|
1
|
Ba T, Ren Q, Gong S, Li M, Lian H, Cai X, Liu W, Luo Y, Zhang S, Zhang R, Zhou L, Zhu Y, Zhang X, Chen J, Wu J, Zhou X, Li Y, Wang X, Wang F, Zhong L, Han X, Ji L. Prevalence and Clinical Characteristics of NEUROD1-MODY in Chinese Early-Onset Type 2 Diabetes Mellitus and a Literature Review. J Diabetes 2025; 17:e70080. [PMID: 40148250 PMCID: PMC11949730 DOI: 10.1111/1753-0407.70080] [Citation(s) in RCA: 0] [Impact Index Per Article: 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: 05/30/2024] [Revised: 02/11/2025] [Accepted: 03/13/2025] [Indexed: 03/29/2025] Open
Abstract
BACKGROUND Maturity-onset diabetes of the young resulting from mutations of the NEUROD1 gene (NEUROD1-MODY) is a rare form of diabetes and has not been well studied. We aimed to estimate its prevalence in Chinese patients with early-onset type 2 diabetes mellitus (EOD) and summarize its clinical and genetic characteristics. METHODS We performed next-generation sequencing in 679 patients with EOD to screen rare variants in NEUROD1 exons and evaluated the effects of variants using in vitro experiments. All the reported NEUROD1-MODY cases were reviewed. Patients carrying pathogenic or likely pathogenic variants were diagnosed with NEUROD1-MODY according to the American College of Medical Genetics and Genomics guidelines. RESULTS Four rare variants were identified in 679 patients with EOD, but only P197H decreased the transcriptional activity in in vitro functional assays to an extent comparable to the well-known mutation causing NEUROD1-MODY. Its frequency was pretty higher in the European population (0.024) than that in the East Asian population (0.00034) according to the gnomAD database. Twenty-eight previously reported patients could be confirmed as diagnosed. The patients in Asia had a lower body mass index and a higher rate of ketosis compared with Caucasians, and the mutations present in Asia often occurred in the transactivation domain. Neurological abnormalities were observed in 10.7% of the patients with NEUROD1-MODY. CONCLUSIONS NEUROD1-MODY in Chinese patients with EOD is not common (≤ 0.15%). The P197H might account for MODY in Chinese with a higher penetrance than Caucasian and needs further exploration. The possible differences of phenotypes exist between the two ethnic populations.
Collapse
Affiliation(s)
- Tianhao Ba
- Department of Endocrinology and MetabolismPeking University People's Hospital, Peking University Diabetes CenterBeijingChina
| | - Qian Ren
- Department of Endocrinology and MetabolismPeking University People's Hospital, Peking University Diabetes CenterBeijingChina
| | - Siqian Gong
- Department of Endocrinology and MetabolismPeking University People's Hospital, Peking University Diabetes CenterBeijingChina
| | - Meng Li
- Department of Endocrinology and MetabolismPeking University People's Hospital, Peking University Diabetes CenterBeijingChina
| | - Hong Lian
- Department of Endocrinology and MetabolismPeking University People's Hospital, Peking University Diabetes CenterBeijingChina
| | - Xiaoling Cai
- Department of Endocrinology and MetabolismPeking University People's Hospital, Peking University Diabetes CenterBeijingChina
| | - Wei Liu
- Department of Endocrinology and MetabolismPeking University People's Hospital, Peking University Diabetes CenterBeijingChina
| | - Yingying Luo
- Department of Endocrinology and MetabolismPeking University People's Hospital, Peking University Diabetes CenterBeijingChina
| | - Simin Zhang
- Department of Endocrinology and MetabolismPeking University People's Hospital, Peking University Diabetes CenterBeijingChina
| | - Rui Zhang
- Department of Endocrinology and MetabolismPeking University People's Hospital, Peking University Diabetes CenterBeijingChina
| | - Lingli Zhou
- Department of Endocrinology and MetabolismPeking University People's Hospital, Peking University Diabetes CenterBeijingChina
| | - Yu Zhu
- Department of Endocrinology and MetabolismPeking University People's Hospital, Peking University Diabetes CenterBeijingChina
| | - Xiuying Zhang
- Department of Endocrinology and MetabolismPeking University People's Hospital, Peking University Diabetes CenterBeijingChina
| | - Jing Chen
- Department of Endocrinology and MetabolismPeking University People's Hospital, Peking University Diabetes CenterBeijingChina
| | - Jing Wu
- Department of Endocrinology and MetabolismPeking University People's Hospital, Peking University Diabetes CenterBeijingChina
| | - Xianghai Zhou
- Department of Endocrinology and MetabolismPeking University People's Hospital, Peking University Diabetes CenterBeijingChina
| | | | | | - Fang Wang
- Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Liyong Zhong
- Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Xueyao Han
- Department of Endocrinology and MetabolismPeking University People's Hospital, Peking University Diabetes CenterBeijingChina
| | - Linong Ji
- Department of Endocrinology and MetabolismPeking University People's Hospital, Peking University Diabetes CenterBeijingChina
| |
Collapse
|
|
2
|
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.
Collapse
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.
| |
Collapse
|
|
3
|
Lee Y, Lee K. Pancreatic Diseases: Genetics and Modeling Using Human Pluripotent Stem Cells. Int J Stem Cells 2024; 17:253-269. [PMID: 38664226 PMCID: PMC11361847 DOI: 10.15283/ijsc24036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 04/01/2024] [Accepted: 04/01/2024] [Indexed: 08/31/2024] Open
Abstract
Pancreas serves endocrine and exocrine functions in the body; thus, their pathology can cause a broad range of irreparable consequences. Endocrine functions include the production of hormones such as insulin and glucagon, while exocrine functions involve the secretion of digestive enzymes. Disruption of these functions can lead to conditions like diabetes mellitus and exocrine pancreatic insufficiency. Also, the symptoms and causality of pancreatic cancer very greatly depends on their origin: pancreatic ductal adenocarcinoma is one of the most fatal cancer; however, most of tumor derived from endocrine part of pancreas are benign. Pancreatitis, an inflammation of the pancreatic tissues, is caused by excessive alcohol consumption, the bile duct obstruction by gallstones, and the premature activation of digestive enzymes in the pancreas. Hereditary pancreatic diseases, such as maturity-onset diabetes of the young and hereditary pancreatitis, can be a candidate for disease modeling using human pluripotent stem cells (hPSCs), due to their strong genetic influence. hPSC-derived pancreatic differentiation has been established for cell replacement therapy for diabetic patients and is robustly used for disease modeling. The disease modeling platform that allows interactions between immune cells and pancreatic cells is necessary to perform in-depth investigation of disease pathogenesis.
Collapse
Affiliation(s)
- Yuri Lee
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea
| | - Kihyun Lee
- Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea
- College of Pharmacy, Ewha Womans University, Seoul, Korea
| |
Collapse
|
|
4
|
Pavlinkova G, Smolik O. NEUROD1: transcriptional and epigenetic regulator of human and mouse neuronal and endocrine cell lineage programs. Front Cell Dev Biol 2024; 12:1435546. [PMID: 39105169 PMCID: PMC11298428 DOI: 10.3389/fcell.2024.1435546] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Accepted: 07/02/2024] [Indexed: 08/07/2024] Open
Abstract
Transcription factors belonging to the basic helix-loop-helix (bHLH) family are key regulators of cell fate specification and differentiation during development. Their dysregulation is implicated not only in developmental abnormalities but also in various adult diseases and cancers. Recently, the abilities of bHLH factors have been exploited in reprogramming strategies for cell replacement therapy. One such factor is NEUROD1, which has been associated with the reprogramming of the epigenetic landscape and potentially possessing pioneer factor abilities, initiating neuronal developmental programs, and enforcing pancreatic endocrine differentiation. The review aims to consolidate current knowledge on NEUROD1's multifaceted roles and mechanistic pathways in human and mouse cell differentiation and reprogramming, exploring NEUROD1 roles in guiding the development and reprogramming of neuroendocrine cell lineages. The review focuses on NEUROD1's molecular mechanisms, its interactions with other transcription factors, its role as a pioneer factor in chromatin remodeling, and its potential in cell reprogramming. We also show a differential potential of NEUROD1 in differentiation of neurons and pancreatic endocrine cells, highlighting its therapeutic potential and the necessity for further research to fully understand and utilize its capabilities.
Collapse
Affiliation(s)
- Gabriela Pavlinkova
- Laboratory of Molecular Pathogenetics, Institute of Biotechnology Czech Academy of Sciences, Vestec, Czechia
| | | |
Collapse
|
|
5
|
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.
Collapse
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.
| |
Collapse
|
|
6
|
Ducza L, Gaál B. The Neglected Sibling: NLRP2 Inflammasome in the Nervous System. Aging Dis 2024; 15:1006-1028. [PMID: 38722788 PMCID: PMC11081174 DOI: 10.14336/ad.2023.0926-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Accepted: 09/26/2023] [Indexed: 05/13/2024] Open
Abstract
While classical NOD-like receptor pyrin domain containing protein 1 (NLRP1) and NLRP3 inflammasomal proteins have been extensively investigated, the contribution of NLRP2 is still ill-defined in the nervous system. Given the putative significance of NLRP2 in orchestrating neuroinflammation, further inquiry is needed to gain a better understanding of its connectome, hence its specific targeting may hold a promising therapeutic implication. Therefore, bioinformatical approach for extracting information, specifically in the context of neuropathologies, is also undoubtedly preferred. To the best of our knowledge, there is no review study selectively targeting only NLRP2. Increasing, but still fragmentary evidence should encourage researchers to thoroughly investigate this inflammasome in various animal- and human models. Taken together, herein we aimed to review the current literature focusing on the role of NLRP2 inflammasome in the nervous system and more importantly, we provide an algorithm-based protein network of human NLRP2 for elucidating potentially valuable molecular partnerships that can be the beginning of a new discourse and future therapeutic considerations.
Collapse
Affiliation(s)
- László Ducza
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, Hungary, Hungary
| | - Botond Gaál
- Department of Anatomy, Histology and Embryology, Faculty of Medicine, University of Debrecen, Hungary, Hungary
| |
Collapse
|
|
7
|
Bawatneh A, Darwish A, Eideh H, Darwish HM. Identification of gene mutations associated with type 1 diabetes by next-generation sequencing in affected Palestinian families. Front Genet 2024; 14:1292073. [PMID: 38274107 PMCID: PMC10808782 DOI: 10.3389/fgene.2023.1292073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 12/04/2023] [Indexed: 01/27/2024] Open
Abstract
Introduction: Diabetes Mellitus is a group of metabolic disorders characterized by hyperglycemia secondary to insulin resistance or deficiency. It is considered a major health problem worldwide. T1DM is a result of a combination of genetics, epigenetics, and environmental factors. Several genes have been associated with T1DM, including HLA, INS, CTLA4, and PTPN22. However, none of these findings have been based on linkage analysis because it is rare to find families with several diabetic individuals. Two Palestinian families with several afflicted members with variations in the mode of inheritance were identified and selected for this study. This study aimed to identify the putative causative gene(s) responsible for T1DM development in these families to improve our understanding of the molecular genetics of the disease. Methods: One afflicted member from each family was selected for Whole-Exome Sequencing. Data were mapped to the reference of the human genome, and the resulting VCF file data were filtered. The variants with the highest phenotype correlation score were checked by Sanger sequencing for all family members. The confirmed variants were analyzed in silico by bioinformatics tools. Results: In one family, the IGF1R p.V579F variant, which follows autosomal dominant inheritance, was confirmed and segregated in the family. In another family, the NEUROD1 p.P197H variant, which follows autosomal recessive inheritance, was positively confirmed and segregated. Conclusion: IGF1R p.V579F and NEUROD1 p.P197H variants were associated with T1DM development in the two inflicted families. Further analysis and functional assays will be performed, including the generation of mutant model cell systems, to unravel their specific molecular mechanism in the disease development.
Collapse
Affiliation(s)
- Abrar Bawatneh
- Molecular Genetics and Genetics Toxicology Program, Faculty of Graduate Studies, Arab American University, Jenin, Palestine
| | - Alaa Darwish
- Faculty of Health Professions, AlQuds University, Jerusalem, Palestine
| | | | - Hisham M. Darwish
- Molecular Genetics and Genetics Toxicology Program, Faculty of Graduate Studies, Arab American University, Jenin, Palestine
- Faculty of Allied Medical Sciences, Arab American University, Jenin, Palestine
| |
Collapse
|
|
8
|
Virk SM, Trujillo-Provencio C, Serrano EE. Transcriptomic Analysis Identifies Candidate Genes for Differential Expression during Xenopus laevis Inner Ear Development. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.12.29.573599. [PMID: 38260420 PMCID: PMC10802236 DOI: 10.1101/2023.12.29.573599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Background The genes involved in inner ear development and maintenance of the adult organ have yet to be fully characterized. Previous genetic analysis has emphasized the early development that gives rise to the otic vesicle. This study aimed to bridge the knowledge gap and identify candidate genes that are expressed as the auditory and vestibular sensory organs continue to grow and develop until the systems reach postmetamorphic maturity. Methods Affymetrix microarrays were used to assess inner ear transcriptome profiles from three Xenopus laevis developmental ages where all eight endorgans comprise mechanosensory hair cells: larval stages 50 and 56, and the post-metamorphic juvenile. Pairwise comparisons were made between the three developmental stages and the resulting differentially expressed X. laevis Probe Set IDs (Xl-PSIDs) were assigned to four groups based on differential expression patterns. DAVID analysis was undertaken to impart functional annotation to the differentially regulated Xl-PSIDs. Results Analysis identified 1510 candidate genes for differential gene expression in one or more pairwise comparison. Annotated genes not previously associated with inner ear development emerged from this analysis, as well as annotated genes with established inner ear function, such as oncomodulin, neurod1, and sp7. Notably, 36% of differentially expressed Xl-PSIDs were unannotated. Conclusions Results draw attention to the complex gene regulatory patterns that characterize Xenopus inner ear development, and underscore the need for improved annotation of the X. laevis genome. Outcomes can be utilized to select candidate inner ear genes for functional analysis, and to promote Xenopus as a model organism for biomedical studies of hearing and balance.
Collapse
Affiliation(s)
- Selene M Virk
- Biology Department, New Mexico State University, Las Cruces NM USA 88003
| | | | - Elba E Serrano
- Biology Department, New Mexico State University, Las Cruces NM USA 88003
| |
Collapse
|
|
9
|
Narayan G, Ronima K R, Agrawal A, Thummer RP. An Insight into Vital Genes Responsible for β-cell Formation. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1450:1-27. [PMID: 37432546 DOI: 10.1007/5584_2023_778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/12/2023]
Abstract
The regulation of glucose homeostasis and insulin secretion by pancreatic β-cells, when disturbed, will result in diabetes mellitus. Replacement of dysfunctional or lost β-cells with fully functional ones can tackle the problem of β-cell generation in diabetes mellitus. Various pancreatic-specific genes are expressed during different stages of development, which have essential roles in pancreatogenesis and β-cell formation. These factors play a critical role in cellular-based studies like transdifferentiation or de-differentiation of somatic cells to multipotent or pluripotent stem cells and their differentiation into functional β-cells. This work gives an overview of crucial transcription factors expressed during various stages of pancreas development and their role in β-cell specification. In addition, it also provides a perspective on the underlying molecular mechanisms.
Collapse
Affiliation(s)
- Gloria Narayan
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Ronima K R
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Akriti Agrawal
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Rajkumar P Thummer
- Laboratory for Stem Cell Engineering and Regenerative Medicine, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India.
| |
Collapse
|
|
10
|
Gojani EG, Wang B, Li DP, Kovalchuk O, Kovalchuk I. Anti-Inflammatory Properties of Eugenol in Lipopolysaccharide-Induced Macrophages and Its Role in Preventing β-Cell Dedifferentiation and Loss Induced by High Glucose-High Lipid Conditions. Molecules 2023; 28:7619. [PMID: 38005341 PMCID: PMC10673503 DOI: 10.3390/molecules28227619] [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: 10/25/2023] [Revised: 11/09/2023] [Accepted: 11/14/2023] [Indexed: 11/26/2023] Open
Abstract
Inflammation is a natural immune response to injury, infection, or tissue damage. It plays a crucial role in maintaining overall health and promoting healing. However, when inflammation becomes chronic and uncontrolled, it can contribute to the development of various inflammatory conditions, including type 2 diabetes. In type 2 diabetes, pancreatic β-cells have to overwork and the continuous impact of a high glucose, high lipid (HG-HL) diet contributes to their loss and dedifferentiation. This study aimed to investigate the anti-inflammatory effects of eugenol and its impact on the loss and dedifferentiation of β-cells. THP-1 macrophages were pretreated with eugenol for one hour and then exposed to lipopolysaccharide (LPS) for three hours to induce inflammation. Additionally, the second phase of NLRP3 inflammasome activation was induced by incubating the LPS-stimulated cells with adenosine triphosphate (ATP) for 30 min. The results showed that eugenol reduced the expression of proinflammatory genes, such as IL-1β, IL-6 and cyclooxygenase-2 (COX-2), potentially by inhibiting the activation of transcription factors NF-κB and TYK2. Eugenol also demonstrated inhibitory effects on the levels of NLRP3 mRNA and protein and Pannexin-1 (PANX-1) activation, eventually impacting the assembly of the NLRP3 inflammasome and the production of mature IL-1β. Additionally, eugenol reduced the elevated levels of adenosine deaminase acting on RNA 1 (ADAR1) transcript, suggesting its role in post-transcriptional mechanisms that regulate inflammatory responses. Furthermore, eugenol effectively decreased the loss of β-cells in response to HG-HL, likely by mitigating apoptosis. It also showed promise in suppressing HG-HL-induced β-cell dedifferentiation by restoring β-cell-specific biomarkers. Further research on eugenol and its mechanisms of action could lead to the development of therapeutic interventions for inflammatory disorders and the preservation of β-cell function in the context of type 2 diabetes.
Collapse
Affiliation(s)
| | | | | | | | - Igor Kovalchuk
- Department of Biological Sciences, University of Lethbridge, Lethbridge, AB T1K 3M4, Canada; (E.G.G.); (B.W.); (D.-P.L.); (O.K.)
| |
Collapse
|
|
11
|
Bohuslavova R, Fabriciova V, Smolik O, Lebrón-Mora L, Abaffy P, Benesova S, Zucha D, Valihrach L, Berkova Z, Saudek F, Pavlinkova G. NEUROD1 reinforces endocrine cell fate acquisition in pancreatic development. Nat Commun 2023; 14:5554. [PMID: 37689751 PMCID: PMC10492842 DOI: 10.1038/s41467-023-41306-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 08/30/2023] [Indexed: 09/11/2023] Open
Abstract
NEUROD1 is a transcription factor that helps maintain a mature phenotype of pancreatic β cells. Disruption of Neurod1 during pancreatic development causes severe neonatal diabetes; however, the exact role of NEUROD1 in the differentiation programs of endocrine cells is unknown. Here, we report a crucial role of the NEUROD1 regulatory network in endocrine lineage commitment and differentiation. Mechanistically, transcriptome and chromatin landscape analyses demonstrate that Neurod1 inactivation triggers a downregulation of endocrine differentiation transcription factors and upregulation of non-endocrine genes within the Neurod1-deficient endocrine cell population, disturbing endocrine identity acquisition. Neurod1 deficiency altered the H3K27me3 histone modification pattern in promoter regions of differentially expressed genes, which resulted in gene regulatory network changes in the differentiation pathway of endocrine cells, compromising endocrine cell potential, differentiation, and functional properties.
Collapse
Affiliation(s)
- Romana Bohuslavova
- Laboratory of Molecular Pathogenetics, Institute of Biotechnology CAS, 25250, Vestec, Czechia
| | - Valeria Fabriciova
- Laboratory of Molecular Pathogenetics, Institute of Biotechnology CAS, 25250, Vestec, Czechia
| | - Ondrej Smolik
- Laboratory of Molecular Pathogenetics, Institute of Biotechnology CAS, 25250, Vestec, Czechia
| | - Laura Lebrón-Mora
- Laboratory of Molecular Pathogenetics, Institute of Biotechnology CAS, 25250, Vestec, Czechia
| | - Pavel Abaffy
- Laboratory of Gene Expression, Institute of Biotechnology CAS, 25250, Vestec, Czechia
| | - Sarka Benesova
- Laboratory of Gene Expression, Institute of Biotechnology CAS, 25250, Vestec, Czechia
| | - Daniel Zucha
- Laboratory of Gene Expression, Institute of Biotechnology CAS, 25250, Vestec, Czechia
| | - Lukas Valihrach
- Laboratory of Gene Expression, Institute of Biotechnology CAS, 25250, Vestec, Czechia
| | - Zuzana Berkova
- Diabetes Centre, Experimental Medicine Centre, Institute for Clinical and Experimental Medicine, 14021, Prague, Czechia
| | - Frantisek Saudek
- Diabetes Centre, Experimental Medicine Centre, Institute for Clinical and Experimental Medicine, 14021, Prague, Czechia
| | - Gabriela Pavlinkova
- Laboratory of Molecular Pathogenetics, Institute of Biotechnology CAS, 25250, Vestec, Czechia.
| |
Collapse
|
|
12
|
Vanheer L, Fantuzzi F, To SK, Schiavo A, Van Haele M, Ostyn T, Haesen T, Yi X, Janiszewski A, Chappell J, Rihoux A, Sawatani T, Roskams T, Pattou F, Kerr-Conte J, Cnop M, Pasque V. Inferring regulators of cell identity in the human adult pancreas. NAR Genom Bioinform 2023; 5:lqad068. [PMID: 37435358 PMCID: PMC10331937 DOI: 10.1093/nargab/lqad068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 06/17/2023] [Accepted: 06/28/2023] [Indexed: 07/13/2023] Open
Abstract
Cellular identity during development is under the control of transcription factors that form gene regulatory networks. However, the transcription factors and gene regulatory networks underlying cellular identity in the human adult pancreas remain largely unexplored. Here, we integrate multiple single-cell RNA-sequencing datasets of the human adult pancreas, totaling 7393 cells, and comprehensively reconstruct gene regulatory networks. We show that a network of 142 transcription factors forms distinct regulatory modules that characterize pancreatic cell types. We present evidence that our approach identifies regulators of cell identity and cell states in the human adult pancreas. We predict that HEYL, BHLHE41 and JUND are active in acinar, beta and alpha cells, respectively, and show that these proteins are present in the human adult pancreas as well as in human induced pluripotent stem cell (hiPSC)-derived islet cells. Using single-cell transcriptomics, we found that JUND represses beta cell genes in hiPSC-alpha cells. BHLHE41 depletion induced apoptosis in primary pancreatic islets. The comprehensive gene regulatory network atlas can be explored interactively online. We anticipate our analysis to be the starting point for a more sophisticated dissection of how transcription factors regulate cell identity and cell states in the human adult pancreas.
Collapse
Affiliation(s)
- Lotte Vanheer
- Department of Development and Regeneration; KU Leuven - University of Leuven; Single-cell Omics Institute and Leuven Stem Cell Institute, Herestraat 49, B-3000 Leuven, Belgium
| | - Federica Fantuzzi
- ULB Center for Diabetes Research; Université Libre de Bruxelles; Route de Lennik 808, B-1070 Brussels, Belgium
| | - San Kit To
- Department of Development and Regeneration; KU Leuven - University of Leuven; Single-cell Omics Institute and Leuven Stem Cell Institute, Herestraat 49, B-3000 Leuven, Belgium
| | - Andrea Schiavo
- ULB Center for Diabetes Research; Université Libre de Bruxelles; Route de Lennik 808, B-1070 Brussels, Belgium
| | - Matthias Van Haele
- Department of Imaging and Pathology; Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven; Herestraat 49, B-3000 Leuven, Belgium
| | - Tessa Ostyn
- Department of Imaging and Pathology; Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven; Herestraat 49, B-3000 Leuven, Belgium
| | - Tine Haesen
- Department of Development and Regeneration; KU Leuven - University of Leuven; Single-cell Omics Institute and Leuven Stem Cell Institute, Herestraat 49, B-3000 Leuven, Belgium
| | - Xiaoyan Yi
- ULB Center for Diabetes Research; Université Libre de Bruxelles; Route de Lennik 808, B-1070 Brussels, Belgium
| | - Adrian Janiszewski
- Department of Development and Regeneration; KU Leuven - University of Leuven; Single-cell Omics Institute and Leuven Stem Cell Institute, Herestraat 49, B-3000 Leuven, Belgium
| | - Joel Chappell
- Department of Development and Regeneration; KU Leuven - University of Leuven; Single-cell Omics Institute and Leuven Stem Cell Institute, Herestraat 49, B-3000 Leuven, Belgium
| | - Adrien Rihoux
- Department of Development and Regeneration; KU Leuven - University of Leuven; Single-cell Omics Institute and Leuven Stem Cell Institute, Herestraat 49, B-3000 Leuven, Belgium
| | - Toshiaki Sawatani
- ULB Center for Diabetes Research; Université Libre de Bruxelles; Route de Lennik 808, B-1070 Brussels, Belgium
| | - Tania Roskams
- Department of Imaging and Pathology; Translational Cell and Tissue Research, KU Leuven and University Hospitals Leuven; Herestraat 49, B-3000 Leuven, Belgium
| | - Francois Pattou
- University of Lille, Inserm, CHU Lille, Institute Pasteur Lille, U1190-EGID, F-59000 Lille, France
- European Genomic Institute for Diabetes, F-59000 Lille, France
- University of Lille, F-59000 Lille, France
| | - Julie Kerr-Conte
- University of Lille, Inserm, CHU Lille, Institute Pasteur Lille, U1190-EGID, F-59000 Lille, France
- European Genomic Institute for Diabetes, F-59000 Lille, France
- University of Lille, F-59000 Lille, France
| | - Miriam Cnop
- ULB Center for Diabetes Research; Université Libre de Bruxelles; Route de Lennik 808, B-1070 Brussels, Belgium
- Division of Endocrinology; Erasmus Hospital, Université Libre de Bruxelles; Route de Lennik 808, B-1070 Brussels, Belgium
| | - Vincent Pasque
- Department of Development and Regeneration; KU Leuven - University of Leuven; Single-cell Omics Institute and Leuven Stem Cell Institute, Herestraat 49, B-3000 Leuven, Belgium
| |
Collapse
|
|
13
|
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.
Collapse
|
|
14
|
Sun C, Chen S. Disease-causing mutations in genes encoding transcription factors critical for photoreceptor development. Front Mol Neurosci 2023; 16:1134839. [PMID: 37181651 PMCID: PMC10172487 DOI: 10.3389/fnmol.2023.1134839] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Accepted: 04/04/2023] [Indexed: 05/16/2023] Open
Abstract
Photoreceptor development of the vertebrate visual system is controlled by a complex transcription regulatory network. OTX2 is expressed in the mitotic retinal progenitor cells (RPCs) and controls photoreceptor genesis. CRX that is activated by OTX2 is expressed in photoreceptor precursors after cell cycle exit. NEUROD1 is also present in photoreceptor precursors that are ready to specify into rod and cone photoreceptor subtypes. NRL is required for the rod fate and regulates downstream rod-specific genes including the orphan nuclear receptor NR2E3 which further activates rod-specific genes and simultaneously represses cone-specific genes. Cone subtype specification is also regulated by the interplay of several transcription factors such as THRB and RXRG. Mutations in these key transcription factors are responsible for ocular defects at birth such as microphthalmia and inherited photoreceptor diseases such as Leber congenital amaurosis (LCA), retinitis pigmentosa (RP) and allied dystrophies. In particular, many mutations are inherited in an autosomal dominant fashion, including the majority of missense mutations in CRX and NRL. In this review, we describe the spectrum of photoreceptor defects that are associated with mutations in the above-mentioned transcription factors, and summarize the current knowledge of molecular mechanisms underlying the pathogenic mutations. At last, we deliberate the outstanding gaps in our understanding of the genotype-phenotype correlations and outline avenues for future research of the treatment strategies.
Collapse
Affiliation(s)
- Chi Sun
- Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, MO, United States
- *Correspondence: Chi Sun,
| | - Shiming Chen
- Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. Louis, MO, United States
- Department of Developmental Biology, Washington University in St. Louis, St. Louis, MO, United States
| |
Collapse
|
|
15
|
Stekelenburg C, Blouin JL, Santoni F, Zaghloul N, O'Hare EA, Dusaulcy R, Maechler P, Schwitzgebel VM. Loss of Nexmif results in the expression of phenotypic variability and loss of genomic integrity. Sci Rep 2022; 12:13815. [PMID: 35970867 PMCID: PMC9378738 DOI: 10.1038/s41598-022-17845-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Accepted: 08/02/2022] [Indexed: 11/17/2022] Open
Abstract
We identified two NEXMIF variants in two unrelated individuals with non-autoimmune diabetes and autistic traits, and investigated the expression of Nexmif in mouse and human pancreas and its function in pancreatic beta cells in vitro and in vivo. In insulin-secreting INS-1E cells, Nexmif expression increased strongly in response to oxidative stress. CRISPR Cas9-generated Nexmif knockout mice exhibited a reduced number of proliferating beta cells in pancreatic islets. RNA sequencing of pancreatic islets showed that the downregulated genes in Nexmif mutant islets are involved in stress response and the deposition of epigenetic marks. They include H3f3b, encoding histone H3.3, which is associated with the regulation of beta-cell proliferation and maintains genomic integrity by silencing transposable elements, particularly LINE1 elements. LINE1 activity has been associated with autism and neurodevelopmental disorders in which patients share characteristics with NEXMIF patients, and can cause genomic instability and genetic variation through retrotransposition. Nexmif knockout mice exhibited various other phenotypes. Mortality and phenotypic abnormalities increased in each generation in both Nexmif mutant and non-mutant littermates. In Nexmif mutant mice, LINE1 element expression was upregulated in the pancreas, brain, and testis, possibly inducing genomic instability in Nexmif mutant mice and causing phenotypic variability in their progeny.
Collapse
Affiliation(s)
- Caroline Stekelenburg
- Pediatric Endocrine and Diabetes Unit, Division of Development and Growth, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals of Geneva, Children's University Hospital, 6, Rue Willy Donze, 1205, Geneva, Switzerland.,Faculty Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Jean-Louis Blouin
- Department of Genetic Medicine and Laboratory, University Hospitals of Geneva, 1211, Geneva, Switzerland.,Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, 1211, Geneva, Switzerland
| | - Federico Santoni
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, 1211, Geneva, Switzerland
| | - Norann Zaghloul
- Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, USA
| | - Elisabeth A O'Hare
- Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, USA
| | - Rodolphe Dusaulcy
- Pediatric Endocrine and Diabetes Unit, Division of Development and Growth, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals of Geneva, Children's University Hospital, 6, Rue Willy Donze, 1205, Geneva, Switzerland.,Faculty Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Pierre Maechler
- Faculty Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland.,Department of Cell Physiology and Metabolism, University of Geneva Medical Center, 1206, Geneva, Switzerland
| | - Valerie M Schwitzgebel
- Pediatric Endocrine and Diabetes Unit, Division of Development and Growth, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals of Geneva, Children's University Hospital, 6, Rue Willy Donze, 1205, Geneva, Switzerland. .,Faculty Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
| |
Collapse
|
|
16
|
Transcriptional control of pancreatic β-cell identity and plasticity during the pathogenesis of type 2 diabetes. J Genet Genomics 2022; 49:316-328. [DOI: 10.1016/j.jgg.2022.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 02/23/2022] [Accepted: 03/06/2022] [Indexed: 11/21/2022]
|
|
17
|
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.
Collapse
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
| |
Collapse
|
|
18
|
Hammoud B, Greeley SAW. Growth and development in monogenic forms of neonatal diabetes. Curr Opin Endocrinol Diabetes Obes 2022; 29:65-77. [PMID: 34864759 PMCID: PMC11056188 DOI: 10.1097/med.0000000000000699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW Neonatal diabetes mellitus (NDM) is a rare disorder in which 80-85% of infants diagnosed under 6 months of age will be found to have an underlying monogenic cause. This review will summarize what is known about growth and neurodevelopmental difficulties among individuals with various forms of NDM. RECENT FINDINGS Patients with NDM often have intrauterine growth restriction and/or low birth weight because of insulin deficiency in utero and the severity and likelihood of ongoing growth concerns after birth depends on the specific cause. A growing list of rare recessive causes of NDM are associated with neurodevelopmental and/or growth problems that can either be related to direct gene effects on brain development, or may be related to a variety of co-morbidities. The most common form of NDM results in spectrum of neurological disability due to expression of mutated KATP channels throughout the brain. SUMMARY Monogenic causes of neonatal diabetes are characterized by variable degree of restriction of growth in utero because of deficiency of insulin that depends on the specific gene cause. Many forms also include a spectrum of neurodevelopmental disability because of mutation-related effects on brain development. Longer term study is needed to clarify longitudinal effects on growth into adulthood.
Collapse
Affiliation(s)
- Batoul Hammoud
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, and Kovler Diabetes Center, University of Chicago, Chicago, Illinois, USA
| | | |
Collapse
|
|
19
|
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.
Collapse
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
| |
Collapse
|
|
20
|
Lezzi M, Aloi C, Salina A, Fragola M, Bassi M, Strati MF, d’Annunzio G, Minuto N, Maghnie M. Diabetes Mellitus Diagnosed in Childhood and Adolescence With Negative Autoimmunity: Results of Genetic Investigation. Front Endocrinol (Lausanne) 2022; 13:894878. [PMID: 35769090 PMCID: PMC9235348 DOI: 10.3389/fendo.2022.894878] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 05/03/2022] [Indexed: 11/22/2022] Open
Abstract
Monogenic diabetes is a rare form of diabetes, accounting for approximately 1% to 6% of pediatric diabetes patients. Some types of monogenic diabetes can be misdiagnosed as type 1 diabetes in children or adolescents because of similar clinical features. Identification of the correct etiology of diabetes is crucial for clinical, therapeutic, and prognostic issues. Our main objective was to determine the prevalence of monogenic diabetes in patients with diabetes mellitus, diagnosed in childhood or in adolescence, and negative autoimmunity. We retrospectively analyzed clinical data of 275 patients diagnosed with insulin-dependent diabetes at age <18yr in the last 10 years. 8.4% of subjects has negative autoimmunity. Their DNA was sequenced by NGS custom panel composed by 45 candidate genes involved in glucose metabolism disorder. Two novel heterozygous pathogenic or likely pathogenic variants (10,5% of autoantibody negative subjects) were detected: the frameshift variant c.617_618insA in NEUROD1 exon 2 and the missense change c.116T>C in INS exon 2. Our study corroborates previous results of other reports in literature. NGS assays are useful methods for a correct diagnosis of monogenic diabetes, even of rarest forms, highlighting mechanisms of pediatric diabetes pathogenesis.
Collapse
Affiliation(s)
- Marilea Lezzi
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
- Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Concetta Aloi
- LABSIEM (Laboratory for the Study of Inborn Errors of Metabolism), IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Alessandro Salina
- LABSIEM (Laboratory for the Study of Inborn Errors of Metabolism), IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Martina Fragola
- Department of Hematology and Oncology, Epidemiology and Biostatistics Section, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Marta Bassi
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
- Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Marina Francesca Strati
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
- Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | | | - Nicola Minuto
- Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
- *Correspondence: Nicola Minuto,
| | - Mohamad Maghnie
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
- Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| |
Collapse
|
|
21
|
Ali Khan I. Do second generation sequencing techniques identify documented genetic markers for neonatal diabetes mellitus? Heliyon 2021; 7:e07903. [PMID: 34584998 PMCID: PMC8455689 DOI: 10.1016/j.heliyon.2021.e07903] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 01/15/2021] [Accepted: 08/27/2021] [Indexed: 12/24/2022] Open
Abstract
Neonatal diabetes mellitus (NDM) is noted as a genetic, heterogeneous, and rare disease in infants. NDM occurs due to a single-gene mutation in neonates. A common source for developing NDM in an infant is the existence of mutations/variants in the KCNJ11 and ABCC8 genes, encoding the subunits of the voltage-dependent potassium channel. Both KCNJ11 and ABCC8 genes are useful in diagnosing monogenic diabetes during infancy. Genetic analysis was previously performed using first-generation sequencing techniques, such as DNA-Sanger sequencing, which uses chain-terminating inhibitors. Sanger sequencing has certain limitations; it can screen a limited region of exons in one gene, but it cannot screen large regions of the human genome. In the last decade, first generation sequencing techniques have been replaced with second-generation sequencing techniques, such as next-generation sequencing (NGS), which sequences nucleic-acids more rapidly and economically than Sanger sequencing. NGS applications are involved in whole exome sequencing (WES), whole genome sequencing (WGS), and targeted gene panels. WES characterizes a substantial breakthrough in human genetics. Genetic testing for custom genes allows the screening of the complete gene, including introns and exons. The aim of this review was to confirm if the 22 genetic variations previously documented to cause NDM by Sanger sequencing could be detected using second generation sequencing techniques. The author has cross-checked global studies performed in NDM using NGS, ES/WES, WGS, and targeted gene panels as second-generation sequencing techniques; WES confirmed the similar variants, which have been previously documented with Sanger sequencing. WES is documented as a powerful tool and WGS as the most comprehensive test for verified the documented variants, as well as novel enhancers. This review recommends for the future studies should be performed with second generation sequencing techniques to identify the verified 22 genetic and novel variants by screening in NDM (PNDM or TNMD) children.
Collapse
Affiliation(s)
- Imran Ali Khan
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, PO Box-10219, Riyadh, 11433, Saudi Arabia
| |
Collapse
|
|
22
|
Shi D, Motamed M, Mejía-Benítez A, Li L, Lin E, Budhram D, Kaur Y, Meyre D. Genetic syndromes with diabetes: A systematic review. Obes Rev 2021; 22:e13303. [PMID: 34268868 DOI: 10.1111/obr.13303] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Revised: 05/19/2021] [Accepted: 05/20/2021] [Indexed: 01/19/2023]
Abstract
Previous reviews and clinical guidelines have identified 10-20 genetic syndromes associated with diabetes, but no systematic review has been conducted to date. We provide the first comprehensive catalog for syndromes with diabetes mellitus. We conducted a systematic review of MEDLINE, Embase, CENTRAL, PubMed, OMIM, and Orphanet databases for case reports, case series, and observational studies published between 1946 and January 15, 2020, that described diabetes mellitus in adults and children with monogenic or chromosomal syndromes. Our literature search identified 7,122 studies, of which 160 fulfilled inclusion criteria. Our analysis of these studies found 69 distinct diabetes syndromes. Thirty (43.5%) syndromes included diabetes mellitus as a cardinal clinical feature, and 56 (81.2%) were fully genetically elucidated. Sixty-three syndromes (91.3%) were described more than once in independent case reports, of which 59 (93.7%) demonstrated clinical heterogeneity. Syndromes associated with diabetes mellitus are more numerous and diverse than previously anticipated. While knowledge of the syndromes is limited by their low prevalence, future reviews will be needed as more cases are identified. The genetic etiologies of these syndromes are well elucidated and provide potential avenues for future gene identification efforts, aid in diagnosis and management, gene therapy research, and developing personalized medicine treatments.
Collapse
Affiliation(s)
- Daniel Shi
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,Faculty of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Mehras Motamed
- Faculty of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Aurora Mejía-Benítez
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Leon Li
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Ethan Lin
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Dalton Budhram
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,Faculty of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Yuvreet Kaur
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - David Meyre
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada.,Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada.,Department of Molecular Medicine, Division of Biochemistry, Molecular Biology, and Nutrition, University Hospital of Nancy, Nancy, France.,Faculty of Medicine of Nancy INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure, University of Lorraine, Nancy, France
| |
Collapse
|
|
23
|
Ikle JM, Gloyn AL. 100 YEARS OF INSULIN: A brief history of diabetes genetics: insights for pancreatic beta-cell development and function. J Endocrinol 2021; 250:R23-R35. [PMID: 34196608 PMCID: PMC9037733 DOI: 10.1530/joe-21-0067] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 06/30/2021] [Indexed: 12/30/2022]
Abstract
Since the discovery of insulin 100 years ago, our knowledge and understanding of diabetes have grown exponentially. Specifically, with regards to the genetics underlying diabetes risk, our discoveries have paralleled developments in our understanding of the human genome and our ability to study genomics at scale; these advancements in genetics have both accompanied and led to those in diabetes treatment. This review will explore the timeline and history of gene discovery and how this has coincided with progress in the fields of genomics. Examples of genetic causes of monogenic diabetes are presented and the continuing expansion of allelic series in these genes and the challenges these now cause for diagnostic interpretation along with opportunities for patient stratification are discussed.
Collapse
Affiliation(s)
- Jennifer M Ikle
- Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA
| | - Anna L Gloyn
- Division of Endocrinology, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA
- Stanford Diabetes Research Center, Stanford University, Stanford, California, USA
| |
Collapse
|
|
24
|
Burgos JI, Vallier L, Rodríguez-Seguí SA. Monogenic Diabetes Modeling: In Vitro Pancreatic Differentiation From Human Pluripotent Stem Cells Gains Momentum. Front Endocrinol (Lausanne) 2021; 12:692596. [PMID: 34295307 PMCID: PMC8290520 DOI: 10.3389/fendo.2021.692596] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/15/2021] [Indexed: 12/14/2022] Open
Abstract
The occurrence of diabetes mellitus is characterized by pancreatic β cell loss and chronic hyperglycemia. While Type 1 and Type 2 diabetes are the most common types, rarer forms involve mutations affecting a single gene. This characteristic has made monogenic diabetes an interesting disease group to model in vitro using human pluripotent stem cells (hPSCs). By altering the genotype of the original hPSCs or by deriving human induced pluripotent stem cells (hiPSCs) from patients with monogenic diabetes, changes in the outcome of the in vitro differentiation protocol can be analyzed in detail to infer the regulatory mechanisms affected by the disease-associated genes. This approach has been so far applied to a diversity of genes/diseases and uncovered new mechanisms. The focus of the present review is to discuss the latest findings obtained by modeling monogenic diabetes using hPSC-derived pancreatic cells generated in vitro. We will specifically focus on the interpretation of these studies, the advantages and limitations of the models used, and the future perspectives for improvement.
Collapse
Affiliation(s)
- Juan Ignacio Burgos
- Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET-Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, Argentina
| | - Ludovic Vallier
- Wellcome-Medical Research Council Cambridge Stem Cell Institute and Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - Santiago A. Rodríguez-Seguí
- Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires and Instituto de Fisiología, Biología Molecular y Neurociencias (IFIBYNE), CONICET-Universidad de Buenos Aires, Ciudad Universitaria, Buenos Aires, Argentina
| |
Collapse
|
|
25
|
Bohuslavova R, Smolik O, Malfatti J, Berkova Z, Novakova Z, Saudek F, Pavlinkova G. NEUROD1 Is Required for the Early α and β Endocrine Differentiation in the Pancreas. Int J Mol Sci 2021; 22:6713. [PMID: 34201511 PMCID: PMC8268837 DOI: 10.3390/ijms22136713] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 06/18/2021] [Accepted: 06/21/2021] [Indexed: 11/17/2022] Open
Abstract
Diabetes is a metabolic disease that involves the death or dysfunction of the insulin-secreting β cells in the pancreas. Consequently, most diabetes research is aimed at understanding the molecular and cellular bases of pancreatic development, islet formation, β-cell survival, and insulin secretion. Complex interactions of signaling pathways and transcription factor networks regulate the specification, growth, and differentiation of cell types in the developing pancreas. Many of the same regulators continue to modulate gene expression and cell fate of the adult pancreas. The transcription factor NEUROD1 is essential for the maturation of β cells and the expansion of the pancreatic islet cell mass. Mutations of the Neurod1 gene cause diabetes in humans and mice. However, the different aspects of the requirement of NEUROD1 for pancreas development are not fully understood. In this study, we investigated the role of NEUROD1 during the primary and secondary transitions of mouse pancreas development. We determined that the elimination of Neurod1 impairs the expression of key transcription factors for α- and β-cell differentiation, β-cell proliferation, insulin production, and islets of Langerhans formation. These findings demonstrate that the Neurod1 deletion altered the properties of α and β endocrine cells, resulting in severe neonatal diabetes, and thus, NEUROD1 is required for proper activation of the transcriptional network and differentiation of functional α and β cells.
Collapse
Affiliation(s)
- Romana Bohuslavova
- Institute of Biotechnology CAS, 25250 Vestec, Czech Republic; (R.B.); (O.S.); (J.M.); (Z.N.)
| | - Ondrej Smolik
- Institute of Biotechnology CAS, 25250 Vestec, Czech Republic; (R.B.); (O.S.); (J.M.); (Z.N.)
- Department of Cell Biology, Faculty of Science, Charles University, 12843 Prague, Czech Republic
| | - Jessica Malfatti
- Institute of Biotechnology CAS, 25250 Vestec, Czech Republic; (R.B.); (O.S.); (J.M.); (Z.N.)
- Department of Cell Biology, Faculty of Science, Charles University, 12843 Prague, Czech Republic
| | - Zuzana Berkova
- Laboratory of Pancreatic Islets, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (Z.B.); (F.S.)
| | - Zaneta Novakova
- Institute of Biotechnology CAS, 25250 Vestec, Czech Republic; (R.B.); (O.S.); (J.M.); (Z.N.)
| | - Frantisek Saudek
- Laboratory of Pancreatic Islets, Institute for Clinical and Experimental Medicine, 14021 Prague, Czech Republic; (Z.B.); (F.S.)
| | - Gabriela Pavlinkova
- Institute of Biotechnology CAS, 25250 Vestec, Czech Republic; (R.B.); (O.S.); (J.M.); (Z.N.)
| |
Collapse
|
|
26
|
Tutukova S, Tarabykin V, Hernandez-Miranda LR. The Role of Neurod Genes in Brain Development, Function, and Disease. Front Mol Neurosci 2021; 14:662774. [PMID: 34177462 PMCID: PMC8221396 DOI: 10.3389/fnmol.2021.662774] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 05/11/2021] [Indexed: 01/14/2023] Open
Abstract
Transcriptional regulation is essential for the correct functioning of cells during development and in postnatal life. The basic Helix-loop-Helix (bHLH) superfamily of transcription factors is well conserved throughout evolution and plays critical roles in tissue development and tissue maintenance. A subgroup of this family, called neural lineage bHLH factors, is critical in the development and function of the central nervous system. In this review, we will focus on the function of one subgroup of neural lineage bHLH factors, the Neurod family. The Neurod family has four members: Neurod1, Neurod2, Neurod4, and Neurod6. Available evidence shows that these four factors are key during the development of the cerebral cortex but also in other regions of the central nervous system, such as the cerebellum, the brainstem, and the spinal cord. We will also discuss recent reports that link the dysfunction of these transcription factors to neurological disorders in humans.
Collapse
Affiliation(s)
- Svetlana Tutukova
- Institute of Neuroscience, Lobachevsky University of Nizhny Novgorod, Nizhny Novgorod, Russia.,Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute for Cell- and Neurobiology, Berlin, Germany
| | - Victor Tarabykin
- Institute of Neuroscience, Lobachevsky University of Nizhny Novgorod, Nizhny Novgorod, Russia.,Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute for Cell- and Neurobiology, Berlin, Germany
| | - Luis R Hernandez-Miranda
- Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute for Cell- and Neurobiology, Berlin, Germany
| |
Collapse
|
|
27
|
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.
Collapse
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
| |
Collapse
|
|
28
|
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.
Collapse
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/.
| |
Collapse
|
|
29
|
Sequential progenitor states mark the generation of pancreatic endocrine lineages in mice and humans. Cell Res 2021; 31:886-903. [PMID: 33692492 DOI: 10.1038/s41422-021-00486-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Accepted: 01/27/2021] [Indexed: 12/12/2022] Open
Abstract
The pancreatic islet contains multiple hormone+ endocrine lineages (α, β, δ, PP and ε cells), but the developmental processes that underlie endocrinogenesis are poorly understood. Here, we generated novel mouse lines and combined them with various genetic tools to enrich all types of hormone+ cells for well-based deep single-cell RNA sequencing (scRNA-seq), and gene coexpression networks were extracted from the generated data for the optimization of high-throughput droplet-based scRNA-seq analyses. These analyses defined an entire endocrinogenesis pathway in which different states of endocrine progenitor (EP) cells sequentially differentiate into specific endocrine lineages in mice. Subpopulations of the EP cells at the final stage (EP4early and EP4late) show different potentials for distinct endocrine lineages. ε cells and an intermediate cell population were identified as distinct progenitors that independently generate both α and PP cells. Single-cell analyses were also performed to delineate the human pancreatic endocrinogenesis process. Although the developmental trajectory of pancreatic lineages is generally conserved between humans and mice, clear interspecies differences, including differences in the proportions of cell types and the regulatory networks associated with the differentiation of specific lineages, have been detected. Our findings support a model in which sequential transient progenitor cell states determine the differentiation of multiple cell lineages and provide a blueprint for directing the generation of pancreatic islets in vitro.
Collapse
|
|
30
|
Abdelalim EM. Modeling different types of diabetes using human pluripotent stem cells. Cell Mol Life Sci 2021; 78:2459-2483. [PMID: 33242105 PMCID: PMC11072720 DOI: 10.1007/s00018-020-03710-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 10/19/2020] [Accepted: 11/11/2020] [Indexed: 12/22/2022]
Abstract
Diabetes mellitus (DM) is a metabolic disease characterized by chronic hyperglycemia as a result of progressive loss of pancreatic β cells, which could lead to several debilitating complications. Different paths, triggered by several genetic and environmental factors, lead to the loss of pancreatic β cells and/or function. Understanding these many paths to β cell damage or dysfunction could help in identifying therapeutic approaches specific for each path. Most of our knowledge about diabetes pathophysiology has been obtained from studies on animal models, which do not fully recapitulate human diabetes phenotypes. Currently, human pluripotent stem cell (hPSC) technology is a powerful tool for generating in vitro human models, which could provide key information about the disease pathogenesis and provide cells for personalized therapies. The recent progress in generating functional hPSC-derived β cells in combination with the rapid development in genomic and genome-editing technologies offer multiple options to understand the cellular and molecular mechanisms underlying the development of different types of diabetes. Recently, several in vitro hPSC-based strategies have been used for studying monogenic and polygenic forms of diabetes. This review summarizes the current knowledge about different hPSC-based diabetes models and how these models improved our current understanding of the pathophysiology of distinct forms of diabetes. Also, it highlights the progress in generating functional β cells in vitro, and discusses the current challenges and future perspectives related to the use of the in vitro hPSC-based strategies.
Collapse
Affiliation(s)
- Essam M Abdelalim
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), PO Box 34110, Doha, Qatar.
- College of Health and Life Sciences, Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), Education City, Doha, Qatar.
| |
Collapse
|
|
31
|
Liu M, Huang Y, Xu X, Li X, Alam M, Arunagiri A, Haataja L, Ding L, Wang S, Itkin-Ansari P, Kaufman RJ, Tsai B, Qi L, Arvan P. Normal and defective pathways in biogenesis and maintenance of the insulin storage pool. J Clin Invest 2021; 131:142240. [PMID: 33463547 PMCID: PMC7810482 DOI: 10.1172/jci142240] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Both basal and glucose-stimulated insulin release occur primarily by insulin secretory granule exocytosis from pancreatic β cells, and both are needed to maintain normoglycemia. Loss of insulin-secreting β cells, accompanied by abnormal glucose tolerance, may involve simple exhaustion of insulin reserves (which, by immunostaining, appears as a loss of β cell identity), or β cell dedifferentiation, or β cell death. While various sensing and signaling defects can result in diminished insulin secretion, somewhat less attention has been paid to diabetes risk caused by insufficiency in the biosynthetic generation and maintenance of the total insulin granule storage pool. This Review offers an overview of insulin biosynthesis, beginning with the preproinsulin mRNA (translation and translocation into the ER), proinsulin folding and export from the ER, and delivery via the Golgi complex to secretory granules for conversion to insulin and ultimate hormone storage. All of these steps are needed for generation and maintenance of the total insulin granule pool, and defects in any of these steps may, weakly or strongly, perturb glycemic control. The foregoing considerations have obvious potential relevance to the pathogenesis of type 2 diabetes and some forms of monogenic diabetes; conceivably, several of these concepts might also have implications for β cell failure in type 1 diabetes.
Collapse
Affiliation(s)
- Ming Liu
- Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China
| | - Yumeng Huang
- Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China
- Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Xiaoxi Xu
- Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China
- Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Xin Li
- Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China
| | - Maroof Alam
- Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Anoop Arunagiri
- Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Leena Haataja
- Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Li Ding
- Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, China
| | - Shusen Wang
- Organ Transplant Center, Tianjin First Central Hospital, Tianjin, China
| | | | - Randal J. Kaufman
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, USA
| | - Billy Tsai
- Department of Cell and Developmental Biology, and
| | - Ling Qi
- Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA
| | - Peter Arvan
- Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical School, Ann Arbor, Michigan, USA
| |
Collapse
|
|
32
|
Aarthy R, Aston-Mourney K, Mikocka-Walus A, Radha V, Amutha A, Anjana RM, Unnikrishnan R, Mohan V. Clinical features, complications and treatment of rarer forms of maturity-onset diabetes of the young (MODY) - A review. J Diabetes Complications 2021; 35:107640. [PMID: 32763092 DOI: 10.1016/j.jdiacomp.2020.107640] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/21/2020] [Accepted: 05/21/2020] [Indexed: 12/15/2022]
Abstract
Maturity onset diabetes of the young (MODY) is the most common form of monogenic diabetes and is currently believed to have 14 subtypes. While much is known about the common subtypes of MODY (MODY-1, 2, 3 and 5) little is known about its rare subtypes (MODY4, 6-14). With the advent of next-generation sequencing (NGS) there are several reports of the rarer subtypes of MODY emerging from across the world. Therefore, a greater understanding on these rarer subtypes is needed. A search strategy was created, and common databases were searched, and 51 articles finally selected. INS-(MODY10) and ABCC8-(MODY12) mutations were reported in relatively large numbers compared to the other rare subtypes. The clinical characteristics of the rare MODY subtypes exhibited heterogeneity between families reported with the same mutation. Obesity and diabetic ketoacidosis (DKA) were also reported among rarer MODY subtypes which presents as a challenge as these are not part of the original description of MODY by Tattersal and Fajans. The treatment modalities of the rarer subtypes included oral drugs, predominantly sulfonylureas, insulin but also diet alone. Newer drugs like DPP-4 and SGLT2 inhibitors have also been tried as new modes of treatment. The microvascular and macrovascular complications among the patients with various MODY subtypes are less commonly reported. Recently, there is a view that not all the 14 forms of 'MODY' are true MODY and the very existence of some of these rarer subtypes as MODY has been questioned. This scoping review aims to report on the clinical characteristics, treatment and complications of the rarer MODY subtypes published in the literature.
Collapse
Affiliation(s)
- Ramasamy Aarthy
- School of Medicine, Deakin University, Australia; Madras Diabetes Research Foundation, Chennai, India
| | | | | | | | | | - Ranjit Mohan Anjana
- Dr Mohan's Diabetes Specialities Centre, Madras Diabetes Research Foundation, Chennai, India
| | - Ranjit Unnikrishnan
- Dr Mohan's Diabetes Specialities Centre, Madras Diabetes Research Foundation, Chennai, India
| | - Viswanathan Mohan
- Dr Mohan's Diabetes Specialities Centre, Madras Diabetes Research Foundation, Chennai, India.
| |
Collapse
|
|
33
|
Balboa D, Iworima DG, Kieffer TJ. Human Pluripotent Stem Cells to Model Islet Defects in Diabetes. Front Endocrinol (Lausanne) 2021; 12:642152. [PMID: 33828531 PMCID: PMC8020750 DOI: 10.3389/fendo.2021.642152] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Accepted: 02/03/2021] [Indexed: 12/17/2022] Open
Abstract
Diabetes mellitus is characterized by elevated levels of blood glucose and is ultimately caused by insufficient insulin production from pancreatic beta cells. Different research models have been utilized to unravel the molecular mechanisms leading to the onset of diabetes. The generation of pancreatic endocrine cells from human pluripotent stem cells constitutes an approach to study genetic defects leading to impaired beta cell development and function. Here, we review the recent progress in generating and characterizing functional stem cell-derived beta cells. We summarize the diabetes disease modeling possibilities that stem cells offer and the challenges that lie ahead to further improve these models.
Collapse
Affiliation(s)
- Diego Balboa
- Regulatory Genomics and Diabetes, Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain
- *Correspondence: Diego Balboa,
| | - Diepiriye G. Iworima
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
- School of Biomedical Engineering, The University of British Columbia, Vancouver, BC, Canada
| | - Timothy J. Kieffer
- Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC, Canada
- School of Biomedical Engineering, The University of British Columbia, Vancouver, BC, Canada
- Department of Surgery, University of British Columbia, Vancouver, BC, Canada
| |
Collapse
|
|
34
|
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.
Collapse
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
| |
Collapse
|
|
35
|
Vermeiren S, Bellefroid EJ, Desiderio S. Vertebrate Sensory Ganglia: Common and Divergent Features of the Transcriptional Programs Generating Their Functional Specialization. Front Cell Dev Biol 2020; 8:587699. [PMID: 33195244 PMCID: PMC7649826 DOI: 10.3389/fcell.2020.587699] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 09/08/2020] [Indexed: 12/13/2022] Open
Abstract
Sensory fibers of the peripheral nervous system carry sensation from specific sense structures or use different tissues and organs as receptive fields, and convey this information to the central nervous system. In the head of vertebrates, each cranial sensory ganglia and associated nerves perform specific functions. Sensory ganglia are composed of different types of specialized neurons in which two broad categories can be distinguished, somatosensory neurons relaying all sensations that are felt and visceral sensory neurons sensing the internal milieu and controlling body homeostasis. While in the trunk somatosensory neurons composing the dorsal root ganglia are derived exclusively from neural crest cells, somato- and visceral sensory neurons of cranial sensory ganglia have a dual origin, with contributions from both neural crest and placodes. As most studies on sensory neurogenesis have focused on dorsal root ganglia, our understanding of the molecular mechanisms underlying the embryonic development of the different cranial sensory ganglia remains today rudimentary. However, using single-cell RNA sequencing, recent studies have made significant advances in the characterization of the neuronal diversity of most sensory ganglia. Here we summarize the general anatomy, function and neuronal diversity of cranial sensory ganglia. We then provide an overview of our current knowledge of the transcriptional networks controlling neurogenesis and neuronal diversification in the developing sensory system, focusing on cranial sensory ganglia, highlighting specific aspects of their development and comparing it to that of trunk sensory ganglia.
Collapse
Affiliation(s)
- Simon Vermeiren
- ULB Neuroscience Institute, Université Libre de Bruxelles, Gosselies, Belgium
| | - Eric J Bellefroid
- ULB Neuroscience Institute, Université Libre de Bruxelles, Gosselies, Belgium
| | - Simon Desiderio
- Institute for Neurosciences of Montpellier, INSERM U1051, University of Montpellier, Montpellier, France
| |
Collapse
|
|
36
|
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.
Collapse
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
| |
Collapse
|
|
37
|
cnd-1/NeuroD1 Functions with the Homeobox Gene ceh-5/Vax2 and Hox Gene ceh-13/labial To Specify Aspects of RME and DD Neuron Fate in Caenorhabditis elegans. G3-GENES GENOMES GENETICS 2020; 10:3071-3085. [PMID: 32601060 PMCID: PMC7466980 DOI: 10.1534/g3.120.401515] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Identifying the mechanisms behind neuronal fate specification are key to understanding normal neural development in addition to neurodevelopmental disorders such as autism and schizophrenia. In vivo cell fate specification is difficult to study in vertebrates. However, the nematode Caenorhabditis elegans, with its invariant cell lineage and simple nervous system of 302 neurons, is an ideal organism to explore the earliest stages of neural development. We used a comparative transcriptome approach to examine the role of cnd-1/NeuroD1 in C. elegans nervous system development and function. This basic helix-loop-helix transcription factor is deeply conserved across phyla and plays a crucial role in cell fate specification in both the vertebrate nervous system and pancreas. We find that cnd-1 controls expression of ceh-5, a Vax2-like homeobox class transcription factor, in the RME head motorneurons and PVQ tail interneurons. We also show that cnd-1 functions redundantly with the Hox gene ceh-13/labial in defining the fate of DD1 and DD2 embryonic ventral nerve cord motorneurons. These data highlight the utility of comparative transcriptomes for identifying transcription factor targets and understanding gene regulatory networks.
Collapse
|
|
38
|
Soltani Asl M, Azimnasab-Sorkhabi P, Abolfathi AA, Hashemi Aghdam Y. Identification of nucleotide polymorphism within the NeuroD1 candidate gene and its association with type 1 diabetes susceptibility in Iranian people by polymerase chain reaction-restriction fragment length polymorphism. J Pediatr Endocrinol Metab 2020; 33:1293-1297. [PMID: 32845865 DOI: 10.1515/jpem-2019-0441] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2019] [Accepted: 06/29/2020] [Indexed: 11/15/2022]
Abstract
Objectives Diabetes is a serious disease, and the number of affected individuals with diabetes is considerably high. The aim of this study is the identification of NeuroD1 Ala45Thr polymorphism and its association with type 1 diabetes susceptibility in Iranian people. Methods Clinical and biochemical characteristics for 146 people (76 diabetics and 70 nondiabetics) were measured, such as fasting blood sugar, triacylglycerol, total cholesterol, age, and weight in each individual. Polymerase chain reaction-restriction fragment length polymorphism technique (MwoI restriction-enzyme) was used for genotyping of the NeuroD1 Ala45Thr polymorphism. Results In this study, the frequency of the A allele in diabetic patients in comparison with the healthy control group had a significantly higher percentage (p < 0.01), whereas diabetic patients had the AA genotype, approximately four times more than the healthy control group (p < 0.01). In addition, we observed that fasting blood sugar had a higher concentration in the AA genotype than in AG + GG genotypes (p < 0.01). Conclusions The A allele may be a risk factor for the expansion of type 1 diabetes in the Iranian population. However, the NeuroD1 Ala45Thr polymorphism and its role in type 1 diabetes in different populations are controversial.
Collapse
Affiliation(s)
- Maryam Soltani Asl
- Department of Biology, Faculty of Science, Ahar Branch, Azad University, Ahar, Iran
| | | | - Ali-Akbar Abolfathi
- Department of Biochemistry, Faculty of Medicine, Tabriz University, Tabriz, Iran
| | - Yashar Hashemi Aghdam
- Department of Traumatology, Spine and Orthopedic Surgery, Asklepios Hospital Altona, Faculty of Medicine, University of Hamburg, Hamburg, Germany
| |
Collapse
|
|
39
|
β-Cell specific transcription factors in the context of diabetes mellitus and β-cell regeneration. Mech Dev 2020; 163:103634. [PMID: 32711047 DOI: 10.1016/j.mod.2020.103634] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2020] [Revised: 07/15/2020] [Accepted: 07/15/2020] [Indexed: 02/06/2023]
Abstract
All pancreatic cell populations arise from the standard gut endoderm layer in developing embryos, requiring a regulatory gene network to originate and maintain endocrine lineages and endocrine function. The pancreatic organogenesis is regulated by the temporal expression of transcription factors and plays a diverse role in the specification, development, differentiation, maturation, and functional maintenance. Altered expression and activity of these transcription factors are often associated with diabetes mellitus. Recent advancements in the stem cells and invitro derived islets to treat diabetes mellitus has attracted a great deal of interest in the understanding of factors regulating the development, differentiation, and functions of islets including transcription factors. This review discusses the myriad of transcription factors regulating the development of the pancreas, differentiation of β-islets, and how these factors regulated in normal and disease states. Exploring these factors in such critical context and exogenous or endogenous expression of development and differentiation-specific transcription factors with improved epigenetic plasticity/signaling axis in diabetic milieu would useful for the development of β-cells from other cell sources.
Collapse
|
|
40
|
Nicolaides NC, Kanaka-Gantenbein C, Papadopoulou-Marketou N, Sertedaki A, Chrousos GP, Papassotiriou I. Emerging technologies in pediatrics: the paradigm of neonatal diabetes mellitus. Crit Rev Clin Lab Sci 2020; 57:522-531. [PMID: 32356495 DOI: 10.1080/10408363.2020.1752141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
In the era of precision medicine, the tremendous progress in next-generation sequencing technologies has allowed the identification of an ever-increasing number of genes associated with known Mendelian disorders. Neonatal diabetes mellitus is a rare, genetically heterogeneous endocrine disorder diagnosed before 6 months of age. It may occur alone or in the context of genetic syndromes. Neonatal diabetes mellitus has been linked with genetic defects in at least 26 genes to date. Novel mutations in these disease-causing genes are being reported, giving us a better knowledge of the molecular events that occur upon insulin biosynthesis and secretion from the pancreatic β-cell. Of great importance, some of the identified genes encode proteins that can be therapeutically targeted by drugs per os, leading to transitioning from insulin to sulfonylureas. In this review, we provide an overview of pancreatic β-cell physiology, present the clinical manifestations and the genetic causes of the different forms of neonatal diabetes, and discuss the application of next-generation sequencing methods in the diagnosis and therapeutic management of neonatal diabetes and on research in this area.
Collapse
Affiliation(s)
- Nicolas C Nicolaides
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece.,Division of Endocrinology and Metabolism, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.,University Research Institute of Maternal and Child Health and Precision Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Christina Kanaka-Gantenbein
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - Nektaria Papadopoulou-Marketou
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - Amalia Sertedaki
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - George P Chrousos
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece.,Division of Endocrinology and Metabolism, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.,University Research Institute of Maternal and Child Health and Precision Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Ioannis Papassotiriou
- Department of Clinical Biochemistry, "Aghia Sophia" Children's Hospital, Athens, Greece.,IFCC Emerging Technologies Division, Emerging Technologies in Pediatric Laboratory Medicine (C-ETPLM), Milano, Italy
| |
Collapse
|
|
41
|
Lorberbaum DS, Docherty FM, Sussel L. Animal Models of Pancreas Development, Developmental Disorders, and Disease. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1236:65-85. [PMID: 32304069 DOI: 10.1007/978-981-15-2389-2_3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The pancreas is a glandular organ responsible for diverse homeostatic functions, including hormone production from the endocrine islet cells to regulate blood sugar levels and enzyme secretion from the exocrine acinar cells to facilitate food digestion. These pancreatic functions are essential for life; therefore, preserving pancreatic function is of utmost importance. Pancreas dysfunction can arise either from developmental disorders or adult onset disease, both of which are caused by defects in shared molecular pathways. In this chapter, we discuss what is known about the molecular mechanisms controlling pancreas development, how disruption of these mechanisms can lead to developmental defects and disease, and how essential pancreas functions can be modeled using human pluripotent stem cells. At the core of understanding of these molecular processes are animal model studies that continue to be essential for elucidating the mechanisms underlying human pancreatic functions and diseases.
Collapse
Affiliation(s)
- David S Lorberbaum
- Barbara Davis Center, University of Colorado Anschutz Medical Center, Aurora, CO, USA
| | - Fiona M Docherty
- Barbara Davis Center, University of Colorado Anschutz Medical Center, Aurora, CO, USA
| | - Lori Sussel
- Barbara Davis Center, University of Colorado Anschutz Medical Center, Aurora, CO, USA.
| |
Collapse
|
|
42
|
Chia CY, Madrigal P, Denil SLIJ, Martinez I, Garcia-Bernardo J, El-Khairi R, Chhatriwala M, Shepherd MH, Hattersley AT, Dunn NR, Vallier L. GATA6 Cooperates with EOMES/SMAD2/3 to Deploy the Gene Regulatory Network Governing Human Definitive Endoderm and Pancreas Formation. Stem Cell Reports 2020; 12:57-70. [PMID: 30629940 PMCID: PMC6335596 DOI: 10.1016/j.stemcr.2018.12.003] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2017] [Revised: 12/09/2018] [Accepted: 12/10/2018] [Indexed: 12/17/2022] Open
Abstract
Heterozygous de novo mutations in GATA6 are the most frequent cause of pancreatic agenesis in humans. In mice, however, a similar phenotype requires the biallelic loss of Gata6 and its paralog Gata4. To elaborate the human-specific requirements for GATA6, we chose to model GATA6 loss in vitro by combining both gene-edited and patient-derived pluripotent stem cells (hPSCs) and directed differentiation toward β-like cells. We find that GATA6 heterozygous hPSCs show a modest reduction in definitive endoderm (DE) formation, while GATA6-null hPSCs fail to enter the DE lineage. Consistent with these results, genome-wide studies show that GATA6 binds and cooperates with EOMES/SMAD2/3 to regulate the expression of cardinal endoderm genes. The early deficit in DE is accompanied by a significant reduction in PDX1+ pancreatic progenitors and C-PEPTIDE+ β-like cells. Taken together, our data position GATA6 as a gatekeeper to early human, but not murine, pancreatic ontogeny.
Collapse
Affiliation(s)
- Crystal Y Chia
- Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Institute of Medical Biology, A(∗)STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, #06-06 Immunos, 138648, Singapore
| | - Pedro Madrigal
- Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, Cambridge, UK, and Department of Surgery, University of Cambridge, Cambridge, UK
| | - Simon L I J Denil
- Institute of Medical Biology, A(∗)STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, #06-06 Immunos, 138648, Singapore
| | - Iker Martinez
- Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
| | | | | | | | - Maggie H Shepherd
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Level 3 RILD Building, Barrack Road, Exeter EX25DW, UK
| | - Andrew T Hattersley
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Level 3 RILD Building, Barrack Road, Exeter EX25DW, UK
| | - N Ray Dunn
- Institute of Medical Biology, A(∗)STAR (Agency for Science, Technology and Research), 8A Biomedical Grove, #06-06 Immunos, 138648, Singapore; Lee Kong Chian School of Medicine, Nanyang Technological University, 50 Nanyang Avenue, 639798, Singapore; School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore.
| | - Ludovic Vallier
- Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK; Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Anne McLaren Laboratory for Regenerative Medicine, University of Cambridge, Cambridge, UK, and Department of Surgery, University of Cambridge, Cambridge, UK.
| |
Collapse
|
|
43
|
Jang KM. Maturity-onset diabetes of the young: update and perspectives on diagnosis and treatment. Yeungnam Univ J Med 2020; 37:13-21. [PMID: 31914718 PMCID: PMC6986955 DOI: 10.12701/yujm.2019.00409] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Accepted: 12/16/2019] [Indexed: 12/17/2022] Open
Abstract
Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous group of monogenic disorders characterized by ß-cell dysfunction. MODY accounts for between 2% and 5% of all diabetes cases, and distinguishing it from type 1 or type 2 diabetes is a diagnostic challenge. Recently, MODY-causing mutations have been identified in 14 different genes. Sanger DNA sequencing is the gold standard for identifying the mutations in MODY-related genes, and may facilitate the diagnosis. Despite the lower frequency among diabetes mellitus cases, a correct genetic diagnosis of MODY is important for optimizing treatment strategies. There is a discrepancy in the disease-causing locus between the Asian and Caucasian patients with MODY. Furthermore, the prevalence of the disease in Asian populations remains to be studied. In this review, the current understanding of MODY is summarized and the Asian studies of MODY are discussed in detail.
Collapse
Affiliation(s)
- Kyung Mi Jang
- Department of Pediatrics, Yeungnam University College of Medicine, Daegu, Korea
| |
Collapse
|
|
44
|
Yahaya TO, Anyebe DA. Genes predisposing to neonatal diabetes mellitus and pathophysiology: Current findings. J Neonatal Perinatal Med 2020; 13:543-553. [PMID: 32333556 DOI: 10.3233/npm-190353] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Precision medicine, described as a therapeutic procedure in which complex diseases are treated based on the causal gene and pathophysiology, is being considered for diabetes mellitus (DM). To this end, several monogenetic mutations in the beta cells have been linked with neonatal diabetes mellitus (NDM), however, the list of suspect genes is expansive, necessitating an update. This study, therefore, provides an update on NDM candidate genes and pathophysiology. RESULTS Reputable online academic databases were searched for relevant information, which led to the identification of 43 genes whose mutations are linked to the condition. Of the linked genes, mutations in the KCNJ11, ABCC8, and INS genes as well as the genes on 6q24 chromosomal region are the most frequently implicated. Mutations in these genes can cause pancreatic agenesis and developmental errors, resulting in NDM in the first six to twelve months of birth. The clinical presentations of NDM include frequent urination, rapid breathing, and dehydration, among others. CONCLUSIONS Monogenetic mutations in the beta cells may cause NDM with distinct pathophysiology from other DM. Treatment options that target NDM candidate genes and pathophysiology may lead to an improved treatment compared with the present generalized treatment for all forms of DM.
Collapse
Affiliation(s)
- T O Yahaya
- Department of Biology, Federal University Birnin Kebbi, Nigeria
| | - D A Anyebe
- Department of Biochemistry and Molecular Biology, Federal University Birnin Kebbi, Nigeria
| |
Collapse
|
|
45
|
Abstract
Neonatal diabetes mellitus (DM) is defined by the onset of persistent hyperglycemia within the first six months of life but may present up to 12 months of life. A gene mutation affecting pancreatic beta cells or synthesis/secretion of insulin is present in more than 80% of the children with neonatal diabetes. Neonatal DM can be transient, permanent, or be a component of a syndrome. Genetic testing is important as a specific genetic mutation can significantly alter the treatment and outcome. Patients with mutations of either KCNJ11 or ABCC8 that encode subunits of the KATP channel gene mutation can be managed with sulfonylurea oral therapy while patients with other genetic mutations require insulin treatment.
Collapse
Affiliation(s)
- Amanda Dahl
- Division of Pediatric Endocrinology and Metabolism, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
| | - Seema Kumar
- Division of Pediatric Endocrinology and Metabolism, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
- Correspondence: Seema Kumar Division of Pediatric Endocrinology and Metabolism, Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN55590, USATel +1 507-284-3300Fax +1 507-284-0727 Email
| |
Collapse
|
|
46
|
de Santana LS, Caetano LA, Costa‐Riquetto AD, Franco PC, Dotto RP, Reis AF, Weinert LS, Silveiro SP, Vendramini MF, do Prado FA, Abrahão GCP, de Almeida AGFP, Tavares MDGR, Gonçalves WRB, Santomauro Junior AC, Halpern B, Jorge AAL, Nery M, Teles MG. Targeted sequencing identifies novel variants in common and rare MODY genes. Mol Genet Genomic Med 2019; 7:e962. [PMID: 31595705 PMCID: PMC6900361 DOI: 10.1002/mgg3.962] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2018] [Revised: 08/09/2019] [Accepted: 08/13/2019] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. To date, mutations in 11 genes have been frequently associated with this phenotype. In Brazil, few cohorts have been screened for MODY, all using a candidate gene approach, with a high prevalence of undiagnosed cases (MODY-X). METHODS We conducted a next-generation sequencing target panel (tNGS) study to investigate, for the first time, a Brazilian cohort of MODY patients with a negative prior genetic analysis. One hundred and two patients were selected, of which 26 had an initial clinical suspicion of MODY-GCK and 76 were non-GCK MODY. RESULTS After excluding all benign and likely benign variants and variants of uncertain significance, we were able to assign a genetic cause for 12.7% (13/102) of the probands. Three rare MODY subtypes were identified (PDX1/NEUROD1/ABCC8), and eight variants had not been previously described/mapped in genomic databases. Important clinical findings were evidenced in some cases after genetic diagnosis, such as MODY-PDX1/HNF1B. CONCLUSION A multiloci genetic approach allowed the identification of rare MODY subtypes, reducing the large percentage of MODY-X in Brazilian cases and contributing to a better clinical, therapeutic, and prognostic characterization of these rare phenotypes.
Collapse
Affiliation(s)
- Lucas S. de Santana
- Monogenic Diabetes GroupGenetic Endocrinology Unit and Laboratory of Molecular & Cellular Endocrinology/LIM25School of MedicineUniversity of Sao Paulo (USP)Sao PauloSPBrazil
| | - Lilian A. Caetano
- Monogenic Diabetes GroupGenetic Endocrinology Unit and Laboratory of Molecular & Cellular Endocrinology/LIM25School of MedicineUniversity of Sao Paulo (USP)Sao PauloSPBrazil
- Diabetes UnitClinics HospitalSchool of MedicineUniversity of Sao Paulo (USP)Sao PauloSPBrazil
| | - Aline D. Costa‐Riquetto
- Monogenic Diabetes GroupGenetic Endocrinology Unit and Laboratory of Molecular & Cellular Endocrinology/LIM25School of MedicineUniversity of Sao Paulo (USP)Sao PauloSPBrazil
- Diabetes UnitClinics HospitalSchool of MedicineUniversity of Sao Paulo (USP)Sao PauloSPBrazil
| | - Pedro C. Franco
- Monogenic Diabetes GroupGenetic Endocrinology Unit and Laboratory of Molecular & Cellular Endocrinology/LIM25School of MedicineUniversity of Sao Paulo (USP)Sao PauloSPBrazil
- Diabetes UnitClinics HospitalSchool of MedicineUniversity of Sao Paulo (USP)Sao PauloSPBrazil
| | - Renata P. Dotto
- Departamento de MedicinaDisciplina de EndocrinologiaUniversidade Federal de São Paulo (UNIFESP)Sao PauloSPBrazil
| | - André F. Reis
- Departamento de MedicinaDisciplina de EndocrinologiaUniversidade Federal de São Paulo (UNIFESP)Sao PauloSPBrazil
| | | | | | - Marcio F. Vendramini
- Serviço de EndocrinologiaHospital do Servidor Público Estadual de São Paulo (HSPE‐SP)Sao PauloSPBrazil
| | - Flaviene A. do Prado
- Hospital Regional de Taguatinga da Secretaria de Saúde do Distrito FederalTaguatingaDFBrazil
| | | | | | | | | | - Augusto C. Santomauro Junior
- Serviço de Endocrinologia Prof. Dr. Fadlo Fraige FilhoHospital Beneficência Portuguesa de São Paulo (BP‐SP)Sao PauloSPBrazil
| | - Bruno Halpern
- Departamento de Endocrinologia e MetabologiaHospital das ClínicasFaculdade de MedicinaUniversidade de São Paulo (USP)Sao PauloSPBrazil
| | - Alexander A. L. Jorge
- Monogenic Diabetes GroupGenetic Endocrinology Unit and Laboratory of Molecular & Cellular Endocrinology/LIM25School of MedicineUniversity of Sao Paulo (USP)Sao PauloSPBrazil
| | - Marcia Nery
- Diabetes UnitClinics HospitalSchool of MedicineUniversity of Sao Paulo (USP)Sao PauloSPBrazil
| | - Milena G. Teles
- Monogenic Diabetes GroupGenetic Endocrinology Unit and Laboratory of Molecular & Cellular Endocrinology/LIM25School of MedicineUniversity of Sao Paulo (USP)Sao PauloSPBrazil
- Diabetes UnitClinics HospitalSchool of MedicineUniversity of Sao Paulo (USP)Sao PauloSPBrazil
| |
Collapse
|
|
47
|
Romer AI, Singer RA, Sui L, Egli D, Sussel L. Murine Perinatal β-Cell Proliferation and the Differentiation of Human Stem Cell-Derived Insulin-Expressing Cells Require NEUROD1. Diabetes 2019; 68:2259-2271. [PMID: 31519700 PMCID: PMC6868472 DOI: 10.2337/db19-0117] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Accepted: 09/03/2019] [Indexed: 12/13/2022]
Abstract
Inactivation of the β-cell transcription factor NEUROD1 causes diabetes in mice and humans. In this study, we uncovered novel functions of NEUROD1 during murine islet cell development and during the differentiation of human embryonic stem cells (HESCs) into insulin-producing cells. In mice, we determined that Neurod1 is required for perinatal proliferation of α- and β-cells. Surprisingly, apoptosis only makes a minor contribution to β-cell loss when Neurod1 is deleted. Inactivation of NEUROD1 in HESCs severely impaired their differentiation from pancreatic progenitors into insulin-expressing (HESC-β) cells; however, survival or proliferation was not affected at the time points analyzed. NEUROD1 was also required in HESC-β cells for the full activation of an essential β-cell transcription factor network. These data reveal conserved and distinct functions of NEUROD1 during mouse and human β-cell development and maturation, with important implications about the function of NEUROD1 in diabetes.
Collapse
Affiliation(s)
- Anthony I Romer
- Department of Genetics and Development, Columbia University, New York, NY
- Department of Pediatrics, Columbia University, New York, NY
| | - Ruth A Singer
- Department of Genetics and Development, Columbia University, New York, NY
- Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University, New York, NY
| | - Lina Sui
- Department of Pediatrics, Columbia University, New York, NY
| | - Dieter Egli
- Department of Pediatrics, Columbia University, New York, NY
| | - Lori Sussel
- Department of Genetics and Development, Columbia University, New York, NY
- Department of Pediatrics, University of Colorado Denver School of Medicine, Denver, CO
| |
Collapse
|
|
48
|
Oliveira SC, Neves JS, Pérez A, Carvalho D. Maturity-onset diabetes of the young: From a molecular basis perspective toward the clinical phenotype and proper management. ACTA ACUST UNITED AC 2019; 67:137-147. [PMID: 31718996 DOI: 10.1016/j.endinu.2019.07.012] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 07/04/2019] [Accepted: 07/09/2019] [Indexed: 12/28/2022]
Abstract
Maturity-onset diabetes of the young (MODY) comprises a heterogeneous group of monogenic disorders characterized by primary defect in pancreatic β-cell function, early onset and autosomal dominant inheritance, accounting for about 1-5% of all diabetes diagnoses. Mutations in 14 genes are responsible for the majority of all MODY cases described so far. The clinical phenotype relies on genetic defects, with important implications in the optimal treatment and prognosis definition. MODY's early diagnosis remains a challenge, since this group of inherited disorders comprises a large clinical spectrum and it usually overlaps with other types of diabetes, requiring a high index of suspicion even if the definitive statement demands a molecular genetic study. Recent advances on the genetic determinants and pathophysiology of MODY have allowed a better understanding of its underlying molecular mechanisms, providing a proper genetic counseling and early diagnosis. These new management insights will make possible to set up new therapeutic strategies, with drugs able to prevent, correct or at least delay the decline of pancreatic β-cell function, thus affording for a more personalized treatment and, ultimately, for a better patient care.
Collapse
Affiliation(s)
- Sofia Castro Oliveira
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal; Faculty of Medicine of the Universidade do Porto, Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
| | - João Sérgio Neves
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal; Faculty of Medicine of the Universidade do Porto, Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| | - Antonio Pérez
- Department of Endocrinology and Nutrition, Hospital Santa Creu i Sant Pau, Barcelona, Spain; Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain; CIBER de Diabetes y Enfermidades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
| | - Davide Carvalho
- Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal; Faculty of Medicine of the Universidade do Porto, Porto, Portugal; Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
| |
Collapse
|
|
49
|
Abstract
A comprehensive understanding of mechanisms that underlie the development and function of human cells requires human cell models. For the pancreatic lineage, protocols have been developed to differentiate human pluripotent stem cells (hPSCs) into pancreatic endocrine and exocrine cells through intermediates resembling in vivo development. In recent years, this differentiation system has been employed to decipher mechanisms of pancreatic development, congenital defects of the pancreas, as well as genetic forms of diabetes and exocrine diseases. In this review, we summarize recent insights gained from studies of pancreatic hPSC models. We discuss how genome-scale analyses of the differentiation system have helped elucidate roles of chromatin state, transcription factors, and noncoding RNAs in pancreatic development and how the analysis of cells with disease-relevant mutations has provided insight into the molecular underpinnings of genetically determined diseases of the pancreas.
Collapse
Affiliation(s)
- Bjoern Gaertner
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, California 92093, USA
| | - Andrea C Carrano
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, California 92093, USA
| | - Maike Sander
- Departments of Pediatrics and Cellular & Molecular Medicine, Pediatric Diabetes Research Center, University of California, San Diego, La Jolla, California 92093, USA
| |
Collapse
|
|
50
|
Abreu GDM, Tarantino RM, Cabello PH, Zembrzuski VM, da Fonseca ACP, Rodacki M, Zajdenverg L, Campos Junior M. The first case of NEUROD1-MODY reported in Latin America. Mol Genet Genomic Med 2019; 7:e989. [PMID: 31578821 PMCID: PMC6900366 DOI: 10.1002/mgg3.989] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2019] [Revised: 08/01/2019] [Accepted: 08/18/2019] [Indexed: 01/06/2023] Open
Abstract
Background MODY‐NEUROD1 is a rare form of monogenic diabetes caused by mutations in Neuronal differentiation 1 (NEUROD1). Until now, only a few cases of MODY‐NEUROD1 have been reported worldwide and the real contribution of mutations in NEUROD1 in monogenic diabetes and its clinical impact remain unclear. Methods Genomic DNA was isolated from peripheral blood lymphocytes of 25 unrelated Brazilians patients with clinical characteristics suggestive of monogenic diabetes and the screening of the entire coding region of NEUROD1 was performed by Sanger sequencing. Results We identified one novel frameshift deletion (p.Phe256Leufs*2) in NEUROD1 segregating in an autosomal dominant inheritance fashion. Almost 20 years after the first report of NEUROD1‐MODY, only a few families in Europe and Asia had shown mutations in NEUROD1 as the cause of monogenic diabetes. Conclusion To our knowledge, we described the first case of NEUROD1‐MODY in a Latin American family.
Collapse
Affiliation(s)
| | - Roberta Magalhães Tarantino
- Diabetes and Nutrology Section, Internal Medicine Department, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.,Ambulatory of Diabetes, State Institute of Diabetes and Endocrinology, Rio de Janeiro, Brazil
| | - Pedro Hernan Cabello
- Human Genetics Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.,Laboratory of Genetics, School of Health Science, Grande Rio University, Rio de Janeiro, Brazil
| | | | | | - Melanie Rodacki
- Diabetes and Nutrology Section, Internal Medicine Department, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Lenita Zajdenverg
- Diabetes and Nutrology Section, Internal Medicine Department, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - Mário Campos Junior
- Human Genetics Laboratory, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
| |
Collapse
|