab Emirates
| | - Bright Starling Emerald
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, PO Box 15551, Al Ain, Abu Dhabi, United Arab Emirates.
- Zayed Center for Health Sciences, United Arab Emirates University, Abu Dhabi, United Arab Emirates.
- ASPIRE Precision Medicine Research Institute, Abu Dhabi, United Arab Emirates.
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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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Bansal V, Winkelmann BR, Dietrich JW, Boehm BO. Whole-exome sequencing in familial type 2 diabetes identifies an atypical missense variant in the RyR2 gene. Front Endocrinol (Lausanne) 2024; 15:1258982. [PMID: 38444585 PMCID: PMC10913019 DOI: 10.3389/fendo.2024.1258982] [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: 07/14/2023] [Accepted: 01/10/2024] [Indexed: 03/07/2024] Open
Abstract
Genome-wide association studies have identified several hundred loci associated with type 2 diabetes mellitus (T2DM). Additionally, pathogenic variants in several genes are known to cause monogenic diabetes that overlaps clinically with T2DM. Whole-exome sequencing of related individuals with T2DM is a powerful approach to identify novel high-penetrance disease variants in coding regions of the genome. We performed whole-exome sequencing on four related individuals with T2DM - including one individual diagnosed at the age of 33 years. The individuals were negative for mutations in monogenic diabetes genes, had a strong family history of T2DM, and presented with several characteristics of metabolic syndrome. A missense variant (p.N2291D) in the type 2 ryanodine receptor (RyR2) gene was one of eight rare coding variants shared by all individuals. The variant was absent in large population databases and affects a highly conserved amino acid located in a mutational hotspot for pathogenic variants in Catecholaminergic polymorphic ventricular tachycardia (CPVT). Electrocardiogram data did not reveal any cardiac abnormalities except a lower-than-normal resting heart rate (< 60 bpm) in two individuals - a phenotype observed in CPVT individuals with RyR2 mutations. RyR2-mediated Ca2+ release contributes to glucose-mediated insulin secretion and pathogenic RyR2 mutations cause glucose intolerance in humans and mice. Analysis of glucose tolerance testing data revealed that missense mutations in a CPVT mutation hotspot region - overlapping the p.N2291D variant - are associated with complete penetrance for glucose intolerance. In conclusion, we have identified an atypical missense variant in the RyR2 gene that co-segregates with diabetes in the absence of overt CPVT.
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Affiliation(s)
- Vikas Bansal
- Department of Pediatrics, University of California San Diego, La Jolla, CA, United States
- Institute of Genomic Medicine, University of California San Diego, La Jolla, CA, United States
| | | | - Johannes W Dietrich
- Diabetes, Endocrinology and Metabolism Section, Department of Internal Medicine I, St. Josef Hospital, Ruhr University Hospitals, Bochum, Germany
- Diabetes Center Bochum-Hattingen, St. Elisabeth-Hospital Blankenstein, Hattingen, Germany
- Center for Rare Endocrine Diseases, Ruhr Center for Rare Diseases (CeSER), Ruhr University Bochum and Witten/Herdecke University, Bochum, Germany
- Center for Diabetes Technology, Catholic Hospitals Bochum, Bochum, Germany
| | - Bernhard O Boehm
- Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
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Shi P, Tian Y, Xu F, Liu LN, Wu WH, Shi YZ, Dai AQ, Fang HY, Li KX, Xu C. Assessment of pathogenicity and functional characterization of APPL1 gene mutations in diabetic patients. World J Diabetes 2024; 15:275-286. [PMID: 38464380 PMCID: PMC10921161 DOI: 10.4239/wjd.v15.i2.275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 11/22/2023] [Accepted: 01/09/2024] [Indexed: 02/04/2024] Open
Abstract
BACKGROUND Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1) plays a crucial role in regulating insulin signaling and glucose metabolism. Mutations in the APPL1 gene have been associated with the development of maturity-onset diabetes of the young type 14 (MODY14). Currently, only two mutations [c.1655T>A (p.Leu552*) and c.281G>A p.(Asp94Asn)] have been identified in association with this disease. Given the limited understanding of MODY14, it is imperative to identify additional cases and carry out comprehensive research on MODY14 and APPL1 mutations. AIM To assess the pathogenicity of APPL1 gene mutations in diabetic patients and to characterize the functional role of the APPL1 domain. METHODS Patients exhibiting clinical signs and a medical history suggestive of MODY were screened for the study. Whole exome sequencing was performed on the patients as well as their family members. The pathogenicity of the identified APPL1 variants was predicted on the basis of bioinformatics analysis. In addition, the pathogenicity of the novel APPL1 variant was preliminarily evaluated through in vitro functional experiments. Finally, the impact of these variants on APPL1 protein expression and the insulin pathway were assessed, and the potential mechanism underlying the interaction between the APPL1 protein and the insulin receptor was further explored. RESULTS A total of five novel mutations were identified, including four missense mutations (Asp632Tyr, Arg633His, Arg532Gln, and Ile642Met) and one intronic mutation (1153-16A>T). Pathogenicity prediction analysis revealed that the Arg532Gln was pathogenic across all predictions. The Asp632Tyr and Arg633His variants also had pathogenicity based on MutationTaster. In addition, multiple alignment of amino acid sequences showed that the Arg532Gln, Asp632Tyr, and Arg633His variants were conserved across different species. Moreover, in in vitro functional experiments, both the c.1894G>T (at Asp632Tyr) and c.1595G>A (at Arg532Gln) mutations were found to downregulate the expression of APPL1 on both protein and mRNA levels, indicating their pathogenic nature. Therefore, based on the patient's clinical and family history, combined with the results from bioinformatics analysis and functional experiment, the c.1894G>T (at Asp632Tyr) and c.1595G>A (at Arg532Gln) mutations were classified as pathogenic mutations. Importantly, all these mutations were located within the phosphotyrosine-binding domain of APPL1, which plays a critical role in the insulin sensitization effect. CONCLUSION This study provided new insights into the pathogenicity of APPL1 gene mutations in diabetes and revealed a potential target for the diagnosis and treatment of the disease.
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Affiliation(s)
- Ping Shi
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Yang Tian
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Feng Xu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Lu-Na Liu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Wan-Hong Wu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Ying-Zhou Shi
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - An-Qi Dai
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Hang-Yu Fang
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
| | - Kun-Xia Li
- Department of Pediatric, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai 264099, Shandong Province, China
| | - Chao Xu
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, Shandong Province, China
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Fauzi A, Thoe ES, Quan TY, Yin ACY. Insights from insulin resistance pathways: Therapeutic approaches against Alzheimer associated diabetes mellitus. J Diabetes Complications 2023; 37:108629. [PMID: 37866274 DOI: 10.1016/j.jdiacomp.2023.108629] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 09/03/2023] [Accepted: 10/15/2023] [Indexed: 10/24/2023]
Abstract
Alzheimer Associated Diabetes Mellitus, commonly known as Type 3 Diabetes Mellitus (T3DM) is a distinct subtype of diabetes with a pronounced association with Alzheimer's disease (AD). Insulin resistance serves as a pivotal link between these two conditions, leading to diminished insulin sensitivity, hyperglycemia, and impaired glucose uptake. The brain, a vital organ in AD context, is also significantly impacted by insulin resistance, resulting in energy deficits and neuronal damage, which are hallmark features of the neurodegenerative disorder. To pave the way for potential therapeutic interventions targeting the insulin resistance pathway, it is crucial to comprehend the intricate pathophysiology of T3DM and identify the overlapped features between diabetes and AD. This comprehensive review article aims to explore various pathway such as AMPK, PPARγ, cAMP and P13K/Akt pathway as potential target for management of T3DM. Through the analysis of these complex mechanisms, our goal is to reveal their interdependencies and support the discovery of innovative therapeutic strategies. The review extensively discusses several promising pharmaceutical candidates that have demonstrated dual drug action mechanisms, addressing both peripheral and cerebral insulin resistance observed in T3DM. These candidates hold significant promise for restoring insulin function and mitigating the detrimental effects of insulin resistance on the brain. The exploration of these therapeutic options contributes to the development of innovative interventions that alleviate the burden of T3DM and enhance patient care.
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Affiliation(s)
- Ayesha Fauzi
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia
| | - Ewen Se Thoe
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia
| | - Tang Yin Quan
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia; Medical Advancement for Better Quality of Life Impact Lab, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia
| | - Adeline Chia Yoke Yin
- School of Biosciences, Faculty of Health & Medical Sciences, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia; Medical Advancement for Better Quality of Life Impact Lab, Taylor's University Lakeside Campus, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia.
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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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Boehm BO, Kratzer W, Bansal V. Whole-genome sequencing of multiple related individuals with type 2 diabetes reveals an atypical likely pathogenic mutation in the PAX6 gene. Eur J Hum Genet 2023; 31:89-96. [PMID: 36202929 PMCID: PMC9823100 DOI: 10.1038/s41431-022-01182-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 06/21/2022] [Accepted: 08/18/2022] [Indexed: 02/08/2023] Open
Abstract
Pathogenic variants in more than 14 genes have been implicated in monogenic diabetes; however, a significant fraction of individuals with young-onset diabetes and a strong family history of diabetes have unknown genetic etiology. To identify novel pathogenic alleles for monogenic diabetes, we performed whole-genome sequencing (WGS) on four related individuals with type 2 diabetes - including one individual diagnosed at the age of 31 years - that were negative for mutations in known monogenic diabetes genes. The individuals were ascertained from a large case-control study and had a multi-generation family history of diabetes. Identity-by-descent (IBD) analysis revealed that the four individuals represent two sib-pairs that are third-degree relatives. A novel missense mutation (p.P81S) in the PAX6 gene was one of eight rare coding variants across the genome shared IBD by all individuals and was inherited from affected mothers in both sib-pairs. The mutation affects a highly conserved amino acid located in the paired-domain of PAX6 - a hotspot for missense mutations that cause aniridia and other eye abnormalities. However, no eye-related phenotype was observed in any individual. The well-established functional role of PAX6 in glucose-induced insulin secretion and the co-segregation of diabetes in families with aniridia provide compelling support for the pathogenicity of this mutation for diabetes. The mutation could be classified as "likely pathogenic" with a posterior probability of 0.975 according to the ACMG/AMP guidelines. This is the first PAX6 missense mutation that is likely pathogenic for autosomal-dominant adult-onset diabetes without eye abnormalities.
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Affiliation(s)
- Bernhard O. Boehm
- grid.59025.3b0000 0001 2224 0361Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
| | - Wolfgang Kratzer
- grid.6582.90000 0004 1936 9748Department of Internal Medicine I, Ulm University Medical Centre, Ulm, Germany
| | - Vikas Bansal
- grid.266100.30000 0001 2107 4242Department of Pediatrics, University of California San Diego, La Jolla, CA USA
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12
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Billings LK, Shi Z, Resurreccion WK, Wang C, Wei J, Pollin TI, Udler MS, Xu J. Statistical evidence for high-penetrance MODY-causing genes in a large population-based cohort. Endocrinol Diabetes Metab 2022; 5:e372. [PMID: 36208030 PMCID: PMC9659663 DOI: 10.1002/edm2.372] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 08/29/2022] [Accepted: 09/04/2022] [Indexed: 11/15/2022] Open
Abstract
AIMS Numerous genes have been proposed as causal for maturity-onset diabetes of the young (MODY). Scoring systems to annotate mutation pathogenicity have been widely used; however, statistical evidence for being a highly penetrant MODY gene has not been well-established. METHODS Participants were from the UK Biobank with whole-exome sequencing data, including 14,622 with and 185,509 without diagnosis of diabetes. Pathogenic/likely pathogenic (P/LP) mutations in 14 reported and 3 possible MODY genes were annotated using American College of Medical Genetics criteria. Evidence for being a high-penetrant MODY gene used two statistical criteria: frequency of aggregate P/LP mutations in each gene are (1) significantly more common in participants with a diagnosis of diabetes than without using the SKAT-O (p < .05) and (2) lower than the maximum credible frequency in the general population. RESULTS Among the 17 genes, 6 (GCK, HNF1A, HNF4A, NEUROD1, KCNJ11 and HNF1B) met both criteria, 7 (ABCC8, KLF11, RFX6, PCBD1, WFS1, INS and PDX1) met only one criterion, and the remaining 4 (CEL, BLK, APPL1 and PAX4) failed both criteria, and were classified as 'consistent', 'inconclusive' and 'inconsistent' for being highly penetrant diabetes genes, respectively. Diabetes participants with mutations in the 'consistent' genes had clinical presentations that were most consistent with MODY. In contrast, the 'inconclusive' and 'inconsistent' genes did not differ clinically from non-carriers in diabetes-related characteristics. CONCLUSIONS Data from a large population-based study provided novel statistical evidence to identify 6 MODY genes as consistent with being highly penetrant. These results have potential implications for interpreting genetic testing results and clinical diagnosis of MODY.
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Affiliation(s)
- Liana K. Billings
- Department of MedicineNorthShore University HealthSystemSkokieIllinoisUSA
- University of Chicago Pritzker School of MedicineChicagoIllinoisUSA
| | - Zhuqing Shi
- Program for Personalized Cancer CareNorthShore University HealthSystemEvanstonIllinoisUSA
| | - W. Kyle Resurreccion
- Program for Personalized Cancer CareNorthShore University HealthSystemEvanstonIllinoisUSA
| | - Chi‐Hsiung Wang
- Program for Personalized Cancer CareNorthShore University HealthSystemEvanstonIllinoisUSA
| | - Jun Wei
- Program for Personalized Cancer CareNorthShore University HealthSystemEvanstonIllinoisUSA
| | - Toni I. Pollin
- Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, and Program in Personalized and Genomic MedicineUniversity of Maryland School of MedicineBaltimoreMarylandUSA
| | - Miriam S. Udler
- Diabetes UnitMassachusetts General HospitalBostonMassachusettsUSA
- Department of MedicineHarvard Medical SchoolBostonMassachusettsUSA
| | - Jianfeng Xu
- University of Chicago Pritzker School of MedicineChicagoIllinoisUSA
- Program for Personalized Cancer CareNorthShore University HealthSystemEvanstonIllinoisUSA
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13
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Younis H, Ha SE, Jorgensen BG, Verma A, Ro S. Maturity-Onset Diabetes of the Young: Mutations, Physiological Consequences, and Treatment Options. J Pers Med 2022; 12:jpm12111762. [PMID: 36573710 PMCID: PMC9697644 DOI: 10.3390/jpm12111762] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 10/13/2022] [Accepted: 10/18/2022] [Indexed: 02/01/2023] Open
Abstract
Maturity-Onset Diabetes of the Young (MODY) is a rare form of diabetes which affects between 1% and 5% of diagnosed diabetes cases. Clinical characterizations of MODY include onset of diabetes at an early age (before the age of 30), autosomal dominant inheritance pattern, impaired glucose-induced secretion of insulin, and hyperglycemia. Presently, 14 MODY subtypes have been identified. Within these subtypes are several mutations which contribute to the different MODY phenotypes. Despite the identification of these 14 subtypes, MODY is often misdiagnosed as type 1 or type 2 diabetes mellitus due to an overlap in clinical features, high cost and limited availability of genetic testing, and unfamiliarity with MODY outside of the medical profession. The primary aim of this review is to investigate the genetic characterization of the MODY subtypes. Additionally, this review will elucidate the link between the genetics, function, and clinical manifestations of MODY in each of the 14 subtypes. In providing this knowledge, we hope to assist in the accurate diagnosis of MODY patients and, subsequently, in ensuring they receive appropriate treatment.
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Affiliation(s)
- Hazar Younis
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA
| | - Se Eun Ha
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA
| | - Brian G. Jorgensen
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA
| | - Arushi Verma
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Nevada School of Medicine, Reno, NV 89557, USA
| | - Seungil Ro
- Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV 89557, USA
- RosVivo Therapeutics, Applied Research Facility, Reno, NV 89557, USA
- Correspondence:
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14
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Colclough K, Patel K. How do I diagnose Maturity Onset Diabetes of the Young in my patients? Clin Endocrinol (Oxf) 2022; 97:436-447. [PMID: 35445424 PMCID: PMC9544561 DOI: 10.1111/cen.14744] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 03/21/2022] [Accepted: 04/13/2022] [Indexed: 11/28/2022]
Abstract
Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes diagnosed in young individuals that lack the typical features of type 1 and type 2 diabetes. The genetic subtype of MODY determines the most effective treatment and this is the driver for MODY genetic testing in diabetes populations. Despite the obvious clinical and health economic benefits, MODY is significantly underdiagnosed with the majority of patients being inappropriately managed as having type 1 or type 2 diabetes. Low detection rates result from the difficulty in identifying patients with a likely diagnosis of MODY from the high background population of young onset type 1 and type 2 diabetes, compounded by the lack of MODY awareness and education in diabetes care physicians. MODY diagnosis can be improved through (1) access to education and training, (2) the use of sensitive and specific selection criteria based on accurate prediction models and biomarkers to identify patients for testing, (3) the development and mainstream implementation of simple criteria-based selection pathways applicable across a range of healthcare settings and ethnicities to select the most appropriate patients for genetic testing and (4) the correct use of next generation sequencing technology to provide accurate and comprehensive testing of all known MODY and monogenic diabetes genes. The creation and public sharing of educational materials, clinical and scientific best practice guidelines and genetic variants will help identify the missing patients so they can benefit from the more effective clinical care that a genetic diagnosis brings.
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Affiliation(s)
- Kevin Colclough
- Exeter Genomics LaboratoryRoyal Devon & Exeter NHS Foundation TrustExeterUK
| | - Kashyap Patel
- Institute of Biomedical and Clinical ScienceUniversity of Exeter Medical SchoolExeterUK
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15
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Wang DW, Yuan J, Yang FY, Qiu HY, Lu J, Yang JK. Early-onset diabetes involving three consecutive generations had different clinical features from age-matched type 2 diabetes without a family history in China. Endocrine 2022; 78:47-56. [PMID: 35921062 PMCID: PMC9474578 DOI: 10.1007/s12020-022-03144-2] [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: 04/08/2022] [Accepted: 07/12/2022] [Indexed: 11/29/2022]
Abstract
PURPOSE Early-onset, multigenerational diabetes is a heterogeneous disease, which is often simplistically classified as type 1 diabetes (T1D) or type 2 diabetes(T2D). However, its clinical and genetic characteristics have not been clearly elucidated. The aim of our study is to investigate the clinical features of early-onset diabetes involving three consecutive generations (eDia3) in a Chinese diabetes cohort. METHODS Of 6470 type 2 diabetic patients, 105 were identified as eDia3 (1.6%). After a case-control match on age, we compared the clinical characteristics of 89 eDia3 patients with 89 early-onset T2D patients without a family history of diabetes (eDia0). WES was carried out in 89 patients with eDia3. We primarily focused on 14 known maturity-onset diabetes of the young (MODY) genes. Variants were predicted by ten tools (SIFT, PolyPhen2_HDIV, PolyPhen2_HVAR, LRT, Mutation Assessor, Mutation Taster, FATHMM, GERP++, PhyloP, and PhastCons). All suspected variants were then validated by Sanger sequencing and further investigated in the proband families. RESULTS Compared to age-matched eDia0, eDia3 patients had a younger age at diagnosis (26.5 ± 5.8 vs. 29.4 ± 5.3 years, P = 0.001), lower body mass index (25.5 ± 3.9 vs. 27.4 ± 4.6 kg/m2, P = 0.003), lower systolic blood pressure (120 ± 15 vs. 128 ± 18 mmHg, P = 0.003), and better metabolic profiles (including glucose and lipids). Of the 89 eDia3 patients, 10 (11.2%) carried likely pathogenic variants in genes (KLF11, GCK, ABCC8, PAX4, BLK and HNF1A) of MODY. CONCLUSIONS eDia3 patients had unique clinical features. Known MODY genes were not common causes in these patients.
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Affiliation(s)
- Da-Wei Wang
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
- Department of General Medicine, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Jing Yuan
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | - Fang-Yuan Yang
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute, Beijing, 100730, China
| | - Hai-Yan Qiu
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
- Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute, Beijing, 100730, China
| | - Jing Lu
- Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute, Beijing, 100730, China
| | - Jin-Kui Yang
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
- Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute, Beijing, 100730, China.
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16
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Zhao L, Li Q, Kuang Y, Xu P, Sun X, Meng Q, Wang W, Zeng Y, Chen B, Fu J, Dong J, Zhu J, Luo Y, Gu H, Li C, Li C, Wu L, Mao X, Fan H, Liu R, Zhang Z, Li Q, Du J, He L, Jin L, Wang L, Sang Q. Heterozygous loss-of-function variants in LHX8 cause female infertility characterized by oocyte maturation arrest. Genet Med 2022; 24:2274-2284. [PMID: 36029299 DOI: 10.1016/j.gim.2022.07.027] [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: 04/01/2022] [Revised: 07/21/2022] [Accepted: 07/22/2022] [Indexed: 11/26/2022] Open
Abstract
PURPOSE The genetic causes of oocyte maturation arrest leading to female infertility are largely unknown, and no population-based genetic analysis has been applied in cohorts of patients with infertility. We aimed to identify novel pathogenic genes causing oocyte maturation arrest by using a gene-based burden test. METHODS Through comparison of exome sequencing data from 716 females with infertility characterized by oocyte maturation arrest and 3539 controls, we performed a gene-based burden test and identified a novel pathogenic gene LHX8. Splicing event was evaluated using a minigene assay, expression of LHX8 protein was assessed in HeLa cells, and nuclear subcellular localization was determined in both HeLa cells and mouse oocytes. RESULTS A total of 5 heterozygous loss-of-function LHX8 variants were identified from 6 independent families (c.389+1G>T, c.412C>T [p.Arg138∗], c.282C>A [p.Cys94∗]; c.257dup [p.Tyr86∗]; and c.180del, [p.Ser61Profs∗30]). All the identified variants in LHX8 produced truncated LHX8 protein and resulted in loss of LHX8 nuclear localization in both HeLa cells and mouse oocytes. CONCLUSION By combining genetic evidence and functional evaluations, we identified a novel pathogenic gene LHX8 and established the causative relationship between LHX8 haploinsufficiency and female infertility characterized by oocyte maturation arrest.
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Affiliation(s)
- Lin Zhao
- Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China; NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, China
| | - Qun Li
- Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China; Human Phenome Institute, Fudan University, Shanghai, China
| | - Yanping Kuang
- Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Peng Xu
- Hainan Jinghua Hejing Hospital for Reproductive Medicine, Haikou, China
| | - Xiaoxi Sun
- Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Qingxia Meng
- Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Wenjing Wang
- Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Yang Zeng
- Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Biaobang Chen
- NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, China
| | - Jing Fu
- Shanghai Ji Ai Genetics and IVF Institute, Obstetrics and Gynecology Hospital, Fudan University, Shanghai, China
| | - Jie Dong
- Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Jiawei Zhu
- Center for Reproduction and Genetics, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Yuxi Luo
- Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Hao Gu
- Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Caihong Li
- Shenyang Jinghua Hospital, Liaoning, China
| | - Chunyi Li
- Shenyang Jinghua Hospital, Liaoning, China
| | - Ling Wu
- Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Xiaoyan Mao
- Reproductive Medicine Center, Shanghai Ninth Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Huizhen Fan
- Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Ruyi Liu
- Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Zhihua Zhang
- Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Qiaoli Li
- Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Jing Du
- NHC Key Lab of Reproduction Regulation, Shanghai Institute for Biomedical and Pharmaceutical Technologies, Fudan University, Shanghai, China
| | - Lin He
- Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Ministry of Education, Shanghai Jiao Tong University, Shanghai, China
| | - Li Jin
- State Key Laboratory of Genetic Engineering and Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Lei Wang
- Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China.
| | - Qing Sang
- Institute of Pediatrics, Children's Hospital of Fudan University, the Institutes of Biomedical Sciences, the State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China.
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Zhang Y, Liu W, Yuan W, Cai Z, Ye G, Zheng G, Xu C, Wang X, Zeng C, Mi R, Feng P, Chen F, Wu Y, Shen H, Wang P. Impairment of APPL1/Myoferlin facilitates adipogenic differentiation of mesenchymal stem cells by blocking autophagy flux in osteoporosis. Cell Mol Life Sci 2022; 79:488. [PMID: 35984564 PMCID: PMC9391247 DOI: 10.1007/s00018-022-04511-y] [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: 05/24/2022] [Revised: 07/21/2022] [Accepted: 08/02/2022] [Indexed: 11/30/2022]
Abstract
An imbalance of human mesenchymal stem cells (hMSCs) adipogenic and osteogenic differentiation is crucial in the pathogenesis of osteoporosis, and elucidation of the underlying mechanism is urgently needed. APPL1, an adaptor protein of the adiponectin receptor, was recently shown to be closely related to bone mass. However, the role of APPL1 in the imbalance of hMSC differentiation in osteoporosis is unclear. Therefore, we aimed to explore the mechanisms by which APPL1 alters hMSCs adipogenic differentiation in osteoporosis. Here, we found that APPL1 expression was downregulated in elderly patients with osteoporosis and in mouse osteoporosis model. APPL1 negatively regulated hMSC adipogenic differentiation in vivo and in vitro. Mechanistically, by enhancing ubiquitination-mediated Myoferlin degradation, downregulated APPL1 expression increased the risk of lysosome dysfunction during hMSCs adipogenic differentiation. Lysosomal dysfunction inhibited autophagy flux by suppressing autophagosome degradation and promoted hMSC differentiation towards the adipocyte lineage. Our findings suggest that APPL1/Myoferlin downregulation promoted hMSCs adipogenic differentiation by inhibiting autophagy flux, further impairing the balance of hMSCs adipogenic and osteogenic differentiation in osteoporosis; the APPL1/ Myoferlin axis may be a promising diagnostic and therapeutic target for osteoporosis.
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Affiliation(s)
- Yunhui Zhang
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518000, People's Republic of China
| | - Wenjie Liu
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518000, People's Republic of China
| | - Weiquan Yuan
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518000, People's Republic of China
| | - Zhaopeng Cai
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518000, People's Republic of China
| | - Guiwen Ye
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518000, People's Republic of China
| | - Guan Zheng
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518000, People's Republic of China
| | - Chenhao Xu
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518000, People's Republic of China
| | - Xinglang Wang
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518000, People's Republic of China
| | - Chenying Zeng
- Center for Biotherapy, The Eighth Affiliated Hospital, Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518000, People's Republic of China
| | - Rujia Mi
- Center for Biotherapy, The Eighth Affiliated Hospital, Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518000, People's Republic of China
| | - Pei Feng
- Center for Biotherapy, The Eighth Affiliated Hospital, Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518000, People's Republic of China
| | - Fenglei Chen
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518000, People's Republic of China
| | - Yanfeng Wu
- Center for Biotherapy, The Eighth Affiliated Hospital, Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518000, People's Republic of China.
| | - Huiyong Shen
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518000, People's Republic of China.
| | - Peng Wang
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-Sen University, 3025# Shennan Road, Shenzhen, 518000, People's Republic of China.
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18
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Zhang H, Kleinberger JW, Maloney KA, Guan Y, Mathias TJ, Bisordi K, Streeten EA, Blessing K, Snyder MN, Bromberger LA, Goehringer J, Kimball A, Damcott CM, Taylor CO, Nicholson M, Nwaba D, Palmer K, Sewell D, Ambulos N, Jeng LJB, Shuldiner AR, Levin P, Carey DJ, Pollin TI. Model for Integration of Monogenic Diabetes Diagnosis Into Routine Care: The Personalized Diabetes Medicine Program. Diabetes Care 2022; 45:1799-1806. [PMID: 35763601 PMCID: PMC9346978 DOI: 10.2337/dc21-1975] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 05/03/2022] [Indexed: 02/03/2023]
Abstract
OBJECTIVE To implement, disseminate, and evaluate a sustainable method for identifying, diagnosing, and promoting individualized therapy for monogenic diabetes. RESEARCH DESIGN AND METHODS Patients were recruited into the implementation study through a screening questionnaire completed in the waiting room or through the patient portal, physician recognition, or self-referral. Patients suspected of having monogenic diabetes based on the processing of their questionnaire and other data through an algorithm underwent next-generation sequencing for 40 genes implicated in monogenic diabetes and related conditions. RESULTS Three hundred thirteen probands with suspected monogenic diabetes (but most diagnosed with type 2 diabetes) were enrolled from October 2014 to January 2019. Sequencing identified 38 individuals with monogenic diabetes, with most variants found in GCK or HNF1A. Positivity rates for ascertainment methods were 3.1% for clinic screening, 5.3% for electronic health record portal screening, 16.5% for physician recognition, and 32.4% for self-referral. The algorithmic criterion of non-type 1 diabetes before age 30 years had an overall positivity rate of 15.0%. CONCLUSIONS We successfully modeled the efficient incorporation of monogenic diabetes diagnosis into the diabetes care setting, using multiple strategies to screen and identify a subpopulation with a 12.1% prevalence of monogenic diabetes by molecular testing. Self-referral was particularly efficient (32% prevalence), suggesting that educating the lay public in addition to clinicians may be the most effective way to increase the diagnosis rate in monogenic diabetes. Scaling up this model will assure access to diagnosis and customized treatment among those with monogenic diabetes and, more broadly, access to personalized medicine across disease areas.
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Affiliation(s)
- Haichen Zhang
- Department of Endocrinology, Peking Union Medical College Hospital, Beijing, China.,Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - Jeffrey W Kleinberger
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - Kristin A Maloney
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - Yue Guan
- Rollins School of Public Health, Emory University, Atlanta, GA
| | - Trevor J Mathias
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - Katharine Bisordi
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - Elizabeth A Streeten
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | | | | | - Lee A Bromberger
- Metabolism, Osteoporosis/Obesity, Diabetes, Endocrinology and Lipids (MODEL) Clinical Research, Research Division of Bay Endocrinology Associates, Baltimore, MD
| | | | - Amy Kimball
- Harvey Institute for Human Genetics, Greater Baltimore Medical Center, Baltimore, MD
| | - Coleen M Damcott
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - Casey O Taylor
- Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.,Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Michaela Nicholson
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - Devon Nwaba
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - Kathleen Palmer
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - Danielle Sewell
- University of Maryland Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD
| | - Nicholas Ambulos
- University of Maryland Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD
| | - Linda J B Jeng
- Division of Rare Diseases and Medical Genetics, US Food and Drug Administration, Silver Spring, MD
| | - Alan R Shuldiner
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
| | - Philip Levin
- Bay West Endocrinology Associates, Baltimore, MD
| | | | - Toni I Pollin
- Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD
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19
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Aydogan HY, Gul N, Demirci DK, Mutlu U, Gulfidan G, Arga KY, Ozder A, Camli AA, Tutuncu Y, Ozturk O, Cacina C, Darendeliler F, Poyrazoglu S, Satman I. Precision Diagnosis of Maturity-Onset Diabetes of the Young with Next-Generation Sequencing: Findings from the MODY-IST Study in Adult Patients. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2022; 26:218-235. [PMID: 35333605 DOI: 10.1089/omi.2022.0006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Maturity-onset diabetes of the young (MODY) is a highly heterogeneous group of monogenic and nonautoimmune diseases. Misdiagnosis of MODY is a widespread problem and about 5% of patients with type 2 diabetes mellitus and nearly 10% with type 1 diabetes mellitus may actually have MODY. Using next-generation DNA sequencing (NGS) to facilitate accurate diagnosis of MODY, this study investigated mutations in 13 MODY genes (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, and KCNJ11). In addition, we comprehensively investigated the clinical phenotypic effects of the genetic variations identified. Fifty-one adult patients with suspected MODY and 64 healthy controls participated in the study. We identified 7 novel and 10 known missense mutations localized in PDX1, HNF1B, KLF11, CEL, BLK, and ABCC8 genes in 29.4% of the patient sample. Importantly, we report several mutations that were classified as "deleterious" as well as those predicted as "benign." Notably, the ABCC8 p.R1103Q, ABCC8 p.V421I, CEL I336T, CEL p.N493H, BLK p.L503P, HNF1B p.S362P, and PDX1 p.E69A mutations were identified for the first time as causative variants for MODY. More aggressive clinical features were observed in three patients with double- and triple-heterozygosity of PDX1-KLF11 (p.E69A/p.S182R), CEL-ABCC8-KCNJ11 (p.I336, p.G157R/p.R1103Q/p.A157A), and HNF1B-KLF11 (p.S362P/p.P261L). Interestingly, the clinical effects of the BLK mutations appear to be exacerbated in the presence of obesity. In conclusion, NGS analyses of the adult patients with suspected MODY appear to be informative in a clinical context. These findings warrant further clinical diagnostic research and development in different world populations suffering from diabetes with genetic underpinnings.
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Affiliation(s)
- Hulya Yilmaz Aydogan
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Nurdan Gul
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Deniz Kanca Demirci
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
- Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Halic University, Istanbul, Turkey
| | - Ummu Mutlu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Gizem Gulfidan
- Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Turkey
| | - Kazim Yalcin Arga
- Department of Bioengineering, Faculty of Engineering, Marmara University, Istanbul, Turkey
- Genetic and Metabolic Diseases Research and Investigation Center, Marmara University, Istanbul, Turkey
| | - Aclan Ozder
- Department of Family Medicine, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Ahmet Adil Camli
- Department of Internal Medicine, Faculty of Medicine, Bezmialem Vakif University, Istanbul, Turkey
| | - Yildiz Tutuncu
- Department of Immunology, School of Medicine, KUTTAM, Koc University, Istanbul, Turkey
| | - Oguz Ozturk
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Canan Cacina
- Department of Molecular Medicine, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey
| | - Feyza Darendeliler
- Pediatric Endocrinology Unit, Department of Pediatrics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Sukran Poyrazoglu
- Pediatric Endocrinology Unit, Department of Pediatrics, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Ilhan Satman
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
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20
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Vázquez-Mosquera ME, González-Vioque E, Barbosa-Gouveia S, Bellido-Guerrero D, Tejera-Pérez C, Martinez-Olmos MA, Fernández-Pombo A, Castaño-González LA, Chans-Gerpe R, Couce ML. Transcriptomic analysis of patients with clinical suspicion of maturity-onset diabetes of the young (MODY) with a negative genetic diagnosis. Orphanet J Rare Dis 2022; 17:105. [PMID: 35246208 PMCID: PMC8896342 DOI: 10.1186/s13023-022-02263-3] [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: 09/27/2021] [Accepted: 02/20/2022] [Indexed: 12/04/2022] Open
Abstract
Background Diagnosis of mature-onset diabetes of the young (MODY), a non-autoimmune monogenic form of diabetes mellitus, is confirmed by genetic testing. However, a positive genetic diagnosis is achieved in only around 50% of patients with clinical characteristics of this disease. Results We evaluated the diagnostic utility of transcriptomic analysis in patients with clinical suspicion of MODY but a negative genetic diagnosis. Using Nanostring nCounter technology, we conducted transcriptomic analysis of 19 MODY-associated genes in peripheral blood samples from 19 patients and 8 healthy controls. Normalized gene expression was compared between patients and controls and correlated with each patient’s biochemical and clinical variables. Z-scores were calculated to identify significant changes in gene expression in patients versus controls. Only 7 of the genes analyzed were detected in peripheral blood. HADH expression was significantly lower in patients versus controls. Among patients with suspected MODY, GLIS3 expression was higher in obese versus normal-weight patients, and in patients aged < 25 versus > 25 years at diabetes onset. Significant alteration with respect to controls of any gene was observed in 57.9% of patients. Conclusions Although blood does not seem to be a suitable sample for transcriptomic analysis of patients with suspected MODY, in our study, we detected expression alterations in some of the genes studied in almost 58% of patients. That opens the door for future studies that can clarify the molecular cause of the clinic of these patients and thus be able to maintain a more specific follow-up and treatment in each case. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-022-02263-3.
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Affiliation(s)
- María E Vázquez-Mosquera
- Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain.,Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Universidad de Santiago de Compostela, Santiago de Compostela, Spain.,European Reference Network for Hereditary Metabolic Disorders (MetabERN), Padova, Italy
| | - Emiliano González-Vioque
- Division of Clinical Biochemistry, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
| | - Sofía Barbosa-Gouveia
- Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain.,Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Universidad de Santiago de Compostela, Santiago de Compostela, Spain.,European Reference Network for Hereditary Metabolic Disorders (MetabERN), Padova, Italy
| | | | - Cristina Tejera-Pérez
- Division of Endocrinology, Complejo Hospitalario Universitario de Ferrol, Ferrol, Spain
| | - Miguel A Martinez-Olmos
- Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain.,Universidad de Santiago de Compostela, Santiago de Compostela, Spain.,Division of Endocrinology and Nutrition, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain.,Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Madrid, Spain
| | - Antía Fernández-Pombo
- Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain.,Universidad de Santiago de Compostela, Santiago de Compostela, Spain.,Division of Endocrinology and Nutrition, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain.,Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERobn), Madrid, Spain
| | - Luis A Castaño-González
- Endocrinology and Diabetes Research Group, Instituto de Investigación Sanitaria BioCruces, Barakaldo, Spain
| | - Roi Chans-Gerpe
- Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain.,Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.,Universidad de Santiago de Compostela, Santiago de Compostela, Spain.,European Reference Network for Hereditary Metabolic Disorders (MetabERN), Padova, Italy
| | - María L Couce
- Unit of Diagnosis and Treatment of Congenital Metabolic Diseases, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain. .,Instituto de Investigación Sanitaria de Santiago (IDIS), Santiago de Compostela, Spain. .,Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. .,Universidad de Santiago de Compostela, Santiago de Compostela, Spain. .,European Reference Network for Hereditary Metabolic Disorders (MetabERN), Padova, Italy.
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21
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Barbetti F, Rapini N, Schiaffini R, Bizzarri C, Cianfarani S. The application of precision medicine in monogenic diabetes. Expert Rev Endocrinol Metab 2022; 17:111-129. [PMID: 35230204 DOI: 10.1080/17446651.2022.2035216] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 01/25/2022] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Monogenic diabetes, a form of diabetes mellitus, is caused by a mutation in a single gene and may account for 1-2% of all clinical forms of diabetes. To date, more than 40 loci have been associated with either isolated or syndromic monogenic diabetes. AREAS COVERED While the request of a genetic test is mandatory for cases with diabetes onset in the first 6 months of life, a decision may be difficult for childhood or adolescent diabetes. In an effort to assist the clinician in this task, we have grouped monogenic diabetes genes according to the age of onset (or incidental discovery) of hyperglycemia and described the additional clinical features found in syndromic diabetes. The therapeutic options available are reviewed. EXPERT OPINION Technical improvements in DNA sequencing allow for rapid, simultaneous analysis of all genes involved in monogenic diabetes, progressively shrinking the area of unsolved cases. However, the complexity of the analysis of genetic data requires close cooperation between the geneticist and the diabetologist, who should play a proactive role by providing a detailed clinical phenotype that might match a specific disease gene.
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Affiliation(s)
- Fabrizio Barbetti
- Department of Experimental Medicine, University of Rome Tor Vergata, Rome, Italy
- Diabetology and Growth Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Novella Rapini
- Diabetology and Growth Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Riccardo Schiaffini
- Diabetology and Growth Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Carla Bizzarri
- Diabetology and Growth Disorders Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
| | - Stefano Cianfarani
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- Dipartimento Pediatrico Universitario Ospedaliero, IRCCS "Bambino Gesù" Children's Hospital, Rome, Italy
- Department of Women's and Children Health, Karolisnska Institute and University Hospital, Sweden
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22
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Jungtrakoon Thamtarana P, Marucci A, Pannone L, Bonnefond A, Pezzilli S, Biagini T, Buranasupkajorn P, Hastings T, Mendonca C, Marselli L, Di Paola R, Abubakar Z, Mercuri L, Alberico F, Flex E, Ceròn J, Porta-de-la-Riva M, Ludovico O, Carella M, Martinelli S, Marchetti P, Mazza T, Froguel P, Trischitta V, Doria A, Prudente S. Gain of Function of Malate Dehydrogenase 2 and Familial Hyperglycemia. J Clin Endocrinol Metab 2022; 107:668-684. [PMID: 34718610 PMCID: PMC8852227 DOI: 10.1210/clinem/dgab790] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Genes causing familial forms of diabetes mellitus are only partially known. OBJECTIVE We set out to identify the genetic cause of hyperglycemia in multigenerational families with an apparent autosomal dominant form of adult-onset diabetes not due to mutations in known monogenic diabetes genes. METHODS Existing whole-exome sequencing (WES) data were used to identify exonic variants segregating with diabetes in 60 families from the United States and Italy. Functional studies were carried out in vitro (transduced MIN6-K8 cells) and in vivo (Caenorhabditis elegans) to assess the diabetogenic potential of 2 variants in the malate dehydrogenase 2 (MDH2) gene linked with hyperglycemia in 2 of the families. RESULTS A very rare mutation (p.Arg52Cys) in MDH2 strongly segregated with hyperglycemia in 1 family from the United States. An infrequent MDH2 missense variant (p.Val160Met) also showed disease cosegregation in a family from Italy, although with reduced penetrance. In silico, both Arg52Cys and Val160Met were shown to affect MDH2 protein structure and function. In transfected HepG2 cells, both variants significantly increased MDH2 enzymatic activity, thereby decreasing the NAD+/NADH ratio-a change known to affect insulin signaling and secretion. Stable expression of human wild-type MDH2 in MIN6-K8 cell lines enhanced glucose- and GLP-1-stimulated insulin secretion. This effect was blunted by the Cys52 or Met160 substitutions. Nematodes carrying equivalent changes at the orthologous positions of the mdh-2 gene showed impaired glucose-stimulated insulin secretion. CONCLUSION Our findings suggest a central role of MDH2 in human glucose homeostasis and indicate that gain of function variants in this gene may be involved in the etiology of familial forms of diabetes.
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Affiliation(s)
- Prapaporn Jungtrakoon Thamtarana
- Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, MA, USA
- Cellular and Molecular Biology of Diabetes Research Group, Siriraj Center of Research Excellence for Diabetes and Obesity, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Antonella Marucci
- Research Unit of Diabetes and Endocrine Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Luca Pannone
- Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, Rome, Italy
| | - Amélie Bonnefond
- Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, France
- Université de Lille, CHU de Lille, Lille, France
- Department of Metabolism, Imperial College London, London, UK
| | - Serena Pezzilli
- Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo,Italy
- Medical Genetics, University of Chieti, Chieti, Italy
| | - Tommaso Biagini
- Unit of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo,Italy
| | | | - Timothy Hastings
- Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, MA, USA
| | - Christine Mendonca
- Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, MA, USA
| | - Lorella Marselli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Rosa Di Paola
- Research Unit of Diabetes and Endocrine Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Zuroida Abubakar
- Cellular and Molecular Biology of Diabetes Research Group, Siriraj Center of Research Excellence for Diabetes and Obesity, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Luana Mercuri
- Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo,Italy
| | - Federica Alberico
- Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo,Italy
| | - Elisabetta Flex
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Julian Ceròn
- Modeling human diseases in C. elegans. Genes, Diseases and Therapies Program, Bellvitge Biomedical Research Institute – IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain
| | - Montserrat Porta-de-la-Riva
- Modeling human diseases in C. elegans. Genes, Diseases and Therapies Program, Bellvitge Biomedical Research Institute – IDIBELL, L’Hospitalet de Llobregat, Barcelona, Spain
| | - Ornella Ludovico
- Department of Clinical Sciences, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo,Italy
| | - Massimo Carella
- Research Unit of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo,Italy
| | - Simone Martinelli
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Tommaso Mazza
- Unit of Bioinformatics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo,Italy
| | - Philippe Froguel
- Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille, France
- Université de Lille, CHU de Lille, Lille, France
- Department of Metabolism, Imperial College London, London, UK
| | - Vincenzo Trischitta
- Research Unit of Diabetes and Endocrine Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
- Department of Experimental Medicine, Sapienza University, Rome, Italy
| | - Alessandro Doria
- Research Division, Joslin Diabetes Center, and Harvard Medical School, Boston, MA, USA
- Alessandro Doria, MD, PhD, MPH, Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA.
| | - Sabrina Prudente
- Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo,Italy
- Correspondence: Sabrina Prudente, PhD, Fondazione IRCCS Casa Sollievo della Sofferenza, CSS-Mendel Institute, Viale Regina Margherita 261, 00198 Rome, Italy.
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23
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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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24
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Zhou M, Ren G, Zhang B, Ma F, Fan J, Qiu Z. Screening and identification of a novel antidiabetic peptide from collagen hydrolysates of Chinese giant salamander skin: Network pharmacology, inhibition kinetics and protection of IR-HepG2 cells. Food Funct 2022; 13:3329-3342. [DOI: 10.1039/d1fo03527d] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
In this study, a novel peptide GPPGPA was screened from the collagen hydrolysates of Chinese giant salamander (Andrias davidianus) skin, and anti-diabetes mechanism was predicted by network pharmacology, and inhibitory...
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25
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Dabi YT, Degechisa ST. Genome Editing and Human Pluripotent Stem Cell Technologies for in vitro Monogenic Diabetes Modeling. Diabetes Metab Syndr Obes 2022; 15:1785-1797. [PMID: 35719247 PMCID: PMC9199525 DOI: 10.2147/dmso.s366967] [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: 03/25/2022] [Accepted: 06/08/2022] [Indexed: 12/01/2022] Open
Abstract
Diabetes is a metabolic disease characterized by chronic hyperglycemia. Polygenic diabetes, which encompasses type-1 and type-2 diabetes, is the most prevalent kind of diabetes and is caused by a combination of different genetic and environmental factors, whereas rare phenotype monogenic diabetes is caused by a single gene mutation. Monogenic diabetes includes Neonatal diabetes mellitus and Maturity-onset diabetes of the young. The majority of our current knowledge about the pathogenesis of diabetes stems from studies done on animal models. However, the genetic difference between these creatures and humans makes it difficult to mimic human clinical pathophysiology, limiting their value in modeling key aspects of human disease. Human pluripotent stem cell technologies combined with genome editing techniques have been shown to be better alternatives for creating in vitro models that can provide crucial knowledge about disease etiology. This review paper addresses genome editing and human pluripotent stem cell technologies for in vitro monogenic diabetes modeling.
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Affiliation(s)
- Yosef Tsegaye Dabi
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
- Department of Medical Laboratory Science, Wollega University, Nekemte, Ethiopia
- Correspondence: Yosef Tsegaye Dabi, Email
| | - Sisay Teka Degechisa
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
- Department of Medical Laboratory Sciences, College of Medicine and Health Sciences, Arba Minch University, Arba Minch, Ethiopia
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26
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Maturity-Onset Diabetes of the Young (MODY): Genetic Causes, Clinical Characteristics, Considerations for Testing, and Treatment Options. ENDOCRINES 2021. [DOI: 10.3390/endocrines2040043] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Maturity Onset Diabetes of the Young (MODY) encompasses a group of rare monogenic forms of diabetes distinct in etiology and clinical presentation from the more common forms of Type 1 (autoimmune) and Type 2 diabetes. Since its initial description as a clinical entity nearly 50 years ago, the underlying genetic basis for the various forms of MODY has been increasingly better elucidated. Clinically, the diagnosis may be made in childhood or young adulthood and can present as overt hyperglycemia requiring insulin therapy or as a subtle form of slowly progressive glucose impairment. Due to the heterogeneity of clinical symptoms, patients with MODY may be misdiagnosed as possessing another form of diabetes, resulting in potentially inappropriate treatment and delays in screening of affected family members and associated comorbidities. In this review, we highlight the various known genetic mutations associated with MODY, clinical presentation, indications for testing, and the treatment options available.
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27
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Zhou X, Guo W, Yin H, Chen J, Ma L, Yang Q, Zhao Y, Li S, Liu W, Li H. Whole Exome Sequencing Study in a Family with Type 2 Diabetes Mellitus. Int J Gen Med 2021; 14:8217-8229. [PMID: 34815695 PMCID: PMC8605871 DOI: 10.2147/ijgm.s335090] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/01/2021] [Indexed: 12/25/2022] Open
Abstract
Background Type 2 diabetes mellitus (T2DM) is characterized by β cell decline in the pancreas and insulin resistance. This study aimed to investigate the possible pathogenic gene mutation sites of T2DM patients using whole exome sequencing. Materials and Methods We recruited a Chinese family with 3-generation history of diabetes. The whole blood genomic DNA of seven members of the family was extracted and sent for whole exome sequencing. Biological information was analyzed with in silico prediction methods, including significance analysis of single nucleotide polymorphism (SNP)/Indel site, and analysis of specific SNP/Indel proteins and their potential mechanisms. Results Six out of seven members of the family were diagnosed with diabetes. All DNA samples (23 kb) met quality requirements of library construction. Clean reads of each sample demonstrated high Q20 and Q30 (>80%), indicating good sequencing quality of sequencing data. A total of 130,693 SNPs and 15,928 Indels were found in DNA samples. A total of 22 significant SNPs and Indel mutation sites located on 19 genes were obtained, including ZCCHC3, SYN2, RPL14, SRRD, AMD1, CAMKK2, ZNF787, RNF157, NPIPB15, ALG3, KIAA0040, MAST2, ESRRA, C8orf58, PNLIPRP1, DACH1, MACC1, CAPN9 and DMKN. An rs2305205 mutation of PNLIPRP1 gene and an rs778701848 mutation of CAMKK2 gene may be associated with the pathogenesis of T2DM in this family. Conclusion Exons of these diabetic patients demonstrated an rs2305205 mutation in PNLIPRP1 gene and an rs778701848 mutation in CAMKK2 gene. These two mutations might promote T2DM occurrence through reducing sensitivity of peripheral tissue to insulin and reducing insulin secretion.
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Affiliation(s)
- Xiaowei Zhou
- Department of Diabetes, The First Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China
| | - Weichang Guo
- Department of Physical Education, Kunming Medical University, Kunming, People's Republic of China
| | - Hejia Yin
- Department of Diabetes, The First Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China
| | - Jie Chen
- Department of Diabetes, The First Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China
| | - Liju Ma
- Department of Clinical Laboratory, First Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China
| | - Qiuping Yang
- Department of Geriatrics, The First Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China
| | - Yan Zhao
- Department of Diabetes, The First Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China
| | - Shaoyou Li
- Department of NHC Key Laboratory of Drug Addiction Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China
| | - Weijun Liu
- Department of Diabetes, The First Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China
| | - Huifang Li
- Department of Diabetes, The First Affiliated Hospital of Kunming Medical University, Kunming, People's Republic of China
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The APPL1-Rab5 axis restricts NLRP3 inflammasome activation through early endosomal-dependent mitophagy in macrophages. Nat Commun 2021; 12:6637. [PMID: 34789781 PMCID: PMC8599493 DOI: 10.1038/s41467-021-26987-1] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 10/22/2021] [Indexed: 12/26/2022] Open
Abstract
Although mitophagy is known to restrict NLRP3 inflammasome activation, the underlying regulatory mechanism remains poorly characterized. Here we describe a type of early endosome-dependent mitophagy that limits NLRP3 inflammasome activation. Deletion of the endosomal adaptor protein APPL1 impairs mitophagy, leading to accumulation of damaged mitochondria producing reactive oxygen species (ROS) and oxidized cytosolic mitochondrial DNA, which in turn trigger NLRP3 inflammasome overactivation in macrophages. NLRP3 agonist causes APPL1 to translocate from early endosomes to mitochondria, where it interacts with Rab5 to facilitate endosomal-mediated mitophagy. Mice deficient for APPL1 specifically in hematopoietic cell are more sensitive to endotoxin-induced sepsis, obesity-induced inflammation and glucose dysregulation. These are associated with increased expression of systemic interleukin-1β, a major product of NLRP3 inflammasome activation. Our findings indicate that the early endosomal machinery is essential to repress NLRP3 inflammasome hyperactivation by promoting mitophagy in macrophages.
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Tosur M, Soler-Alfonso C, Chan KM, Khayat MM, Jhangiani SN, Meng Q, Refaey A, Muzny D, Gibbs RA, Murdock DR, Posey JE, Balasubramanyam A, Redondo MJ, Sabo A. Exome sequencing in children with clinically suspected maturity-onset diabetes of the young. Pediatr Diabetes 2021; 22:960-968. [PMID: 34387403 PMCID: PMC8530905 DOI: 10.1111/pedi.13257] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Accepted: 08/09/2021] [Indexed: 01/24/2023] Open
Abstract
OBJECTIVE Commercial gene panels identify pathogenic variants in as low as 27% of patients suspected to have MODY, suggesting the role of yet unidentified pathogenic variants. We sought to identify novel gene variants associated with MODY. RESEARCH DESIGN AND METHODS We recruited 10 children with a clinical suspicion of MODY but non-diagnostic commercial MODY gene panels. We performed exome sequencing (ES) in them and their parents. RESULTS Mean age at diabetes diagnosis was 10 (± 3.8) years. Six were females; 4 were non-Hispanic white, 5 Hispanic, and 1 Asian. Our variant prioritization analysis identified a pathogenic, de novo variant in INS (c.94G > A, p.Gly32Ser), confirmed by Sanger sequencing, in a proband who was previously diagnosed with "autoantibody-negative type 1 diabetes (T1D)" at 3 y/o. This rare variant, absent in the general population (gnomAD database), has been reported previously in neonatal diabetes. We also identified a frameshift deletion (c.2650delC, p.Gln884AsnfsTer57) in RFX6 in a child with a previous diagnosis of "autoantibody-negative T1D" at 12 y/o. The variant was inherited from the mother, who was diagnosed with "thin type 2 diabetes" at 25 y/o. Heterozygous protein-truncating variants in RFX6 gene have been recently reported in individuals with MODY. CONCLUSIONS We diagnosed two patients with MODY using ES in children initially classified as "T1D". One has a likely pathogenic novel gene variant not previously associated with MODY. We demonstrate the clinical utility of ES in patients with clinical suspicion of MODY.
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Affiliation(s)
- Mustafa Tosur
- Department of Pediatrics, The Section of Diabetes and Endocrinology, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA
| | - Claudia Soler-Alfonso
- Department of Molecular and Human Genetics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA
| | - Katie M Chan
- Department of Molecular and Human Genetics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA
| | - Michael M Khayat
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
| | - Shalini N Jhangiani
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
| | - Qingchang Meng
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
| | | | - Donna Muzny
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
| | - Richard A Gibbs
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
| | - David R Murdock
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
| | - Jennifer E Posey
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
| | - Ashok Balasubramanyam
- Baylor College of Medicine, Division of Diabetes, Endocrinology and Metabolism, Houston, TX, USA
| | - Maria J Redondo
- Department of Pediatrics, The Section of Diabetes and Endocrinology, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, USA
| | - Aniko Sabo
- Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA
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Abstract
This review focuses on the human pancreatic islet-including its structure, cell composition, development, function, and dysfunction. After providing a historical timeline of key discoveries about human islets over the past century, we describe new research approaches and technologies that are being used to study human islets and how these are providing insight into human islet physiology and pathophysiology. We also describe changes or adaptations in human islets in response to physiologic challenges such as pregnancy, aging, and insulin resistance and discuss islet changes in human diabetes of many forms. We outline current and future interventions being developed to protect, restore, or replace human islets. The review also highlights unresolved questions about human islets and proposes areas where additional research on human islets is needed.
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Affiliation(s)
- John T Walker
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Diane C Saunders
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Marcela Brissova
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
| | - Alvin C Powers
- Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
- Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- VA Tennessee Valley Healthcare System, Nashville, Tennessee, USA
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31
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Chen Y, Hu X, Cui J, Zhao M, Yao H. A novel mutation KCNJ11 R136C caused KCNJ11-MODY. Diabetol Metab Syndr 2021; 13:91. [PMID: 34465386 PMCID: PMC8406974 DOI: 10.1186/s13098-021-00708-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 08/11/2021] [Indexed: 11/16/2022] Open
Abstract
A young female patient, diagnosed with diabetes mellitus at the age of 28 years old in 2009, carries KCNJ11 R136C by whole exome sequencing and her daughter doesn't carry this mutation. Bioinformatics software predicted that the 136th amino acid is highly conservative and the mutation is deleterious. KCNJ11 R136C can result in the change of channel port structure of KATP channel. So she was diagnosed as KCNJ11-MODY.
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Affiliation(s)
- Yaning Chen
- Department of Endocrinology, Sixth Medical Center of PLA General Hospital, 6# Fucheng Road, Haidian District, Beijing, 100048, China
| | - Xiaodong Hu
- Department of Endocrinology, Sixth Medical Center of PLA General Hospital, 6# Fucheng Road, Haidian District, Beijing, 100048, China
| | - Jia Cui
- Department of Endocrinology, Sixth Medical Center of PLA General Hospital, 6# Fucheng Road, Haidian District, Beijing, 100048, China
| | - Mingwei Zhao
- Department of Endocrinology, Sixth Medical Center of PLA General Hospital, 6# Fucheng Road, Haidian District, Beijing, 100048, China
| | - Hebin Yao
- Department of Endocrinology, Sixth Medical Center of PLA General Hospital, 6# Fucheng Road, Haidian District, Beijing, 100048, China.
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32
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Heller S, Melzer MK, Azoitei N, Julier C, Kleger A. Human Pluripotent Stem Cells Go Diabetic: A Glimpse on Monogenic Variants. Front Endocrinol (Lausanne) 2021; 12:648284. [PMID: 34079523 PMCID: PMC8166226 DOI: 10.3389/fendo.2021.648284] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Accepted: 04/13/2021] [Indexed: 12/17/2022] Open
Abstract
Diabetes, as one of the major diseases in industrial countries, affects over 350 million people worldwide. Type 1 (T1D) and type 2 diabetes (T2D) are the most common forms with both types having invariable genetic influence. It is accepted that a subset of all diabetes patients, generally estimated to account for 1-2% of all diabetic cases, is attributed to mutations in single genes. As only a subset of these genes has been identified and fully characterized, there is a dramatic need to understand the pathophysiological impact of genetic determinants on β-cell function and pancreatic development but also on cell replacement therapies. Pluripotent stem cells differentiated along the pancreatic lineage provide a valuable research platform to study such genes. This review summarizes current perspectives in applying this platform to study monogenic diabetes variants.
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Affiliation(s)
- Sandra Heller
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Michael Karl Melzer
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
- Department of Urology, Ulm University Hospital, Ulm, Germany
| | - Ninel Azoitei
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
| | - Cécile Julier
- Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR-8104, Paris, France
| | - Alexander Kleger
- Department of Internal Medicine I, Ulm University Hospital, Ulm, Germany
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Sanchez Caballero L, Gorgogietas V, Arroyo MN, Igoillo-Esteve M. Molecular mechanisms of β-cell dysfunction and death in monogenic forms of diabetes. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2021; 359:139-256. [PMID: 33832649 DOI: 10.1016/bs.ircmb.2021.02.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Monogenetic forms of diabetes represent 1%-5% of all diabetes cases and are caused by mutations in a single gene. These mutations, that affect genes involved in pancreatic β-cell development, function and survival, or insulin regulation, may be dominant or recessive, inherited or de novo. Most patients with monogenic diabetes are very commonly misdiagnosed as having type 1 or type 2 diabetes. The severity of their symptoms depends on the nature of the mutation, the function of the affected gene and, in some cases, the influence of additional genetic or environmental factors that modulate severity and penetrance. In some patients, diabetes is accompanied by other syndromic features such as deafness, blindness, microcephaly, liver and intestinal defects, among others. The age of diabetes onset may also vary from neonatal until early adulthood manifestations. Since the different mutations result in diverse clinical presentations, patients usually need different treatments that range from just diet and exercise, to the requirement of exogenous insulin or other hypoglycemic drugs, e.g., sulfonylureas or glucagon-like peptide 1 analogs to control their glycemia. As a consequence, awareness and correct diagnosis are crucial for the proper management and treatment of monogenic diabetes patients. In this chapter, we describe mutations causing different monogenic forms of diabetes associated with inadequate pancreas development or impaired β-cell function and survival, and discuss the molecular mechanisms involved in β-cell demise.
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Affiliation(s)
- Laura Sanchez Caballero
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/
| | - Vyron Gorgogietas
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/
| | - Maria Nicol Arroyo
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/
| | - Mariana Igoillo-Esteve
- ULB Center for Diabetes Research (UCDR), Université Libre de Bruxelles, Brussels, Belgium. http://www.ucdr.be/.
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Charoensuk C, Thamtarana PJ, Chanprasert C, Tangjittipokin W, Shirakawa J, Togashi Y, Orime K, Songprakhon P, Chaichana C, Abubakar Z, Ouying P, Sujjitjoon J, Doria A, Plengvidhya N, Yenchitsomanus PT. Autosomal dominant diabetes associated with a novel ZYG11A mutation resulting in cell cycle arrest in beta-cells. Mol Cell Endocrinol 2021; 522:111126. [PMID: 33321115 DOI: 10.1016/j.mce.2020.111126] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 12/09/2020] [Accepted: 12/11/2020] [Indexed: 01/20/2023]
Abstract
Diabetes is a genetically heterogeneous disease, for which we are aiming to identify causative genes. Here, we report a missense mutation (c.T1424C:p.L475P) in ZYG11A identified by exome sequencing as segregating with hyperglycemia in a Thai family with autosomal dominant diabetes. ZYG11A functions as a target recruitment subunit of an E3 ubiquitin ligase complex that plays an important role in the regulation of cell cycle. We demonstrate an increase in cells arrested at G2/mitotic phase among beta-cells deficient for ZYG11A or overexpressing L475P-ZYG11A, which is associated with a decreased growth rate. This is the first evidence linking a ZYG11A mutation to hyperglycemia, and suggesting ZYG11A as a cell cycle regulator required for beta-cell growth. Since most family members were either overweight or obese, but only mutation carriers developed hyperglycemia, our data also suggests the ZYG11A mutation as a genetic factor predisposing obese individuals to beta-cell failure in maintenance of glucose homeostasis.
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Affiliation(s)
- Chutima Charoensuk
- Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Cellular and Molecular Biology of Diabetes Research Group, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Prapaporn Jungtrakoon Thamtarana
- Cellular and Molecular Biology of Diabetes Research Group, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
| | - Chutima Chanprasert
- Cellular and Molecular Biology of Diabetes Research Group, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Watip Tangjittipokin
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Jun Shirakawa
- Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi, 371-8512, Japan; Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Yu Togashi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Kazuki Orime
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Yokohama, Japan
| | - Pucharee Songprakhon
- Cellular and Molecular Biology of Diabetes Research Group, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Chartchai Chaichana
- Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Zuroida Abubakar
- Cellular and Molecular Biology of Diabetes Research Group, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Paweena Ouying
- Cellular and Molecular Biology of Diabetes Research Group, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Jatuporn Sujjitjoon
- Cellular and Molecular Biology of Diabetes Research Group, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Alessandro Doria
- Section on Genetics and Epidemiology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Nattachet Plengvidhya
- Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Pa-Thai Yenchitsomanus
- Cellular and Molecular Biology of Diabetes Research Group, Division of Molecular Medicine, Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand.
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35
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Zhang H, Colclough K, Gloyn AL, Pollin TI. Monogenic diabetes: a gateway to precision medicine in diabetes. J Clin Invest 2021; 131:142244. [PMID: 33529164 PMCID: PMC7843214 DOI: 10.1172/jci142244] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Monogenic diabetes refers to diabetes mellitus (DM) caused by a mutation in a single gene and accounts for approximately 1%-5% of diabetes. Correct diagnosis is clinically critical for certain types of monogenic diabetes, since the appropriate treatment is determined by the etiology of the disease (e.g., oral sulfonylurea treatment of HNF1A/HNF4A-diabetes vs. insulin injections in type 1 diabetes). However, achieving a correct diagnosis requires genetic testing, and the overlapping of the clinical features of monogenic diabetes with those of type 1 and type 2 diabetes has frequently led to misdiagnosis. Improvements in sequencing technology are increasing opportunities to diagnose monogenic diabetes, but challenges remain. In this Review, we describe the types of monogenic diabetes, including common and uncommon types of maturity-onset diabetes of the young, multiple causes of neonatal DM, and syndromic diabetes such as Wolfram syndrome and lipodystrophy. We also review methods of prioritizing patients undergoing genetic testing, and highlight existing challenges facing sequence data interpretation that can be addressed by forming collaborations of expertise and by pooling cases.
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Affiliation(s)
- Haichen Zhang
- University of Maryland School of Medicine, Department of Medicine, Baltimore, Maryland, USA
| | - Kevin Colclough
- Exeter Genomics Laboratory, Royal Devon and Exeter Hospital, Exeter, United Kingdom
| | - Anna L. Gloyn
- Department of Pediatrics, Division of Endocrinology, and,Stanford Diabetes Research Center, Stanford School of Medicine, Stanford, California, USA
| | - Toni I. Pollin
- University of Maryland School of Medicine, Department of Medicine, Baltimore, Maryland, USA
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Broome DT, Pantalone KM, Kashyap SR, Philipson LH. Approach to the Patient with MODY-Monogenic Diabetes. J Clin Endocrinol Metab 2021; 106:237-250. [PMID: 33034350 PMCID: PMC7765647 DOI: 10.1210/clinem/dgaa710] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 10/02/2020] [Indexed: 12/14/2022]
Abstract
UNLABELLED Maturity-onset diabetes of the young, or MODY-monogenic diabetes, is a not-so-rare collection of inherited disorders of non-autoimmune diabetes mellitus that remains insufficiently diagnosed despite increasing awareness. These cases are important to efficiently and accurately diagnose, given the clinical implications of syndromic features, cost-effective treatment regimen, and the potential impact on multiple family members. Proper recognition of the clinical manifestations, family history, and cost-effective lab and genetic testing provide the diagnosis. All patients must undergo a thorough history, physical examination, multigenerational family history, lab evaluation (glycated hemoglobin A1c [HbA1c], glutamic acid decarboxylase antibodies [GADA], islet antigen 2 antibodies [IA-2A], and zinc transporter 8 [ZnT8] antibodies). The presence of clinical features with 3 (or more) negative antibodies may be indicative of MODY-monogenic diabetes, and is followed by genetic testing. Molecular genetic testing should be performed before attempting specific treatments in most cases. Additional testing that is helpful in determining the risk of MODY-monogenic diabetes is the MODY clinical risk calculator (>25% post-test probability in patients not treated with insulin within 6 months of diagnosis should trigger genetic testing) and 2-hour postprandial (after largest meal of day) urinary C-peptide to creatinine ratio (with a ≥0.2 nmol/mmol to distinguish HNF1A- or 4A-MODY from type 1 diabetes). Treatment, as well as monitoring for microvascular and macrovascular complications, is determined by the specific variant that is identified. In addition to the diagnostic approach, this article will highlight recent therapeutic advancements when patients no longer respond to first-line therapy (historically sulfonylurea treatment in many variants). LEARNING OBJECTIVES Upon completion of this educational activity, participants should be able to. TARGET AUDIENCE This continuing medical education activity should be of substantial interest to endocrinologists and all health care professionals who care for people with diabetes mellitus.
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Affiliation(s)
- David T Broome
- Department of Endocrinology, Diabetes & Metabolism, Cleveland Clinic Foundation, Cleveland, Ohio
- Correspondence and Reprint Requests: David T. Broome, MD, Department of Endocrinology, Diabetes & Metabolism, Cleveland Clinic Foundation, 9500 Euclid Avenue, Mail code: F-20, Cleveland, OH 44195, USA. E-mail:
| | - Kevin M Pantalone
- Department of Endocrinology, Diabetes & Metabolism, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Sangeeta R Kashyap
- Department of Endocrinology, Diabetes & Metabolism, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Louis H Philipson
- Kovler Diabetes Center, Departments of Medicine and Pediatrics, University of Chicago, Chicago, Illinois
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Jiang F, Yan J, Zhang R, Ma X, Bao Y, Gu Y, Hu C. Functional Characterization of a Novel Heterozygous Mutation in the Glucokinase Gene That Causes MODY2 in Chinese Pedigrees. Front Endocrinol (Lausanne) 2021; 12:803992. [PMID: 34956103 PMCID: PMC8695754 DOI: 10.3389/fendo.2021.803992] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 11/22/2021] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND Glucokinase (GCK) plays a central role in glucose regulation. The heterozygous mutations of GCK can cause a monogenic form of diabetes, maturity-onset diabetes of the young (MODY) directly. In our study, we aimed to explore the mechanism of the novel mutation GCK p.Ala259Thr leading to glucokinase deficiency and hyperglycemia. METHODS Thirty early-onset diabetes pedigrees were referred to whole exome sequencing for novel mutations identification. Purified wild-type and mutant GCK proteins were obtained from E.coli systems and then subjected to the kinetic and thermal stability analysis to test the effects on GCK activity. RESULTS One novel missense mutation GCK p.Ala259Thr was identified and co-segregated with diabetes in a Chinese MODY2 pedigree. The kinetic analysis showed that this mutation result in a decreased affinity and catalytic capability for glucose. The thermal stability analysis also indicated that the mutant protein presented dramatically decreased activity at the same temperature. CONCLUSION Our study firstly identified a novel MODY2 mutation p.Ala259Thr in Chinese diabetes pedigrees. The kinetic and thermal stability analysis confirmed that this mutation caused hyperglycemia through severely damaging the enzyme activities and protein stability.
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Affiliation(s)
- Feng Jiang
- Department of Endocrinology, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Jing Yan
- Department of Endocrinology, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Rong Zhang
- Department of Endocrinology, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Xiaojing Ma
- Department of Endocrinology, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Yuqian Bao
- Department of Endocrinology, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Yujuan Gu
- Department of Endocrinology, Affiliated Hospital of Nantong University, Jiangsu, China
- *Correspondence: Cheng Hu, ; Yujuan Gu,
| | - Cheng Hu
- Department of Endocrinology, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
- Department of Endocrinology, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai, China
- *Correspondence: Cheng Hu, ; Yujuan Gu,
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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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Abstract
Although type 1 diabetes mellitus and, to a lesser extent, type 2 diabetes mellitus, are the prevailing forms of diabetes in youth, atypical forms of diabetes are not uncommon and may require etiology-specific therapies. By some estimates, up to 6.5% of children with diabetes have monogenic forms. Mitochondrial diabetes and cystic fibrosis related diabetes are less common but often noted in the underlying disease. Atypical diabetes should be considered in patients with a known disorder associated with diabetes, aged less than 25 years with nonautoimmune diabetes and without typical characteristics of type 2 diabetes mellitus, and/or with comorbidities associated with atypical diabetes.
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Affiliation(s)
- Jaclyn Tamaroff
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, 3500 Civic Center Boulevard, 12th Floor, Philadelphia, PA 19104, USA.
| | - Marissa Kilberg
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, 3500 Civic Center Boulevard, 12th Floor, Philadelphia, PA 19104, USA
| | - Sara E Pinney
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, 3500 Civic Center Boulevard, 12th Floor, Philadelphia, PA 19104, USA
| | - Shana McCormack
- Division of Endocrinology and Diabetes, Children's Hospital of Philadelphia, 3500 Civic Center Boulevard, 12th Floor, Philadelphia, PA 19104, 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: 89] [Impact Index Per Article: 17.8] [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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Yalçın Çapan Ö, Aydın N, Yılmaz T, Berber E. Whole exome sequencing reveals novel candidate gene variants for MODY. Clin Chim Acta 2020; 510:97-104. [DOI: 10.1016/j.cca.2020.07.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/20/2020] [Accepted: 07/02/2020] [Indexed: 11/30/2022]
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The adaptor protein APPL2 controls glucose-stimulated insulin secretion via F-actin remodeling in pancreatic β-cells. Proc Natl Acad Sci U S A 2020; 117:28307-28315. [PMID: 33122440 DOI: 10.1073/pnas.2016997117] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Filamentous actin (F-actin) cytoskeletal remodeling is critical for glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells, and its dysregulation causes type 2 diabetes. The adaptor protein APPL1 promotes first-phase GSIS by up-regulating soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein expression. However, whether APPL2 (a close homology of APPL1 with the same domain organization) plays a role in β-cell functions is unknown. Here, we show that APPL2 enhances GSIS by promoting F-actin remodeling via the small GTPase Rac1 in pancreatic β-cells. β-cell specific abrogation of APPL2 impaired GSIS, leading to glucose intolerance in mice. APPL2 deficiency largely abolished glucose-induced first- and second-phase insulin secretion in pancreatic islets. Real-time live-cell imaging and phalloidin staining revealed that APPL2 deficiency abolished glucose-induced F-actin depolymerization in pancreatic islets. Likewise, knockdown of APPL2 expression impaired glucose-stimulated F-actin depolymerization and subsequent insulin secretion in INS-1E cells, which were attributable to the impairment of Ras-related C3 botulinum toxin substrate 1 (Rac1) activation. Treatment with the F-actin depolymerization chemical compounds or overexpression of gelsolin (a F-actin remodeling protein) rescued APPL2 deficiency-induced defective GSIS. In addition, APPL2 interacted with Rac GTPase activating protein 1 (RacGAP1) in a glucose-dependent manner via the bin/amphiphysin/rvs-pleckstrin homology (BAR-PH) domain of APPL2 in INS-1E cells and HEK293 cells. Concomitant knockdown of RacGAP1 expression reverted APPL2 deficiency-induced defective GSIS, F-actin remodeling, and Rac1 activation in INS-1E cells. Our data indicate that APPL2 interacts with RacGAP1 and suppresses its negative action on Rac1 activity and F-actin depolymerization thereby enhancing GSIS in pancreatic β-cells.
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Lei SQ, Wang JY, Li RM, Chang J, Li Z, Ren L, Sang YM. MODY10 caused by c.309-314del CCAGCT insGCGC mutation of the insulin gene: a case report. Am J Transl Res 2020; 12:6599-6607. [PMID: 33194056 PMCID: PMC7653559] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 08/28/2020] [Indexed: 06/11/2023]
Abstract
OBJECTIVE This study aims to report the clinical features and gene mutation of a rare MODY10 patient in China. METHODS This study summarizes the clinical data of a MODY10 child in the Endocrine Department of our hospital and an analysis and discussion of the results of the gene sequencing of the child. RESULTS The child was a two-year-old boy. The main reason for his visit to our hospital was "founding hyperglycemia for 3 days". The fasting blood glucose was between 8.1-10.7 mmol/L, and two-hour postprandial blood glucose was between 10.6-12.6 mmol/L. Glycosylated hemoglobin was 8.5%, fasting C-peptide was 0.6 ng/mL, fasting insulin was 2.9 μIU/mL, and the islet antibody series were all negative. Whole-genome/exon sequencing results: Exon 3 of the insulin gene in the child carried a c.309-314del CCAGCT insGCGC heterozygous mutation. The mutation was a nonsense mutation, and family sequencing showed that the mutation originated from the mother of the child. The mother of the child was diagnosed with diabetes when she was a year old and developed bilateral fundus hemorrhage and right retinal detachment at the age of 23. CONCLUSION Among Chinese children, the insulin gene c.309-314del CCAGCT insGCGC mutation may induce MODY10. For diabetic children with a negative islet autoantibody, gene detection and analysis is helpful for the diagnosis and typing of MODY.
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Affiliation(s)
- Shu-Qin Lei
- Department of Endocrinology, Baoding Children’s Hospital, Baoding Key Laboratory of Clinical Research on Children’s Respiratory and Digestive DiseasesBao Ding 071000, Hebei, China
| | - Jie-Ying Wang
- Department of Endocrinology, Baoding Children’s Hospital, Baoding Key Laboratory of Clinical Research on Children’s Respiratory and Digestive DiseasesBao Ding 071000, Hebei, China
| | - Rong-Min Li
- Department of Endocrinology, Baoding Children’s Hospital, Baoding Key Laboratory of Clinical Research on Children’s Respiratory and Digestive DiseasesBao Ding 071000, Hebei, China
| | - Jie Chang
- Department of Endocrinology, Baoding Children’s Hospital, Baoding Key Laboratory of Clinical Research on Children’s Respiratory and Digestive DiseasesBao Ding 071000, Hebei, China
| | - Zhen Li
- Department of Endocrinology, Baoding Children’s Hospital, Baoding Key Laboratory of Clinical Research on Children’s Respiratory and Digestive DiseasesBao Ding 071000, Hebei, China
| | - Li Ren
- Department of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthBeijing 100045, China
| | - Yan-Mei Sang
- Department of Endocrinology, Genetics and Metabolism, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s HealthBeijing 100045, China
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Abstract
Diabetes mellitus is a chronic heterogeneous metabolic disorder with complex pathogenesis. It is characterized by elevated blood glucose levels or hyperglycemia, which results from abnormalities in either insulin secretion or insulin action or both. Hyperglycemia manifests in various forms with a varied presentation and results in carbohydrate, fat, and protein metabolic dysfunctions. Long-term hyperglycemia often leads to various microvascular and macrovascular diabetic complications, which are mainly responsible for diabetes-associated morbidity and mortality. Hyperglycemia serves as the primary biomarker for the diagnosis of diabetes as well. In this review, we would be focusing on the classification of diabetes and its pathophysiology including that of its various types.
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Affiliation(s)
- Mujeeb Z Banday
- Department of Biochemistry, Government Medical College and Associated Shri Maharaja Hari Singh Hospital, Srinagar, Kashmir, India
| | - Aga S Sameer
- Department of Basic Medical Sciences, College of Medicine, King Saud Bin Abdul Aziz University for Health Sciences, King Abdullah International Medical Research Centre, National Guard Health Affairs, Jeddah, Saudi Arabia
| | - Saniya Nissar
- Department of Biochemistry, Government Medical College and Associated Shri Maharaja Hari Singh Hospital, Srinagar, Kashmir, India
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Hu M, Cherkaoui I, Misra S, Rutter GA. Functional Genomics in Pancreatic β Cells: Recent Advances in Gene Deletion and Genome Editing Technologies for Diabetes Research. Front Endocrinol (Lausanne) 2020; 11:576632. [PMID: 33162936 PMCID: PMC7580382 DOI: 10.3389/fendo.2020.576632] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 09/17/2020] [Indexed: 12/13/2022] Open
Abstract
The inheritance of variants that lead to coding changes in, or the mis-expression of, genes critical to pancreatic beta cell function can lead to alterations in insulin secretion and increase the risk of both type 1 and type 2 diabetes. Recently developed clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) gene editing tools provide a powerful means of understanding the impact of identified variants on cell function, growth, and survival and might ultimately provide a means, most likely after the transplantation of genetically "corrected" cells, of treating the disease. Here, we review some of the disease-associated genes and variants whose roles have been probed up to now. Next, we survey recent exciting developments in CRISPR/Cas9 technology and their possible exploitation for β cell functional genomics. Finally, we will provide a perspective as to how CRISPR/Cas9 technology may find clinical application in patients with diabetes.
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Affiliation(s)
- Ming Hu
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Ines Cherkaoui
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Shivani Misra
- Metabolic Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, United Kingdom
| | - Guy A. Rutter
- Section of Cell Biology and Functional Genomics, Faculty of Medicine, Imperial College London, London, United Kingdom
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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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Liang H, Zhang Y, Li M, Yan J, Yang D, Luo S, Zheng X, Yang G, Li Z, Xu W, Groop L, Weng J. Recognition of maturity-onset diabetes of the young in China. J Diabetes Investig 2020; 12:501-509. [PMID: 32741144 PMCID: PMC8015824 DOI: 10.1111/jdi.13378] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 07/15/2020] [Accepted: 07/27/2020] [Indexed: 12/14/2022] Open
Abstract
Aims/Introduction Given that mutations related to maturity‐onset diabetes of the young (MODY) are rarely found in Chinese populations, we aim to characterize the mutation spectrum of MODY pedigrees. Materials and Methods Maturity‐onset diabetes of the young candidate gene‐ or exome‐targeted capture sequencing was carried out in 76 probands from unrelated families fulfilling the clinical diagnostic criteria for MODY. MAF <0.01 in the GnomAD or ExAC database was used to filter significant variants. Sanger sequencing was then carried out to validate findings. Function prediction by SIFT, PolyPhen‐2 and PROVEAN or CADD was carried out in missense mutations. Results A total of 32 mutations in six genes were identified in 31 families, accounting for 40.79% of the potential MODY families. The MODY subtype detection rate was 18.42% for GCK, 15.79% for HNF1A, 2.63% for HNF4A, and 1.32% for KLF11, PAX4 and NEUROG3. Seven nonsense/frameshift mutations and four missense mutations with damaging prediction were newly identified novel mutations. The clinical features of MODY2, MODY3/1 and MODYX are similar to previous reports. Clinical phenotype of NEUROG3 p.Arg55Glufs*23 is characterized by hyperglycemia and mild intermittent abdominal pain. Conclusions This study adds to the emerging pattern of MODY epidemiology that the proportion of MODY explained by known pathogenic genes is higher than that previously reported, and found NEUROG3 as a new causative gene for MODY.
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Affiliation(s)
- Hua Liang
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China
| | - Yanan Zhang
- Department of Infertility and Sexual Medicine, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
| | - Maixinyue Li
- Department of Clinical Laboratory, Nanning Children's Hospital, Nanning, China
| | - Jinhua Yan
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China
| | - Daizhi Yang
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China
| | - Sihui Luo
- Division of Life Sciences and Medicine, Department of Endocrinology, The First Affiliated Hospital, University of Science and Technology of China, Hefei, China
| | - Xueying Zheng
- Division of Life Sciences and Medicine, Department of Endocrinology, The First Affiliated Hospital, University of Science and Technology of China, Hefei, China
| | - Guoqing Yang
- Department of Endocrinology, Chinese PLA General Hospital, Beijing, China
| | - Zhuo Li
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China
| | - Wen Xu
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China
| | - Leif Groop
- Department of Clinical Sciences, Lund University Diabetes Center, Lund University, Malmö, Sweden
| | - Jianping Weng
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangdong Provincial Key Laboratory of Diabetology, Guangzhou, China.,Division of Life Sciences and Medicine, Department of Endocrinology, The First Affiliated Hospital, University of Science and Technology of China, Hefei, China
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Terakawa A, Chujo D, Yasuda K, Ueno K, Nakamura T, Hamano S, Ohsugi M, Tanabe A, Ueki K, Kajio H. Maturity-Onset diabetes of the young type 5 treated with the glucagon-like peptide-1 receptor agonist: A case report. Medicine (Baltimore) 2020; 99:e21939. [PMID: 32871938 PMCID: PMC7458169 DOI: 10.1097/md.0000000000021939] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
RATIONALE Maturity-onset diabetes of the young type 5 (MODY 5) is a form of monogenic diabetes that is often accompanied by pancreatic dysfunction. To date, no cases of MODY 5 treated with glucagon-like peptide-1 receptor agonist (GLP-1RA) have been reported. We present the first case of MODY 5 treated with GLP-1RA. PATIENT CONCERNS A 17-year-old woman, with a history of being operated for congenital ileal atresia at birth, was admitted to our hospital due to hyperglycemia. She had been clinically diagnosed with type 1 diabetes 1 month prior, and administered 14 units of insulin glargine 300 U/mL per day. DIAGNOSIS She had hypopotassemia, hypomagnesaemia, pancreatic body, and tail defects, multiple renal cysts, and a family history of diabetes, and urogenital anomaly. Genetic testing revealed heterozygous deletion of hepatocyte nuclear transcription factor-1 beta, leading to the diagnosis of MODY 5. INTERVENTIONS The patient was treated with multiple daily insulin injections for 9 days (22 units/d) before administration of GLP-1RA, and then liraglutide was initiated. OUTCOMES Liraglutide treatment (0.6 mg/d) alone maintained the patient's glycated hemoglobin level below 7.0% for at least 12 months after discharge. A higher dose, 0.9 mg/d, of liraglutide was not tolerated by the patient due to nausea. Serum levels of C-peptide immunoreactivity were 1.15 ng/mL and 1.91 ng/mL, respectively, after 6 and 12 months of liraglutide therapy. LESSONS GLP-1RA might be effective at regulating glucose metabolism by utilizing residual pancreatic endocrine function in patients with MODY 5. Imaging and genetic screening were helpful in the diagnosis of MODY 5.
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Affiliation(s)
- Aiko Terakawa
- Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo
| | - Daisuke Chujo
- Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo
- Center for Clinical Research, Toyama University Hospital, Toyama
| | - Kazuki Yasuda
- Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo
- Department of Diabetes, Endocrinology and Metabolism, Kyorin University, Mitaka
| | - Keisuke Ueno
- Department of Diabetes and Endocrinology, Tokyo Shinjuku Medical Center
| | - Tomoka Nakamura
- Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo
| | - Shoko Hamano
- Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo
- Mishuku Hospital, Tokyo, Japan
| | - Mitsuru Ohsugi
- Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo
| | - Akiyo Tanabe
- Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo
| | - Kohjiro Ueki
- Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo
| | - Hiroshi Kajio
- Department of Diabetes, Endocrinology and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo
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Analysis of APPL1 Gene Polymorphisms in Patients with a Phenotype of Maturity Onset Diabetes of the Young. J Pers Med 2020; 10:jpm10030100. [PMID: 32854233 PMCID: PMC7565648 DOI: 10.3390/jpm10030100] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/03/2020] [Accepted: 08/22/2020] [Indexed: 02/06/2023] Open
Abstract
The APPL1 gene encodes a protein mediating the cross-talk between adiponectin and insulin signaling. Recently, it was found that APPL1 mutations can cause maturity onset diabetes of the young, type 14. Here, an analysis of APPL1 was performed in patients with a maturity-onset diabetes of the young (MODY) phenotype, and prevalence of these mutations was estimated in a Russian population, among type 2 diabetes mellitus (T2DM) and MODY patients. Whole-exome sequencing or targeted sequencing was performed on 151 probands with a MODY phenotype, with subsequent association analysis of one of identified variants, rs11544593, in a white population of Western Siberia (276 control subjects and 169 T2DM patients). Thirteen variants were found in APPL1, three of which (rs79282761, rs138485817, and rs11544593) are located in exons. There were no statistically significant differences in the frequencies of rs11544593 alleles and genotypes between T2DM patients and the general population. In the MODY group, AG rs11544593 genotype carriers were significantly more frequent (AG vs. AA + GG: odds ratio 1.83, confidence interval 1.15-2.90, p = 0.011) compared with the control group. An association of rs11544593 with blood glucose concentration was revealed in the MODY group. The genotyping data suggest that rs11544593 may contribute to carbohydrate metabolism disturbances.
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Delvecchio M, Pastore C, Giordano P. Treatment Options for MODY Patients: A Systematic Review of Literature. Diabetes Ther 2020; 11:1667-1685. [PMID: 32583173 PMCID: PMC7376807 DOI: 10.1007/s13300-020-00864-4] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Indexed: 12/20/2022] Open
Abstract
Maturity-onset diabetes of the young (MODY) is an unusual form of diabetes with specific features that distinguish it from type 1 and type 2 diabetes. There are 14 known subtypes of MODY, and mutations in three genes (HNF1A, HNF4A, GCK) account for about 95% of all MODY cases. Diagnosis usually occurs before the age of 25 years, although less frequent forms may occur more often-but not necessarily-later in life. The molecular diagnosis may tailor the choice of the most appropriate treatment, with the aim to optimize blood glucose control, reduce the risk of hypoglycemic events and long-term complications, and enable proper genetic counseling. Treatment is usually unnecessary for patients with mutations in the GCK gene, while oral hypoglycemic agents (generally sulphonylureas) are recommended for patients with mutations in the HNF4A and HNF1A genes. More recent data show that other glucose-lowering agents can be effective in the latter patients, and additional and alternative therapies have been proposed. Proper management guidelines during pregnancy have been developed for carriers of GCK gene mutations, but such guidelines are still a subject of debate in other cases, although some recommendations are available. The other subtypes of MODY are even more rare, and very little data are available in the literature. In this review we summarize the most pertinent findings and recommendations on the treatment of patients with the different subtypes of MODY. Our aim is to provide the reader with an easy-to-read update that can be used to drive the clinician's therapeutical approach to these patients after the molecular diagnosis.
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Affiliation(s)
- Maurizio Delvecchio
- Metabolic Disorders and Diabetes Unit, "Giovanni XXIII" Children's Hospital, A.O.U. Policlinico di Bari, Bari, Italy.
| | - Carmela Pastore
- Pediatric Unit, Department of Biomedical Science and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
| | - Paola Giordano
- Pediatric Unit, Department of Biomedical Science and Human Oncology, University of Bari "Aldo Moro", Bari, Italy
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