1,231 results on '"Monogenic diabetes"'
Search Results
2. Chinese carrier of the HNF1A p.Gln444fs variant exhibits enhanced response to sulfonylureas
- Author
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Wang, Xiufang, Cheng, Wenzhuo, Wang, Zhongjing, Liu, Chao, Deng, Aiping, and Li, Juyi
- Published
- 2024
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3. Clinical, glycometric features and treatment in a family with monogenic diabetes due to a new mutation in the insulin gene
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Pérez López, Paloma, Bahillo Curieses, Pilar, Fernández, Pablo, Martínez, Rosa, Delgado, Esther, Ortolá, Ana, de Luis, Daniel, and Díaz-Soto, Gonzalo
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- 2024
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4. A novel BLK heterozygous mutation (p.Met121lle) in maturity‐onset diabetes mellitus: A case report and literature review.
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Xu, Fenjuan, Chen, Xiaoting, Hu, Tingting, Sun, Ruqiong, Zhu, Fangying, and Wu, Xiaohong
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MATURITY onset diabetes of the young , *GENETIC testing , *DIABETES , *PEOPLE with diabetes , *AUTOANTIBODIES - Abstract
Maturity onset diabetes of the young (MODY) is a highly heterogeneous monogenic disease that occurs due to β‐cell dysfunction. It is divided into different types depending on the gene mutated, and a total of 16 genes have been found to be associated with MODY. However, due to the current lack of understanding of monogenic diabetes, 90% of MODY is currently misdiagnosed and ignored in clinical practice. In this paper, we report the clinical data of a patient diagnosed with diabetes. Genetic testing revealed a novel BLK heterozygous mutation (c.363G>A) in the patient and in his father and son. He had no islet‐specific autoantibodies and showed a reduced meal‐induced response of insulin. Precise diagnosis of MODY individuals is important to the treatment. [ABSTRACT FROM AUTHOR]
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- 2025
- Full Text
- View/download PDF
5. The Identification of a Novel Pathogenic Variant in the GATA6 Gene in a Child with Neonatal Diabetes.
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Sechko, Elena A., Koltakova, Maria P., Khusainova, Rita I., Minniakhmetov, Ildar R., and Laptev, Dmitry N.
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EXOCRINE pancreatic insufficiency , *DIABETES in children , *MITRAL valve prolapse , *ENZYME replacement therapy , *DIABETES - Abstract
GATA6 syndrome is a rare monogenic disorder caused by heterozygous variants in the gene GATA6, which controls the early embryonic differentiation of germ layers and the development of different organs. We present the results of the 7-year follow-up of a child with this syndrome as well as the following conditions: diabetes mellitus, exocrine pancreatic insufficiency, gallbladder atresia, and congenital heart disease (CHD). At birth, the patient was diagnosed with neonatal diabetes mellitus (NDM) associated with heart (mitral valve prolapse) and gastrointestinal abnormalities (gallbladder atresia). Diabetes remitted within weeks and relapsed at the age of 2. We identified a de novo variant of a 4-nucleotide deletion (c.1302+4_1302+7del), previously unreported in the literature, in the donor splicing site of exon 3 of the GATA6 gene in a heterozygous state. Screening for other possible components of GATA6 syndrome revealed exocrine pancreatic insufficiency, and pancreatic enzyme replacement therapy resulted in improved dyspeptic symptoms, and growth rates increased. In addition, the patient was diagnosed with autoimmune thyroiditis and progressive myopia. [ABSTRACT FROM AUTHOR]
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- 2024
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6. A homozygous TARS2 variant is a novel cause of syndromic neonatal diabetes.
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Donis, Russell, Patel, Kashyap A., Wakeling, Matthew N., Johnson, Matthew B., Amoli, Masha M., Yildiz, Melek, Akçay, Teoman, Aspi, Irani, Yong, James, Yaghootkar, Hanieh, Weedon, Michael N., Hattersley, Andrew T., Flanagan, Sarah E., and De Franco, Elisa
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MISSENSE mutation , *DEVELOPMENTAL delay , *ETIOLOGY of diabetes , *NUCLEOTIDE sequencing , *DIABETES - Abstract
Aims Methods Results Conclusions Neonatal diabetes is a monogenic condition which can be the presenting feature of complex syndromes. The aim of this study was to identify novel genetic causes of neonatal diabetes with neurological features including developmental delay and epilepsy.We performed genome sequencing in 27 individuals with neonatal diabetes plus epilepsy and/or developmental delay of unknown genetic cause. Replication studies were performed in 123 individuals with diabetes diagnosed aged ≤1 year without a known genetic cause using targeted next‐generation sequencing.Three individuals, all diagnosed with diabetes in the first week of life, shared a rare homozygous missense variant, p.(Arg327Gln), in TARS2. Replication studies identified the same homozygous variant in a fourth individual diagnosed with diabetes at 1 year. One proband had epilepsy, one had development delay and two had both.Biallelic TARS2 variants cause a mitochondrial encephalopathy (COXPD‐21) characterised by severe hypotonia, epilepsy and developmental delay. Diabetes is not a known feature of COXPD‐21. Current evidence suggests that the p.(Arg327Gln) variant disrupts TARS2's regulation of the mTORC1 pathway which is essential for β‐cells.Our findings establish the homozygous p.(Arg327Gln) TARS2 variant as a novel cause of syndromic neonatal diabetes and uncover a role for TARS2 in pancreatic β‐cells. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Clinical characteristics, treatment, and treatment switch after molecular‐genetic classification in individuals with maturity‐onset diabetes of the young: Insights from the multicenter real‐world DPV registry.
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Lanzinger, Stefanie, Laubner, Katharina, Warncke, Katharina, Mader, Julia K., Kummer, Sebastian, Boettcher, Claudia, Biester, Torben, Galler, Angela, Klose, Daniela, and Holl, Reinhard W.
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TYPE 1 diabetes , *MATURITY onset diabetes of the young , *PANCREATIC beta cells , *ORAL medication , *INSULIN therapy - Abstract
Background: Individuals with maturity‐onset diabetes of the young (MODY) are often misdiagnosed as type 1 or type 2 diabetes and receive inappropriate care. We aimed to investigate the characteristics and treatment of all MODY types in a multicenter, real‐world setting. Methods: Individuals with MODY from the diabetes prospective follow‐up (DPV) registry were studied. We compared clinical parameters during the first year of diabetes and the most recent treatment year after MODY diagnosis. Results: A total of 1640 individuals were identified with GCK‐MODY (n = 941) and HNF1A‐MODY (n = 417) as the most frequent types. Among these, 912 individuals were available with information during the first and the most recent treatment year (median duration of follow‐up: 4.2 years [2.6–6.6]). Positive beta cell autoantibodies were present in 20.6% (15.2% IAA). Median age at diagnosis ranged from 9.9 years in GCK‐MODY (Q1–Q3: 6.2–13.1 years) and INS‐MODY (2.7–13.7 years) to 14.3 years (5.0–17.1) in KCNJ11‐MODY. Frequency of oral antidiabetic agents (OAD) use increased and insulin decreased in HNF4A‐MODY (OAD: 18% to 39%, insulin: 34% to 23%) and in HNF1A‐MODY (OAD: 18% to 31%, insulin: 35% to 25%). ABCC8‐MODY was characterized by a decrement in nonpharmacological treatment (26% to 16%) and "insulin only" treatment (53% to 42%), while the proportion of individuals treated with OAD but no insulin increased from 0% to 21%. Conclusions: Our results indicate that some teams caring for individuals with MODY are hesitant with regard to current recommendations. Registries are an essential source of information and provide a basis for discussing treatment guidelines for MODY. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
8. Our Experiences and Learnings in Diagnosing MODY from Non-Institutional-Based Diabetes Care Clinics
- Author
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Arunkumar R. Pande, Santosh Chaubey, Dinesh Kumar, Kumar P. Chandra, Thenral Geetha, and Akshita Sharma
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hnf1a mody ,mody ,monogenic diabetes ,pediatric diabetes ,young diabetes ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Introduction: Maturity-onset diabetes of the young (MODY) is a rare group of disorders characterised by impaired functions or development of pancreatic islets and monogenic diabetes at a young age. Diagnosing MODY can be rewarding for both clinicians and patients as it can change the management from generic to targeted therapy. Methods: This study reports the retrospective analysis of data collected from four clinics between March 2016 and February 2023 from Lucknow, a city in northern India. Fifty-three individuals are suspected to be affected by MODY based on ISPAD guidelines. Following a detailed clinical evaluation, they were referred for genetic diagnostic testing. Results: The cohort consists of 19 females and 34 males with a mean age of diagnosis of 25.3 years and a body mass index of 22.3 Kg/m2. Genetic testing detected variants in 13/53 (~24.5%) individuals. Five cases had significant pathogenic/likely pathogenic variants, HNF1A gene in two [(p.Phe268LeufsTer74) (p.Arg200Gln)], one each in HNF4A (Arg311His), PDX1(p.Ala228GlyfsTer33), and a case with suggestive digenic variants in HNF1A gene (p.Arg200Gln) and HNF1B [(p.Leu13Met)]. Variants of uncertain significance (VUSs) with inconclusive evidence of pathogenicity were reported in eight patients, and five were considered to be clinically significant as they are lean young onset, sulfonylurea-responsive, and presented with diabetes without acanthosis nigricans and with high pretest probability. These individuals harboured variants in HNF1A (p.Thr425_Thr429delinsPro), HNF1B (p.Ser19Phe), CEL (p.Val681ArgfsTer6), ABCC8 (p.Ile872Met), and KCNJ11 (p.Arg221Cys) genes. Conclusion: We found a diagnostic yield of around 10% of pathogenic or likely pathogenic variants in individuals who were suspected to have MODY. As it is a field that is still evolving, we might consider starting with oral agents under close supervision in those individuals who have VUS; there are some proportions of individuals who might not have classical sulfonylurea-responsive genetic variants, but they might respond to it.
- Published
- 2024
- Full Text
- View/download PDF
9. Examining the clinical and genetic spectrum of maturity-onset diabetes of the young (MODY) in Iran
- Author
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Sara Asgarian, Hossein Lanjanian, Shiva Rahimipour Anaraki, Farzad Hadaegh, Maryam Moazzam-Jazi, Leila Najd-Hassan-Bonab, Sajedeh Masjoudi, Asiyeh Sadat Zahedi, Maryam Zarkesh, Bita Shalbafan, Mahdi Akbarzadeh, Sahand Tehrani Fateh, Davood Khalili, Amirabbas Momenan, Narges Sarbazi, Mehdi Hedayati, Fereidoun Azizi, and Maryam S. Daneshpour
- Subjects
Maturity-onset diabetes of the young ,MODY ,Monogenic diabetes ,HNF1A ,HNF4A ,GCK ,Medicine ,Science - Abstract
Abstract Maturity-onset diabetes of the young (MODY) is an uncommon monogenic type of diabetes mellitus. Detecting genetic variants for MODY is a necessity for precise diagnosis and treatment. The majority of MODY genetic predisposition has been documented in European populations and a lack of information is present in Iranians which leads to misdiagnosis as a consequence of defects in unknown variants. In this study, using genetic variant information of 20,002 participants from the family-based TCGS (Tehran Cardiometabolic Genetic Study) cohort, we evaluated the genetic spectrum of MODY in Iran. We concentrated on previously discovered MODY-causing genes. Genetic variants were evaluated for their pathogenicity. We discovered 6 variants that were previously reported in the ClinVar as pathogenic/likely pathogenic (P/LP) for MODY in 45 participants from 24 families (INS in 21 cases, GCK in 13, HNF1B in 8, HNF4A, HNF1A, and CEL in 1 case). One potential MODY variant with Uncertain Risk Allele in ClinVar classification was also identified, which showed complete disease penetrance (100%) in four subjects from one family. This is the first family-based study to define the genetic spectrum and estimate the prevalence of MODY in Iran. The discovered variants need to be investigated by additional studies.
- Published
- 2024
- Full Text
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10. Monogenic Defects of Beta Cell Function: From Clinical Suspicion to Genetic Diagnosis and Management of Rare Types of Diabetes.
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Serbis, Anastasios, Kantza, Evanthia, Siomou, Ekaterini, Galli-Tsinopoulou, Assimina, Kanaka-Gantenbein, Christina, and Tigas, Stelios
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MATURITY onset diabetes of the young , *DIABETES in children , *TYPE 1 diabetes , *PANCREATIC beta cells , *GENETIC counseling - Abstract
Monogenic defects of beta cell function refer to a group of rare disorders that are characterized by early-onset diabetes mellitus due to a single gene mutation affecting insulin secretion. It accounts for up to 5% of all pediatric diabetes cases and includes transient or permanent neonatal diabetes, maturity-onset diabetes of the young (MODY), and various syndromes associated with diabetes. Causative mutations have been identified in genes regulating the development or function of the pancreatic beta cells responsible for normal insulin production and/or release. To date, more than 40 monogenic diabetes subtypes have been described, with those caused by mutations in HNF1A and GCK genes being the most prevalent. Despite being caused by a single gene mutation, each type of monogenic diabetes, especially MODY, can appear with various clinical phenotypes, even among members of the same family. This clinical heterogeneity, its rarity, and the fact that it shares some features with more common types of diabetes, can make the clinical diagnosis of monogenic diabetes rather challenging. Indeed, several cases of MODY or syndromic diabetes are accurately diagnosed in adulthood, after having been mislabeled as type 1 or type 2 diabetes. The recent widespread use of more reliable sequencing techniques has improved monogenic diabetes diagnosis, which is important to guide appropriate treatment and genetic counselling. The current review aims to summarize the latest knowledge on the clinical presentation, genetic confirmation, and therapeutic approach of the various forms of monogenic defects of beta cell function, using three imaginary clinical scenarios and highlighting clinical and laboratory features that can guide the clinician in reaching the correct diagnosis. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
11. Our Experiences and Learnings in Diagnosing MODY from Non-Institutional-Based Diabetes Care Clinics.
- Author
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Pande, Arunkumar R., Chaubey, Santosh, Kumar, Dinesh, Chandra, Kumar P., Geetha, Thenral, and Sharma, Akshita
- Subjects
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MATURITY onset diabetes of the young , *DIABETES in children , *ACANTHOSIS nigricans , *BODY mass index , *ISLANDS of Langerhans - Abstract
Introduction: Maturity-onset diabetes of the young (MODY) is a rare group of disorders characterised by impaired functions or development of pancreatic islets and monogenic diabetes at a young age. Diagnosing MODY can be rewarding for both clinicians and patients as it can change the management from generic to targeted therapy. Methods: This study reports the retrospective analysis of data collected from four clinics between March 2016 and February 2023 from Lucknow, a city in northern India. Fifty-three individuals are suspected to be affected by MODY based on ISPAD guidelines. Following a detailed clinical evaluation, they were referred for genetic diagnostic testing. Results: The cohort consists of 19 females and 34 males with a mean age of diagnosis of 25.3 years and a body mass index of 22.3 Kg/m2. Genetic testing detected variants in 13/53 (~24.5%) individuals. Five cases had significant pathogenic/likely pathogenic variants, HNF1A gene in two [(p.Phe268LeufsTer74) (p.Arg200Gln)], one each in HNF4A (Arg311His), PDX1 (p.Ala228GlyfsTer33), and a case with suggestive digenic variants in HNF1A gene (p.Arg200Gln) and HNF1B [(p.Leu13Met)]. Variants of uncertain significance (VUSs) with inconclusive evidence of pathogenicity were reported in eight patients, and five were considered to be clinically significant as they are lean young onset, sulfonylurea-responsive, and presented with diabetes without acanthosis nigricans and with high pretest probability. These individuals harboured variants in HNF1A (p.Thr425_Thr429delinsPro), HNF1B (p.Ser19Phe), CEL (p.Val681ArgfsTer6), ABCC8 (p.Ile872Met), and KCNJ11 (p.Arg221Cys) genes. Conclusion: We found a diagnostic yield of around 10% of pathogenic or likely pathogenic variants in individuals who were suspected to have MODY. As it is a field that is still evolving, we might consider starting with oral agents under close supervision in those individuals who have VUS; there are some proportions of individuals who might not have classical sulfonylurea-responsive genetic variants, but they might respond to it. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
12. The Changing Landscape of Neonatal Diabetes Mellitus in Italy Between 2003 and 2022.
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Rapini, Novella, Delvecchio, Maurizio, Mucciolo, Mafalda, Ruta, Rosario, Rabbone, Ivana, Cherubini, Valentino, Zucchini, Stefano, Cianfarani, Stefano, Prandi, Elena, Schiaffini, Riccardo, Bizzarri, Carla, Piccini, Barbara, Maltoni, Giulio, Predieri, Barbara, Minuto, Nicola, Paola, Rossella Di, Giordano, Mara, Tinto, Nadia, Grasso, Valeria, and Russo, Lucia
- Subjects
PANCREATIC enzymes ,MOLECULAR genetics ,INSULIN resistance ,DIABETES ,NUCLEOTIDE sequencing - Abstract
Context In the last decade the Sanger method of DNA sequencing has been replaced by next-generation sequencing (NGS). NGS is valuable in conditions characterized by high genetic heterogeneity such as neonatal diabetes mellitus (NDM). Objective To compare results of genetic analysis of patients with NDM and congenital severe insulin resistance (c.SIR) identified in Italy in 2003-2012 (Sanger) vs 2013-2022 (NGS). Methods We reviewed clinical and genetic records of 104 cases with diabetes onset before 6 months of age (NDM + c.SIR) of the Italian dataset. Results Fifty-five patients (50 NDM + 5 c.SIR) were identified during 2003-2012 and 49 (46 NDM + 3 c.SIR) in 2013-2022. Twenty-year incidence was 1:103 340 (NDM) and 1:1 240 082 (c.SIR) live births. Frequent NDM/c.SIR genetic defects (KCNJ11 , INS , ABCC8 , 6q24, INSR) were detected in 41 and 34 probands during 2003-2012 and 2013-2022, respectively. We identified a pathogenic variant in rare genes in a single proband (GATA4) (1/42 or 2.4%) during 2003-2012 and in 8 infants (RFX6 , PDX1 , GATA6 , HNF1B , FOXP3 , IL2RA , LRBA , BSCL2) during 2013-2022 (8/42 or 19%, P =.034 vs 2003-2012). Notably, among rare genes 5 were recessive. Swift and accurate genetic diagnosis led to appropriate treatment: patients with autoimmune NDM (FOXP3 , IL2RA , LRBA) were subjected to bone marrow transplant; patients with pancreas agenesis/hypoplasia (RFX6 , PDX1) were supplemented with pancreatic enzymes, and the individual with lipodystrophy caused by BSCL2 was started on metreleptin. Conclusion NGS substantially improved diagnosis and precision therapy of monogenic forms of neonatal diabetes and c.SIR in Italy. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
13. Examining the clinical and genetic spectrum of maturity-onset diabetes of the young (MODY) in Iran.
- Author
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Asgarian, Sara, Lanjanian, Hossein, Rahimipour Anaraki, Shiva, Hadaegh, Farzad, Moazzam-Jazi, Maryam, Najd-Hassan-Bonab, Leila, Masjoudi, Sajedeh, Zahedi, Asiyeh Sadat, Zarkesh, Maryam, Shalbafan, Bita, Akbarzadeh, Mahdi, Tehrani Fateh, Sahand, Khalili, Davood, Momenan, Amirabbas, Sarbazi, Narges, Hedayati, Mehdi, Azizi, Fereidoun, and Daneshpour, Maryam S.
- Abstract
Maturity-onset diabetes of the young (MODY) is an uncommon monogenic type of diabetes mellitus. Detecting genetic variants for MODY is a necessity for precise diagnosis and treatment. The majority of MODY genetic predisposition has been documented in European populations and a lack of information is present in Iranians which leads to misdiagnosis as a consequence of defects in unknown variants. In this study, using genetic variant information of 20,002 participants from the family-based TCGS (Tehran Cardiometabolic Genetic Study) cohort, we evaluated the genetic spectrum of MODY in Iran. We concentrated on previously discovered MODY-causing genes. Genetic variants were evaluated for their pathogenicity. We discovered 6 variants that were previously reported in the ClinVar as pathogenic/likely pathogenic (P/LP) for MODY in 45 participants from 24 families (INS in 21 cases, GCK in 13, HNF1B in 8, HNF4A, HNF1A, and CEL in 1 case). One potential MODY variant with Uncertain Risk Allele in ClinVar classification was also identified, which showed complete disease penetrance (100%) in four subjects from one family. This is the first family-based study to define the genetic spectrum and estimate the prevalence of MODY in Iran. The discovered variants need to be investigated by additional studies. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
14. Monogenic Diabetes: A Comprehensive Overview and Therapeutic Management of Subtypes of Mody.
- Author
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Sharma, Manisha, Maurya, Kajal, Nautiyal, Anuj, and Chitme, Havagiray R.
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MATURITY onset diabetes of the young , *TYPE 2 diabetes , *HYPERGLYCEMIA , *ETIOLOGY of diabetes , *DIABETES - Abstract
BackgroundMethodsResultsConclusionMonogenic diabetes often occurs as a result of single-gene mutations. The illness is minimally affected by environmental and behavioral factors, and it constitutes around one to five percent of all cases of diabetes.Newborn diabetes mellitus (NDM) and maturity-onset diabetes of the young (MODY) are the predominant causes of monogenic diabetes, accounting for a larger proportion of cases, while syndromic diabetes represents a smaller percentage. MODY, a group of inherited non-autoimmune diabetes mellitus disorders, is quite common. However, it remains frequently misdiagnosed despite increasing public awareness. The condition is characterized by insulin resistance, the development of diabetes at a young age (before 25 years), mild high blood sugar levels, inheritance in an autosomal dominant pattern, and the preservation of natural insulin production.Currently, there are 14 distinct subtypes of MODY that have been identified. Each subtype possesses distinct characteristics in terms of their frequency, clinical symptoms, severity of diabetes, related complications, and response to medicinal interventions. Due to the clinical similarities, lack of awareness, and high expense of genetic testing, distinguishing between type I (T1D) and type II diabetes mellitus (T2D) can be challenging, resulting in misdiagnosis of this type of diabetes. As a consequence, a significant number of individuals are being deprived of adequate medical attention. Accurate diagnosis enables the utilization of novel therapeutic strategies and enhances the management of therapy in comparison to type II and type I diabetes.This article offers a concise overview of the clinical subtypes and characteristics of monogenic diabetes. Furthermore, this article discusses the various subtypes of MODY, as well as the process of diagnosing, managing, and treating the condition. It also addresses the difficulties encountered in detecting and treating MODY. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
15. RFX6 haploinsufficiency predisposes to diabetes through impaired beta cell function.
- Author
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Ibrahim, Hazem, Balboa, Diego, Saarimäki-Vire, Jonna, Montaser, Hossam, Dyachok, Oleg, Lund, Per-Eric, Omar-Hmeadi, Muhmmad, Kvist, Jouni, Dwivedi, Om P., Lithovius, Väinö, Barsby, Tom, Chandra, Vikash, Eurola, Solja, Ustinov, Jarkko, Tuomi, Tiinamaija, Miettinen, Päivi J., Barg, Sebastian, Tengholm, Anders, and Otonkoski, Timo
- Abstract
Aims/hypothesis: Regulatory factor X 6 (RFX6) is crucial for pancreatic endocrine development and differentiation. The RFX6 variant p.His293LeufsTer7 is significantly enriched in the Finnish population, with almost 1:250 individuals as a carrier. Importantly, the FinnGen study indicates a high predisposition for heterozygous carriers to develop type 2 and gestational diabetes. However, the precise mechanism of this predisposition remains unknown. Methods: To understand the role of this variant in beta cell development and function, we used CRISPR technology to generate allelic series of pluripotent stem cells. We created two isogenic stem cell models: a human embryonic stem cell model; and a patient-derived stem cell model. Both were differentiated into pancreatic islet lineages (stem-cell-derived islets, SC-islets), followed by implantation in immunocompromised NOD-SCID-Gamma mice. Results: Stem cell models of the homozygous variant RFX6
−/− predictably failed to generate insulin-secreting pancreatic beta cells, mirroring the phenotype observed in Mitchell–Riley syndrome. Notably, at the pancreatic endocrine stage, there was an upregulation of precursor markers NEUROG3 and SOX9, accompanied by increased apoptosis. Intriguingly, heterozygous RFX6+/− SC-islets exhibited RFX6 haploinsufficiency (54.2% reduction in protein expression), associated with reduced beta cell maturation markers, altered calcium signalling and impaired insulin secretion (62% and 54% reduction in basal and high glucose conditions, respectively). However, RFX6 haploinsufficiency did not have an impact on beta cell number or insulin content. The reduced insulin secretion persisted after in vivo implantation in mice, aligning with the increased risk of variant carriers to develop diabetes. Conclusions/interpretation: Our allelic series isogenic SC-islet models represent a powerful tool to elucidate specific aetiologies of diabetes in humans, enabling the sensitive detection of aberrations in both beta cell development and function. We highlight the critical role of RFX6 in augmenting and maintaining the pancreatic progenitor pool, with an endocrine roadblock and increased cell death upon its loss. We demonstrate that RFX6 haploinsufficiency does not affect beta cell number or insulin content but does impair function, predisposing heterozygous carriers of loss-of-function variants to diabetes. Data availability: Ultra-deep bulk RNA-seq data for pancreatic differentiation stages 3, 5 and 7 of H1 RFX6 genotypes are deposited in the Gene Expression Omnibus database with accession code GSE234289. Original western blot images are deposited at Mendeley (https://data.mendeley.com/datasets/g75drr3mgw/2). [ABSTRACT FROM AUTHOR]- Published
- 2024
- Full Text
- View/download PDF
16. Clinical characteristics, treatment, and treatment switch after molecular‐genetic classification in individuals with maturity‐onset diabetes of the young: Insights from the multicenter real‐world DPV registry
- Author
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Stefanie Lanzinger, Katharina Laubner, Katharina Warncke, Julia K. Mader, Sebastian Kummer, Claudia Boettcher, Torben Biester, Angela Galler, Daniela Klose, and Reinhard W. Holl
- Subjects
diabetes prospective follow‐up (DPV) registry ,MODY ,monogenic diabetes ,oral antidiabetic drugs ,real‐world data ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Abstract Background Individuals with maturity‐onset diabetes of the young (MODY) are often misdiagnosed as type 1 or type 2 diabetes and receive inappropriate care. We aimed to investigate the characteristics and treatment of all MODY types in a multicenter, real‐world setting. Methods Individuals with MODY from the diabetes prospective follow‐up (DPV) registry were studied. We compared clinical parameters during the first year of diabetes and the most recent treatment year after MODY diagnosis. Results A total of 1640 individuals were identified with GCK‐MODY (n = 941) and HNF1A‐MODY (n = 417) as the most frequent types. Among these, 912 individuals were available with information during the first and the most recent treatment year (median duration of follow‐up: 4.2 years [2.6–6.6]). Positive beta cell autoantibodies were present in 20.6% (15.2% IAA). Median age at diagnosis ranged from 9.9 years in GCK‐MODY (Q1–Q3: 6.2–13.1 years) and INS‐MODY (2.7–13.7 years) to 14.3 years (5.0–17.1) in KCNJ11‐MODY. Frequency of oral antidiabetic agents (OAD) use increased and insulin decreased in HNF4A‐MODY (OAD: 18% to 39%, insulin: 34% to 23%) and in HNF1A‐MODY (OAD: 18% to 31%, insulin: 35% to 25%). ABCC8‐MODY was characterized by a decrement in nonpharmacological treatment (26% to 16%) and “insulin only” treatment (53% to 42%), while the proportion of individuals treated with OAD but no insulin increased from 0% to 21%. Conclusions Our results indicate that some teams caring for individuals with MODY are hesitant with regard to current recommendations. Registries are an essential source of information and provide a basis for discussing treatment guidelines for MODY.
- Published
- 2024
- Full Text
- View/download PDF
17. Editorial: Personalized therapies for monogenic diabetes.
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Delvecchio, Maurizio, Ming Liu, Rapini, Novella, and Barbetti, Fabrizio
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MATURITY onset diabetes of the young ,TYPE 1 diabetes ,TYPE 2 diabetes ,GESTATIONAL diabetes ,METABOLIC syndrome ,INSULIN - Abstract
The editorial discusses personalized therapies for monogenic diabetes, focusing on three main clinical forms: Maturity Onset Diabetes of the Young (MODY), Neonatal Diabetes Mellitus (NDM), and Severe Insulin Resistance syndromes. The article highlights the genetic basis of these conditions and treatment options, such as oral hypoglycemic agents for MODY and NDM, and human recombinant IGF1 for Severe Insulin Resistance syndromes. Additionally, the editorial emphasizes the importance of precision medicine in managing monogenic diabetes and explores potential therapeutic targets through Mendelian randomization. [Extracted from the article]
- Published
- 2024
- Full Text
- View/download PDF
18. Developmentally dynamic changes in DNA methylation in the human pancreas
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Ailsa MacCalman, Elisa De Franco, Alice Franklin, Christine S. Flaxman, Sarah J. Richardson, Kathryn Murrall, Joe Burrage, Barts Pancreas Tissue Bank (BPTB), Emma M. Walker, Noel G. Morgan, Andrew T. Hattersley, Emma L. Dempster, Eilis Hannon, Aaron R. Jeffries, Nick D. L. Owens, and Jonathan Mill
- Subjects
Pancreas ,DNA methylation ,Development ,Sex differences ,Fetal ,Monogenic diabetes ,Biotechnology ,TP248.13-248.65 ,Genetics ,QH426-470 - Abstract
Abstract Development of the human pancreas requires the precise temporal control of gene expression via epigenetic mechanisms and the binding of key transcription factors. We quantified genome-wide patterns of DNA methylation in human fetal pancreatic samples from donors aged 6 to 21 post-conception weeks. We found dramatic changes in DNA methylation across pancreas development, with > 21% of sites characterized as developmental differentially methylated positions (dDMPs) including many annotated to genes associated with monogenic diabetes. An analysis of DNA methylation in postnatal pancreas tissue showed that the dramatic temporal changes in DNA methylation occurring in the developing pancreas are largely limited to the prenatal period. Significant differences in DNA methylation were observed between males and females at a number of autosomal sites, with a small proportion of sites showing sex-specific DNA methylation trajectories across pancreas development. Pancreas dDMPs were not distributed equally across the genome and were depleted in regulatory domains characterized by open chromatin and the binding of known pancreatic development transcription factors. Finally, we compared our pancreas dDMPs to previous findings from the human brain, identifying evidence for tissue-specific developmental changes in DNA methylation. This study represents the first systematic exploration of DNA methylation patterns during human fetal pancreas development and confirms the prenatal period as a time of major epigenomic plasticity.
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- 2024
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19. MODY diabetes as an orphan disease: literature review
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A.V. Garnytska, O.S. Orlyk, L.M. Zenkina, and S.O. Osadcha
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diabetes ,mody ,monogenic diabetes ,microbiome ,diagnosis ,treatment ,Therapeutics. Pharmacology ,RM1-950 - Abstract
BACKGROUND. Maturity-onset diabetes of the young (MODY) is the most common form of monogenic diabetes, usually diagnosed before the age of 30 years in non-obese patients with a family history of diabetes mellitus (DM). MODY is relatively rare compared to type 1 and type 2 DM, with various literature estimates affecting only 1-2 % of people with diabetes, but because it is rare, clinicians may misdiagnose it as type 1 or type 2 DM, which happens in most cases. Unlike type 1 DM patients, patients with MODY have preserved pancreatic β-cell function, so lifestyle modification in combination with glucose-lowering therapy, which in some cases may include insulin, may be sufficient interventions as treatment. OBJECTIVE. With the help of literary sources, familiarize yourself with the classification, clinical manifestations, aspects of treatment and prognosis of the main forms of MODY diabetes. MATERIALS AND METHODS. Object: MODY diabetes as an orphan disease. Research method: a review of literary sources. RESULTS. MODY is most often an autosomal dominant disease and is divided into subtypes (MODY1 to MODY14) based on genetic mutation. Subtypes 1-3 are the most common, accounting for 95 % of cases. Treatment usually includes diet, exercise, and, in some cases, insulin or oral hypoglycemic drugs. In general, the prognosis can be quite favorable, provided that carbohydrate metabolism is compensated. CONCLUSIONS. MODY diabetes is a complex genetically determined pathology, and understanding the features of this disease, diagnosis and treatment are of great importance for patients and their families. The development of modern methods of treatment and monitoring of glucose, such as insulin pumps, 24-hour glycemic monitoring and other technologies, may improve the prognosis for patients with MODY. Each patient with MODY diabetes has individual characteristics, which leaves an imprint on the prognosis of the disease and approaches to treatment. The main goal is to maintain a normal level of glucose in the blood to avoid complications.
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- 2024
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20. Pregnancy in various forms of monogenic diabetes: A systematic review.
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Aarthe, Veeraraghavan, Unnikrishnan, Ranjit, Anjana, Ranjit Mohan, Jaggi, Shalini, Chawla, Rajeev, and Mohan, Viswanathan
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DIAGNOSIS of diabetes , *TREATMENT of diabetes , *DIABETES complications , *INSULIN therapy , *GESTATIONAL diabetes , *MATURITY onset diabetes of the young , *HYPOGLYCEMIC agents , *SULFONYLUREAS , *PREGNANCY complications , *DIABETES , *GENETIC testing - Abstract
Monogenic diabetes (MD) represents a cluster of different types of diabetes produced by a mutation of a single gene. The commonest type of MD is maturity-onset diabetes of the young (MODY) which has several subtypes, and neonatal diabetes mellitus (NDM). With improved diagnostic facilities, more cases of monogenic diabetes are being described, and pregnancy is being reported in different forms of monogenic diabetes as these patients enter the reproductive age group. The treatment of monogenic diabetes may change once pregnancy sets in. For example, some forms of monogenic diabetes which respond to oral antidiabetic drugs (OHA), particularly the sulfonylurea agents (SUs), may need insulin during pregnancy. However, this depends on the fetal inheritance of mutation from the mother. This review attempts to put together published reports of pregnancy in various types of monogenic diabetes focussing on the most frequently seen forms of MD. [ABSTRACT FROM AUTHOR]
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- 2024
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21. Monogenic diabetes in a Chinese population with young‐onset diabetes: A 17‐year prospective follow‐up study in Hong Kong.
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Tsoi, Sandra T. F., Lim, Cadmon, Ma, Ronald C. W., Lau, Eric S. H., Fan, Baoqi, Chow, Elaine, Kong, Alice P. S., Chan, Juliana C. N., and Luk, Andrea O. Y.
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CHINESE people ,MATURITY onset diabetes of the young ,CHRONIC kidney failure ,DIABETES ,DIABETES complications ,CARDIOVASCULAR diseases - Abstract
Aims: Asians have a high prevalence of young‐onset diabetes, but the pattern of monogenic diabetes is unknown. We aimed to determine the prevalence of monogenic diabetes in Chinese patients with young‐onset diabetes and compare the clinical characteristics and outcome between patients with and without monogenic diabetes. Materials and Methods: We sequenced a targeted panel of 33 genes related to monogenic diabetes in 1021 Chinese patients with non‐type 1 diabetes diagnosed at age ≤40 years. Incident complications including cardiovascular disease (CVD), end‐stage kidney disease (ESKD) and all‐cause death were captured since enrolment (1995–2012) until 2019. Results: In this cohort (mean ± SD age at diagnosis: 33.0 ± 6.0 years, median[IQR] diabetes duration 7.0[1.0–15.0] years at baseline, 44.9% men), 22(2.2%, 95% confidence interval[CI] 1.4%–3.2%) had monogenic diabetes. Pathogenic (P) or likely pathogenic (LP) variants were detected in GCK (n = 6), HNF1A (n = 9), HNF4A (n = 1), PLIN1 (n = 1) and PPARG (n = 2), together with copy number variations in HNF1B (n = 3). Over a median follow‐up of 17.1 years, 5(22.7%) patients with monogenic diabetes (incidence rate 12.3[95% CI 5.1–29.4] per 1000 person‐years) versus 254(25.4%) without monogenic diabetes (incidence rate 16.7[95% CI 14.8–18.9] per 1000 person‐years) developed the composite outcome of CVD, ESKD and/or death (p = 0.490). The multivariable Cox model did not show any difference in hazards for composite events between groups. Conclusions: In Chinese with young‐onset non‐type 1 diabetes, at least 2% of cases were contributed by monogenic diabetes, over 80% of which were accounted for by P/LP variants in common MODY genes. The incidence of diabetes complications was similar between patients with and without monogenic diabetes. [ABSTRACT FROM AUTHOR]
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- 2024
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22. Transient Neonatal Diabetes Mellitus with an Unknown Cause in a 1-Month-Old Infant: A Case Report.
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Tarasiewicz, Mateusz, Pietrzykowska, Anna, Włodarczyk, Julia, Seget, Sebastian, Gadzalska, Karolina, Jakiel, Paulina, Skoczylas, Sebastian, Jarosz-Chobot, Przemysława, and Borowiec, Maciej
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DIAGNOSIS of diabetes ,ULTRASONIC imaging of the abdomen ,GENETICS of diabetes ,TREATMENT of diabetes ,BLOOD gases analysis ,OLIGONUCLEOTIDE arrays ,FETAL hemoglobin ,AZYGOS vein ,GENOME-wide association studies ,GESTATIONAL diabetes ,NEONATAL intensive care units ,GLYCEMIC control ,INSULIN ,CHILDREN'S hospitals ,FAMILY history (Medicine) ,NEONATAL intensive care ,KETONES ,NEONATAL diseases ,HYPERGLYCEMIA ,BLOOD sugar ,GENETIC variation ,C-peptide ,INTRAVENOUS therapy ,CONTINUOUS glucose monitoring ,GENETIC mutation ,ACID-base equilibrium ,MITOCHONDRIAL DNA ,PHENOTYPES ,ECHOCARDIOGRAPHY ,SEQUENCE analysis ,BLOOD ,CHILDREN - Abstract
Transient neonatal diabetes mellitus (TNDM) is a genetically heterogeneous form of neonatal diabetes characterized by hyperglycemia that remits during infancy with a tendency to recur in later life. This case report presents the history of a male infant with transient neonatal diabetes mellitus. The patient was treated with a continuous subcutaneous insulin infusion (CSII) and a continuous glucose monitoring (CGM) system until the age of 2 months, when the normoglycemia connected with a withdrawal of treatment was noted. The genetic test results excluded the majority of known mutations related to TNDM. This case report focuses on various genetic mutations and the clinical features connected with them that cause TNDM and highlights the difficulties in the diagnostic and therapeutic processes of this disease. CSII and CGM systems seem to be a safe and effective treatment option in TNDM and may be used in the therapy. [ABSTRACT FROM AUTHOR]
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- 2024
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23. Developmentally dynamic changes in DNA methylation in the human pancreas.
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MacCalman, Ailsa, De Franco, Elisa, Franklin, Alice, Flaxman, Christine S., Richardson, Sarah J., Murrall, Kathryn, Burrage, Joe, Walker, Emma M., Morgan, Noel G., Hattersley, Andrew T., Dempster, Emma L., Hannon, Eilis, Jeffries, Aaron R., Owens, Nick D. L., and Mill, Jonathan
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Development of the human pancreas requires the precise temporal control of gene expression via epigenetic mechanisms and the binding of key transcription factors. We quantified genome-wide patterns of DNA methylation in human fetal pancreatic samples from donors aged 6 to 21 post-conception weeks. We found dramatic changes in DNA methylation across pancreas development, with > 21% of sites characterized as developmental differentially methylated positions (dDMPs) including many annotated to genes associated with monogenic diabetes. An analysis of DNA methylation in postnatal pancreas tissue showed that the dramatic temporal changes in DNA methylation occurring in the developing pancreas are largely limited to the prenatal period. Significant differences in DNA methylation were observed between males and females at a number of autosomal sites, with a small proportion of sites showing sex-specific DNA methylation trajectories across pancreas development. Pancreas dDMPs were not distributed equally across the genome and were depleted in regulatory domains characterized by open chromatin and the binding of known pancreatic development transcription factors. Finally, we compared our pancreas dDMPs to previous findings from the human brain, identifying evidence for tissue-specific developmental changes in DNA methylation. This study represents the first systematic exploration of DNA methylation patterns during human fetal pancreas development and confirms the prenatal period as a time of major epigenomic plasticity. [ABSTRACT FROM AUTHOR]
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- 2024
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24. Identification of rare variants in candidate genes associated with monogenic diabetes in polish mody-x patients.
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Jakiel, Paulina, Gadzalska, K., Juścińska, E., Gorządek, M., Płoszaj, T., Skoczylas, S., Borowiec, M., and Zmysłowska, A.
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MATURITY onset diabetes of the young , *GENETIC variation , *DIABETES , *PANCREATIC beta cells , *NUCLEOTIDE sequencing - Abstract
Purpose: Monogenic diabetes (MD) is caused by a mutation in a single gene and accounts for approximately 2.5–6% of all diabetes cases. Maturity-onset diabetes of the young (MODY) is the most common form of MD. To date, 14 different genes have been identified and associated with the presence of MODY phenotype. However, the number of potential candidate genes with relevance to beta cell function and glucose metabolism is increasing as more research is published. The aim of the study was to identify potentially causative variants in selected candidate genes in patients with a clinical diagnosis of MD. Methods: Targeted Next-Generation Sequencing (tNGS) on Illumina NextSeq 550 platform involving Agilent SureSelectQXT Target Enrichment protocol for 994 patients with suspected MD was performed. In the next step, the sequencing data of 617 patients with no pathogenic variants in main MD-related genes were reanalysed for the presence of causative variants in six candidate genes (MTOR, TBC1D4, CACNA1E, MNX1, SLC19A2, KCNH6). The presence of the selected variants was confirmed by Sanger sequencing. Results: Seven heterozygous possibly damaging variants were identified in four candidate genes (MTOR, TBC1D4, CACNA1E, MNX1). Five changes were assessed as novel variants, not previously described in available databases. None of the described variants were present among patients previously diagnosed with MODY diabetes due to causative, pathogenic variants in known MODY-related genes. Conclusions: The results obtained seem to confirm the effectiveness of the NGS method in identifying potentially causative variants in novel candidate genes associated with MODY diabetes. [ABSTRACT FROM AUTHOR]
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- 2024
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25. The Laboratory Diagnosis of Diabetes Mellitus
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Bailey, David N., Fitzgerald, Robert L., Bailey, David N., and Fitzgerald, Robert L.
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- 2024
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26. Editorial: Personalized therapies for monogenic diabetes
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Maurizio Delvecchio, Ming Liu, Novella Rapini, and Fabrizio Barbetti
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monogenic diabetes ,personalized medicine ,MODY ,neonatal diabetes mellitus ,Rabson-Mendenhall syndrome ,severe insulin resistance syndrome ,Genetics ,QH426-470 - Published
- 2024
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27. MODY calculator applied in patients with clinical diagnosis of type 1 diabetes mellitus: Is a higher cutoff needed?
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Vinícius Vigliazzi Peghinelli, Maria Teresa De Sibio, Igor de Carvalho Depra, Milena Gurgel Teles Bezerra, Marna Eliana Sakalem, Adriano Francisco De Marchi Júnior, Paula Barreto da Rocha, Helena Paim Tilli, Bianca Mariani Gonçalves, Ester Mariane Vieira, Mariana Menezes Lourenço, and Célia Regina Nogueira
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MODY ,Monogenic diabetes ,Clinic prediction model ,Genetic sequencing ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
Aim: This study aimed to evaluate the mean post-test probability (PTP) of the Maturity-onset diabetes of the young (MODY) calculator in a multiethnic cohort of patients previously diagnosed with type 1 diabetes (T1DM). Materials and methods: The MODY probability calculator proposed by Shields and colleagues (2012) was applied to 117 patients from a T1DM outpatient clinic at a tertiary hospital in Brazil. Additionally, two exons of the HNF1A gene were sequenced in eight patients who hadn't received insulin treatment within six months after the diagnosis. Results: 17.1 % of patients achieved PTP >10 %; 11.1 % achieved PTP >25 % (and all patients >30 %), and 7.7 % achieved PTP >40 %. Among the patients who were selected for genetic sequencing, 100 % presented PTP >30 %, with 66.6 % achieving PTP >40 % and 41.6 % achieving PTP >75 %. These cutoffs are as suggested for the Brazilian population, according to previous investigations. No mutation was observed in the sequenced exons. Conclusion: Considering that only around 10 % of the evaluated cases achieved PTP >30 %, it is highly probable that the most suitable cutoff to select patients for genetic sequencing in a Brazilian cohort of T1DM is higher than the cutoff used in Caucasian populations.
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- 2024
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28. Chinese carrier of the HNF1A p.Gln444fs variant exhibits enhanced response to sulfonylureas
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Xiufang Wang, Wenzhuo Cheng, Zhongjing Wang, Chao Liu, Aiping Deng, and Juyi Li
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HNF1A ,MODY3 ,Monogenic diabetes ,Precision therapy ,Whole-exome sequencing ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
Background: We assessed the response to sulfonylureas and the functional characteristics of HNF1A mutations in patients with maturity-onset diabetes of the young type 3 (MODY3). Methods: We recruited a family with suspected MODY in this study, and gene sequencing (whole-exome sequencing) was used to screen germline mutations. Luciferase reporter assays were used to evaluate the activity of the mutated genes. Results: Heterozygous HNF1A variant (NM_000545.8:c.1330_1331del, p.Gln444fs) was identified in the proband and was not found in his father, grandmother, and nonrelated healthy controls. The mutant protein had 552 amino acids, 110 fewer than the wild type protein. Furthermore, the amino acid sequence was completely different between the mutant protein and the wild type protein starting from the 444th amino acid. Luciferase reporter assays revealed that the variant had impaired HNF4A promoter–regulation activity. The patient did not achieve good hypoglycemic effects during long-term treatment with insulin and metformin. The effect of hypoglycemic treatment was highly significant after the addition of sulfonylurea drugs. Conclusions: The HNF1A p.Gln444fs variant associated with MODY3, and most likely a truncated protein, impaired HNF1A transcriptional activity. The variant carrier experienced an enhanced response to sulfonylureas.
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- 2024
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29. Case report: Glycaemic management and pregnancy outcomes in a woman with an insulin receptor mutation, p.Met1180Lys
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Mairéad T. Crowley, Eirena Goulden, Begona Sanchez-Lechuga, Aileen Fleming, Maria Kennelly, Ciara McDonnell, and Maria M. Byrne
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Insulin receptor mutation ,Type A insulin resistance ,Diabetes in pregnancy ,Monogenic diabetes ,Hyperinsulinaemic hypoglycaemia ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Abstract Background Heterozygous insulin receptor mutations (INSR) are associated with insulin resistance, hyperglycaemia and hyperinsulinaemic hypoglycaemia in addition to hyperandrogenism and oligomenorrhoea in women. Numerous autosomal dominant heterozygous mutations involving the INSR β-subunit tyrosine kinase domain resulting in type A insulin resistance have been previously described. We describe the phenotype, obstetric management and neonatal outcomes in a woman with type A insulin resistance caused by a mutation in the β-subunit of the INSR. Case presentation We describe a woman with a p.Met1180Lys mutation who presents with hirsutism, oligomenorrhoea and diabetes at age 20. She has autoimmune thyroid disease, Coeliac disease and positive GAD antibodies. She is overweight with no features of acanthosis nigricans and is treated with metformin. She had 11 pregnancies treated with insulin monotherapy (n = 2) or combined metformin and insulin therapy (n = 9). The maximum insulin dose requirement was 134 units/day or 1.68 units/kg/day late in the second pregnancy. Mean birthweight was on the 37th centile in INSR positive offspring (n = 3) and the 94th centile in INSR negative offspring (n = 1). Conclusion The p.Met1180Lys mutation results in a phenotype of diabetes, hirsutism and oligomenorrhoea. This woman had co-existent autoimmune disease. Her insulin dose requirements during pregnancy were similar to doses observed in women with type 2 diabetes. Metformin may be used to improve insulin sensitivity in women with this mutation. Offspring inheriting the mutation tended to be smaller for gestational age.
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- 2024
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30. Investigation of Monogenic Diabetes Genes in Thai Children with Autoantibody Negative Diabetes Requiring Insulin
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Teerawattanapong N, Tangjarusritaratorn T, Narkdontri T, Santiprabhob J, and Tangjittipokin W
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monogenic diabetes ,whole‑exome sequencing ,autoantibody ,Specialties of internal medicine ,RC581-951 - Abstract
Nipaporn Teerawattanapong,1– 3 Thanida Tangjarusritaratorn,1 Tassanee Narkdontri,1– 3 Jeerunda Santiprabhob,4,5 Watip Tangjittipokin1,2 1Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; 2Siriraj Center of Research Excellence for Diabetes and Obesity, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; 3Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; 4Siriraj Diabetes Center of Excellence, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand; 5Division of Endocrinology & Metabolism, Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, ThailandCorrespondence: Watip Tangjittipokin, Department of Immunology Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand, Tel +66 2-419-6635, Fax +66 2-418-1636, Email watip.tan@mahidol.eduPurpose: The objective of this study was to clarify the phenotypic characteristics of monogenic diabetes abnormalities in Thai children with autoantibody-negative insulin.Patients and Methods: Two hundred and thirty-one Thai type 1 diabetes (T1D) patients out of 300 participants with recent-onset diabetes were analyzed for GAD65 and IA2 pancreatic autoantibodies. A total of 30 individuals with T1D patients with negative autoantibody were screened for 32 monogenic diabetes genes by whole-exome sequencing (WES).Results: All participants were ten men and twenty women. The median age to onset of diabetes was 8 years and 3 months. A total of 20 people with monogenic diabetes carried genes related to monogenic diabetes. The PAX4 (rs2233580) in ten patients with monogenic diabetes was found. Seven variants of WFS1 (Val412Ala, Glu737Lys, Gly576Ser, Cys673Tyr, Arg456His, Lys424Glu, and Gly736fs) were investigated in patients in this study. Furthermore, the pathogenic variant, rs115099192 (Pro407Gln) in the GATA4 gene was found. Most patients who carried PAX4 (c.575G>A, rs2233580) did not have a history of DKA. The pathogenic variant GATA4 variant (c.1220C>A, rs115099192) was found in a patient with a history of DKA.Conclusion: This study demonstrated significant genetic overlap between autoantibody-negative diabetes and monogenic diabetes using WES. All candidate variants were considered disease risk with clinically significant variants. WES screening was the first implemented to diagnose monogenic diabetes in Thai children, and fourteen novel variants were identified in this study and need to be investigated in the future.Keywords: monogenic diabetes, whole‑exome sequencing, autoantibody
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- 2024
31. Clinical profile of monogenic diabetes: A case series from a single South Indian diabetes clinic
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Sureshkumar, Pichakacheri, Radha, Venkatesan, Unnikrishnan, Ranjit, and Mohan, Viswanathan
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- 2024
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32. Rare forms of monogenic diabetes in non-European individuals. First reports of CEL and RFX6 mutations from the Indian subcontinent
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Marucci, Antonella, Menzaghi, Claudia, Dodesini, Alessandro Roberto, Albizzi, Mascia, Acquafredda, Angelo, Fini, Grazia, Trischitta, Vincenzo, and Paola, Rosa Di
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- 2024
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33. Case report: Glycaemic management and pregnancy outcomes in a woman with an insulin receptor mutation, p.Met1180Lys
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Crowley, Mairéad T., Goulden, Eirena, Sanchez-Lechuga, Begona, Fleming, Aileen, Kennelly, Maria, McDonnell, Ciara, and Byrne, Maria M.
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- 2024
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34. Identification of causative gene variants for patients with known monogenic diabetes using a targeted next-generation sequencing panel in a single-center study.
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Takase, Kaoru, Susa, Shinji, Sato, Hidenori, Hada, Yurika, Nagaoka, Kyoko, Takakubo, Noe, Karasawa, Shigeru, Kameda, Wataru, Numakura, Chikahiko, and Ishizawa, Kenichi
- Abstract
Aims: We aimed to verify the usefulness of targeted next-generation sequencing (NGS) technology for diagnosing monogenic diabetes in a single center. Methods: We designed an amplicon-based NGS panel targeting 34 genes associated with known monogenic diabetes and performed resequencing in 56 patients with autoantibody-negative diabetes mellitus diagnosed at < 50 years who had not been highly obese. By bioinformatic analysis, we filtered significant variants based on allele frequency (< 0.005 in East Asians) and functional prediction. We estimated the pathogenicity of each variant upon considering the family history. Results: Overall, 16 candidate causative variants were identified in 16 patients. Among them, two previously known heterozygous nonsynonymous single-nucleotide variants associated with monogenic diabetes were confirmed as causative variants: one each in the GCK and WFS1 genes. The former was found in two independent diabetes-affected families. Two novel putatively deleterious heterozygous variants were also assumed to be causative from the family history: one frameshift and one nonsynonymous single-nucleotide variant in the HNF4A gene. Twelve variants remained as candidates associated with the development of diabetes. Conclusion: Targeted NGS panel testing was useful to diagnose various forms of monogenic diabetes in combination with familial analysis, but additional ingenuity would be needed for practice. [ABSTRACT FROM AUTHOR]
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- 2024
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35. Whole-exome sequencing in familial type 2 diabetes identifies an atypical missense variant in the RyR2 gene.
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Bansal, Vikas, Winkelmann, Bernhard R., Dietrich, Johannes W., and Boehm, Bernhard O.
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TYPE 2 diabetes ,MISSENSE mutation ,GENETIC variation ,GLUCOSE intolerance ,RYANODINE receptors ,HEART beat ,GENOME-wide association studies ,ANGIOTENSIN II - Abstract
Genome-wide association studies have identified several hundred loci associated with type 2 diabetes mellitus (T2DM). Additionally, pathogenic variants in several genes are known to cause monogenic diabetes that overlaps clinically with T2DM. Whole-exome sequencing of related individuals with T2DM is a powerful approach to identify novel high-penetrance disease variants in coding regions of the genome. We performed whole-exome sequencing on four related individuals with T2DM - including one individual diagnosed at the age of 33 years. The individuals were negative for mutations in monogenic diabetes genes, had a strong family history of T2DM, and presented with several characteristics of metabolic syndrome. A missense variant (p.N2291D) in the type 2 ryanodine receptor (RyR2) gene was one of eight rare coding variants shared by all individuals. The variant was absent in large population databases and affects a highly conserved amino acid located in a mutational hotspot for pathogenic variants in Catecholaminergic polymorphic ventricular tachycardia (CPVT). Electrocardiogram data did not reveal any cardiac abnormalities except a lower-than-normal resting heart rate (< 60 bpm) in two individuals - a phenotype observed in CPVT individuals with RyR2 mutations. RyR2-mediated Ca
2+ release contributes to glucose-mediated insulin secretion and pathogenic RyR2 mutations cause glucose intolerance in humans and mice. Analysis of glucose tolerance testing data revealed that missense mutations in a CPVT mutation hotspot region - overlapping the p.N2291D variant - are associated with complete penetrance for glucose intolerance. In conclusion, we have identified an atypical missense variant in the RyR2 gene that co-segregates with diabetes in the absence of overt CPVT. [ABSTRACT FROM AUTHOR]- Published
- 2024
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36. High Frequency of Recessive WFS1 Mutations Among Indian Children With Islet Antibody-negative Type 1 Diabetes.
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Menon, Jayakrishnan C, Singh, Pratibha, Archana, Archana, Singh, Preeti, Mittal, Medha, Kanga, Uma, Mandal, Kausik, Seth, Anju, Bhatia, Vijayalakshmi, Dabadghao, Preeti, Sudhanshu, Siddhnath, Garg, Atul, Vishwakarma, Ruchira, Sarangi, Aditya Narayan, Verma, Shivendra, Singh, Surya Kumar, and Bhatia, Eesh
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GENETIC mutation ,TYPE 1 diabetes ,CHILDREN'S health - Abstract
Background: While the frequency of islet antibody-negative (idiopathic) type 1 diabetes mellitus (T1DM) is reported to be increased in Indian children, its aetiology has not been studied. We investigated the role of monogenic diabetes in the causation of islet antibody-negative T1DM. Methods: We conducted a multicenter, prospective, observational study of 169 Indian children (age 1-18 years) with recent-onset T1DM. All were tested for antibodies against GAD65, islet antigen-2, and zinc transporter 8 using validated ELISA. Thirty-four islet antibody-negative children underwent targeted next-generation sequencing for 31 genes implicated in monogenic diabetes using the Illumina platform. All mutations were confirmed by Sanger sequencing. Results: Thirty-five (21%) children were negative for all islet antibodies. Twelve patients (7% of entire cohort, 34% of patients with islet antibody-negative T1DM) were detected to have pathogenic or likely pathogenic genetic variants. The most frequently affected locus was WFS1, with 9 patients (5% of entire cohort, 26% of islet antibody-negative). These included 7 children with homozygous and 1 patient each with a compound heterozygous and heterozygous mutation. Children with Wolfram syndrome 1 (WS) presented with severe insulin-requiring diabetes (including 3 patients with ketoacidosis), but other syndromic manifestations were not detected. In 3 patients, heterozygous mutations in HNF4A, ABCC8, and PTF1A loci were detected. Conclusion: Nearly one-quarter of Indian children with islet antibody-negative T1DM had recessive mutations in the WFS1 gene. These patients did not exhibit other features of WS at the time of diagnosis. Testing for monogenic diabetes, especially WS, should be considered in Indian children with antibody-negative T1DM. [ABSTRACT FROM AUTHOR]
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- 2024
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37. Identification of monogenic diabetes in an Australian cohort using the Exeter maturity-onset diabetes of the young (MODY) probability calculator and next-generation sequencing gene panel testing.
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De Sousa, Sunita M. C., Wu, Kathy H. C., Colclough, Kevin, Rawlings, Lesley, Dubowsky, Andrew, Monnik, Melissa, Poplawski, Nicola, Scott, Hamish S., Horowitz, Michael, and Torpy, David J.
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MATURITY onset diabetes of the young , *TYPE 2 diabetes , *NUCLEOTIDE sequencing , *DIABETES , *GENETIC testing , *CLIFFORD algebras - Abstract
Aims: This study aims to describe the prevalence of monogenic diabetes in an Australian referral cohort, in relation to Exeter maturity-onset diabetes of the young (MODY) probability calculator (EMPC) scores and next-generation sequencing with updated testing where relevant. Methods: State-wide 5-year retrospective cohort study of individuals referred for monogenic diabetes genetic testing. Results: After excluding individuals who had cascade testing for a familial variant (21) or declined research involvement (1), the final cohort comprised 40 probands. Incorporating updated testing, the final genetic result was positive (likely pathogenic/pathogenic variant) in 11/40 (27.5%), uncertain (variant of uncertain significance) in 8/40 (20%) and negative in 21/40 (52.5%) participants. Causative variants were found in GCK, HNF1A, MT-TL1 and HNF4A. Variants of uncertain significance included a novel multi-exonic GCK duplication. Amongst participants with EMPC scores ≥ 25%, a causative variant was identified in 37%. Cascade testing was positive in 9/10 tested relatives with diabetes and 0/6 tested relatives with no history of diabetes. Conclusions: Contemporary genetic testing produces a high yield of positive results in individuals with clinically suspected monogenic diabetes and their relatives with diabetes, highlighting the value of genetic testing for this condition. An EMPC score cutoff of ≥ 25% correctly yielded a positive predictive value of ≥ 25% in this multiethnic demographic. This is the first Australian study to describe EMPC scores in the Australian clinic setting, albeit a biased referral cohort. Larger studies may help characterise EMPC performance between ethnic subsets, noting differences in the expected probability of monogenic diabetes relative to type 2 diabetes. [ABSTRACT FROM AUTHOR]
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- 2024
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38. The MODY-associated KCNK16 L114P mutation increases islet glucagon secretion and limits insulin secretion resulting in transient neonatal diabetes and glucose dyshomeostasis in adults
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Arya Y Nakhe, Prasanna K Dadi, Jinsun Kim, Matthew T Dickerson, Soma Behera, Jordyn R Dobson, Shristi Shrestha, Jean-Philippe Cartailler, Leesa Sampson, Mark A Magnuson, and David A Jacobson
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monogenic diabetes ,TALK-1 ,calcium ,insulin ,glucagon ,islet ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
The gain-of-function mutation in the TALK-1 K+ channel (p.L114P) is associated with maturity-onset diabetes of the young (MODY). TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion. The KCNK16 gene encoding TALK-1 is the most abundant and β-cell-restricted K+ channel transcript. To investigate the impact of KCNK16 L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the Kcnk16 L114P mutation was generated. Heterozygous and homozygous Kcnk16 L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1 (ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygous Kcnk16 L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment. Kcnk16 L114P increased whole-cell β-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and loss of glucose-induced Ca2+ oscillations. Thus, adult Kcnk16 L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated Kcnk16 L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiting islet insulin secretion during development. These data suggest that TALK-1 is an islet-restricted target for the treatment for diabetes.
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- 2024
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39. A Woman With HNF1A-Associated Monogenic Diabetes Treated Successfully With Repaglinide Monotherapy
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Katherine Cuan, DO and Ilana R. Bass, MD
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monogenic diabetes ,meglitinide ,genetic testing ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Background/Objective: Monogenic diabetes is a rare type of diabetes that is commonly misdiagnosed as type 1 or 2 diabetes mellitus, which adversely impacts patient care. Such cases are particularly challenging given the heterogeneity in presentation and overlap with other types of diabetes. As the sole use of meglitinides, especially repaglinide, to treat HNF1A-associated monogenic diabetes has been rarely reported in a few other observational studies, we describe a patient who was treated successfully with repaglinide. Case Report: A 38-year-old woman with type 1 diabetes mellitus, congenital deafness, chronic kidney disease, and retinopathy presented with difficulty controlling her blood glucose levels. Although initially treated with insulin, she had periods of noncompliance with insulin without experiencing diabetic ketoacidosis. Although on insulin therapy, she experienced multiple episodes of hypoglycemia. The laboratory tests showed a hemoglobin A1c level of 10.8%, c-peptide level of 2.7 ng/mL (1.1-4.4 ng/mL), glucose level of 192 mg/dL, creatinine level of 1.23 ng/dL, and severely increased microalbumin-to-creatinine ratio of 638 mg/g (normal range, 0-29 mg/g). Pancreatic autoantibodies were negative. Genetic testing revealed a diagnosis of HNF1A-associated monogenic diabetes (c. 1340C>T (p.P447L)). She was ultimately treated with repaglinide after trials of sulfonylureas and dipeptidyl peptidase 4 inhibitors led to frequent hypoglycemia and a significant increase in the hemoglobin A1c level, respectively. Discussion: This case highlights the importance of correctly diagnosing monogenic diabetes and reports the successful use of repaglinide to treat HNF1A-associated monogenic diabetes. Conclusion: Patients with HNF1A-associated monogenic diabetes who do not achieve euglycemia with sulfonylureas and insulin may be successfully treated with repaglinide monotherapy.
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- 2024
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40. Atypical diabetes with spontaneous remission associated with systemic lupus erythematosus in an adolescent girl of African ancestry, a case report
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Fanny Luterbacher, Jean-Louis Blouin, and Valerie M. Schwitzgebel
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Case report ,Flatbush diabetes ,Monogenic diabetes ,C-peptide ,Beta cell ,Diabetic ketoacidosis ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Abstract Background New-onset diabetes in youth encompasses type 1 diabetes, type 2 diabetes, monogenic diabetes, and rarer subtypes like Type B insulin resistance syndrome and ketosis-prone atypical diabetes in African populations. Some cases defy classification, posing management challenges. Here, we present a case of a unique, reversible diabetes subtype. Case presentation We describe an adolescent African girl recently diagnosed with systemic lupus erythematosus. At age 15, she presented with ketoacidosis, HbA1c of 108.7 mmol/mol (12.1%), and positive anti-insulin antibodies. Initially diagnosed with type 1 diabetes, insulin was prescribed. Due to the presence of obesity and signs of insulin resistance, we added metformin. Concurrently, she received treatment for lupus with hydroxychloroquine, mycophenolate mofetil, and prednisone. After discharge, she stopped insulin due to cultural beliefs. Five months later, her glycemia and HbA1c normalized (37 mmol/mol or 5.5%) without insulin, despite corticosteroid therapy and weight gain. Autoantibodies normalized, and lupus activity decreased. Genetic testing for monogenic diabetes was negative, and the type 1 genetic risk score was exceptionally low. Conclusions We present a complex, reversible diabetes subtype. Features suggest an autoimmune origin, possibly influenced by overlapping HLA risk haplotypes with lupus. Lupus treatment or immunomodulation may have impacted diabetes remission. Ancestry-tailored genetic risk scores are currently designed to improve diagnostic accuracy.
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- 2023
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41. Enhancing fetal outcomes in GCK-MODY pregnancies: a precision medicine approach via non-invasive prenatal GCK mutation detection
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Valérie M. Schwitzgebel, Jean-Louis Blouin, Barbara Dehos, Bettina Köhler-Ballan, Jardena J. Puder, Claudine Rieubland, Maria Triantafyllidou, Anne Zanchi, Marc Abramowicz, and Thierry Nouspikel
- Subjects
Non-invasive prenatal diagnosis ,monogenic diabetes ,GCK-MODY ,cell-free circulating DNA ,fetal DNA ,glucokinase ,Medicine (General) ,R5-920 - Abstract
BackgroundMutations in the GCK gene cause Maturity Onset Diabetes of the Young (GCK-MODY) by impairing glucose-sensing in pancreatic beta cells. During pregnancy, managing this type of diabetes varies based on fetal genotype. Fetuses carrying a GCK mutation can derive benefit from moderate maternal hyperglycemia, stimulating insulin secretion in fetal islets, whereas this may cause macrosomia in wild-type fetuses. Modulating maternal glycemia can thus be viewed as a form of personalized prenatal therapy, highly beneficial but not justifying the risk of invasive testing. We therefore developed a monogenic non-invasive prenatal diagnostic (NIPD-M) test to reliably detect the transmission of a known maternal GCK mutation to the fetus.MethodsA small amount of fetal circulating cell-free DNA is present in maternal plasma but cannot be distinguished from maternal cell-free DNA. Determining transmission of a maternal mutation to the fetus thus implies sequencing adjacent polymorphisms to determine the balance of maternal haplotypes, the transmitted haplotype being over-represented in maternal plasma.ResultsHere we present a series of such tests in which fetal genotype was successfully determined and show that it can be used to guide therapeutic decisions during pregnancy and improve the outcome for the offspring. We discuss several potential hurdles inherent to the technique, and strategies to overcome these.ConclusionOur NIPD-M test allows reliable determination of the presence of a maternal GCK mutation in the fetus, thereby allowing personalized in utero therapy by modulating maternal glycemia, without incurring the risk of miscarriage inherent to invasive testing.
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- 2024
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42. Whole-exome sequencing in familial type 2 diabetes identifies an atypical missense variant in the RyR2 gene
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Vikas Bansal, Bernhard R. Winkelmann, Johannes W. Dietrich, and Bernhard O. Boehm
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type 2 diabetes ,RyR2 ,monogenic diabetes ,pathogenic variant ,metabolic syndrome ,CPVT ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Genome-wide association studies have identified several hundred loci associated with type 2 diabetes mellitus (T2DM). Additionally, pathogenic variants in several genes are known to cause monogenic diabetes that overlaps clinically with T2DM. Whole-exome sequencing of related individuals with T2DM is a powerful approach to identify novel high-penetrance disease variants in coding regions of the genome. We performed whole-exome sequencing on four related individuals with T2DM – including one individual diagnosed at the age of 33 years. The individuals were negative for mutations in monogenic diabetes genes, had a strong family history of T2DM, and presented with several characteristics of metabolic syndrome. A missense variant (p.N2291D) in the type 2 ryanodine receptor (RyR2) gene was one of eight rare coding variants shared by all individuals. The variant was absent in large population databases and affects a highly conserved amino acid located in a mutational hotspot for pathogenic variants in Catecholaminergic polymorphic ventricular tachycardia (CPVT). Electrocardiogram data did not reveal any cardiac abnormalities except a lower-than-normal resting heart rate (< 60 bpm) in two individuals – a phenotype observed in CPVT individuals with RyR2 mutations. RyR2-mediated Ca2+ release contributes to glucose-mediated insulin secretion and pathogenic RyR2 mutations cause glucose intolerance in humans and mice. Analysis of glucose tolerance testing data revealed that missense mutations in a CPVT mutation hotspot region – overlapping the p.N2291D variant – are associated with complete penetrance for glucose intolerance. In conclusion, we have identified an atypical missense variant in the RyR2 gene that co-segregates with diabetes in the absence of overt CPVT.
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- 2024
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43. Congenital Hyperinsulinism in Humans and Insulin Secretory Dysfunction in Mice Caused by Biallelic DNAJC3 Variants.
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Welters, Alena, Nortmann, Oliver, Wörmeyer, Laura, Freiberg, Clemens, Eberhard, Daniel, Bachmann, Nadine, Bergmann, Carsten, Mayatepek, Ertan, Meissner, Thomas, and Kummer, Sebastian
- Subjects
- *
HYPERINSULINISM , *MICE , *INSULIN , *INTRACELLULAR calcium , *HYPOGLYCEMIA , *DIABETES , *ADOLESCENCE , *HOMEOSTASIS - Abstract
The BiP co-chaperone DNAJC3 protects cells during ER stress. In mice, the deficiency of DNAJC3 leads to beta-cell apoptosis and the gradual onset of hyperglycemia. In humans, biallelic DNAJC3 variants cause a multisystem disease, including early-onset diabetes mellitus. Recently, hyperinsulinemic hypoglycemia (HH) has been recognized as part of this syndrome. This report presents a case study of an individual with HH caused by DNAJC3 variants and provides an overview of the metabolic phenotype of individuals with HH and DNAJC3 variants. The study demonstrates that HH may be a primary symptom of DNAJC3 deficiency and can persist until adolescence. Additionally, glycemia and insulin release were analyzed in young DNACJ3 knockout (K.O.) mice, which are equivalent to human infants. In the youngest experimentally accessible age group of 4-week-old mice, the in vivo glycemic phenotype was already dominated by a reduced total insulin secretion capacity. However, on a cellular level, the degree of insulin release of DNAJC3 K.O. islets was higher during periods of increased synthetic activity (high-glucose stimulation). We propose that calcium leakage from the ER into the cytosol, due to disrupted DNAJC3-controlled gating of the Sec61 channel, is the most likely mechanism for HH. This is the first genetic mechanism explaining HH solely by the disruption of intracellular calcium homeostasis. Clinicians should screen for HH in DNAJC3 deficiency and consider DNAJC3 variants in the differential diagnosis of congenital hyperinsulinism. [ABSTRACT FROM AUTHOR]
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- 2024
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44. Partial GCK gene deletion mutations causing maturity-onset diabetes of the young.
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Yu, Ruiqi, Zhang, Haichen, and Xiao, Xinhua
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- *
MATURITY onset diabetes of the young , *DELETION mutation , *GENETIC mutation , *SINGLE nucleotide polymorphisms , *ETIOLOGY of diabetes , *GENE amplification - Abstract
Aims: Maturity-onset diabetes of the young (MODY) is an autosomal dominant monogenic form of diabetes, and glucokinase-maturity-onset diabetes of the young (GCK-MODY), or MODY 2, being the most prevalent type. However, the presence of copy number variants (CNVs) may lead to misdiagnoses, as genetic testing for MODY is typically reliant on sequencing techniques. This study aimed to describe the process of diagnosis in a Chinese pedigree with an exon 8–10 deletion of the GCK gene. Methods: This study collected clinical data and medical history through direct interviews with the patient and reviewing relevant medical records. Sanger sequencing and whole exome sequencing (WES) were conducted over years of follow up. WES-based CNV sequencing technology was used to detect CNVs and the results were validated by multiplex ligation-dependent amplification dosage assay (MLPA). Additionally, we reviewed the previously reported cases caused by heterozygous exon deletion of the GCK gene. Results: WES-based CNV detection revealed a heterozygous exon 8–10 deletion in the GCK gene within this particular pedigree after Sanger sequencing and WES failed to find causal variants in single nucleotide variations (SNVs) and small indels. The deletion was considered pathogenic according to ACMG/AMP and ClinGen guidelines. Most of the previously reported cases caused by heterozygous exon deletion or whole gene deletion of the GCK gene present similarly to GCK-MODY caused by SNVs and small indels. Conclusions: This study contributed to progress in our comprehension of the mutation spectrum of the GCK gene and underscored the significance of CNV detection in the genetic testing of MODY. [ABSTRACT FROM AUTHOR]
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- 2024
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45. Paediatric diabetes subtypes in a consanguineous population: a single-centre cohort study from Kurdistan, Iraq.
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Amaratunga, Shenali A., Hussein Tayeb, Tara, Muhamad Sediq, Rozhan N., Hama Salih, Fareda K., Dusatkova, Petra, Wakeling, Matthew N., De Franco, Elisa, Pruhova, Stepanka, and Lebl, Jan
- Abstract
Aims/hypothesis: Monogenic diabetes is estimated to account for 1–6% of paediatric diabetes cases in primarily non-consanguineous populations, while the incidence and genetic spectrum in consanguineous regions are insufficiently defined. In this single-centre study we aimed to evaluate diabetes subtypes, obtain the consanguinity rate and study the genetic background of individuals with syndromic and neonatal diabetes in a population with a high rate of consanguinity. Methods: Data collection was carried out cross-sectionally in November 2021 at the paediatric diabetic clinic, Dr Jamal Ahmad Rashed Hospital, in Sulaimani, Kurdistan, Iraq. At the time of data collection, 754 individuals with diabetes (381 boys) aged up to 16 years were registered. Relevant participant data was obtained from patient files. Consanguinity status was known in 735 (97.5%) participants. Furthermore, 12 families of children with neonatal diabetes and seven families of children with syndromic diabetes consented to genetic testing by next-generation sequencing. Prioritised variants were evaluated using the American College of Medical Genetics and Genomics guidelines and confirmed by Sanger sequencing. Results: A total of 269 of 735 participants (36.5%) with known consanguinity status were offspring of consanguineous families. An overwhelming majority of participants (714/754, 94.7%) had clinically defined type 1 diabetes (35% of them were born to consanguineous parents), whereas only eight (1.1%) had type 2 diabetes (38% consanguineous). Fourteen (1.9%) had neonatal diabetes (50% consanguineous), seven (0.9%) had syndromic diabetes (100% consanguineous) and 11 (1.5%) had clinically defined MODY (18% consanguineous). We found that consanguinity was significantly associated with syndromic diabetes (p=0.0023) but not with any other diabetes subtype. The genetic cause was elucidated in ten of 12 participants with neonatal diabetes who consented to genetic testing (homozygous variants in GLIS3 [sibling pair], PTF1A and ZNF808 and heterozygous variants in ABCC8 and INS) and four of seven participants with syndromic diabetes (homozygous variants in INSR, SLC29A3 and WFS1 [sibling pair]). In addition, a participant referred as syndromic diabetes was diagnosed with mucolipidosis gamma and probably has type 2 diabetes. Conclusions/interpretation: This unique single-centre study confirms that, even in a highly consanguineous population, clinically defined type 1 diabetes is the prevailing paediatric diabetes subtype. Furthermore, a pathogenic cause of monogenic diabetes was identified in 83% of tested participants with neonatal diabetes and 57% of participants with syndromic diabetes, with most variants being homozygous. Causative genes in our consanguineous participants were markedly different from genes reported from non-consanguineous populations and also from those reported in other consanguineous populations. To correctly diagnose syndromic diabetes in consanguineous populations, it may be necessary to re-evaluate diagnostic criteria and include additional phenotypic features such as short stature and hepatosplenomegaly. [ABSTRACT FROM AUTHOR]
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- 2024
- Full Text
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46. Characterisation of HNF1A variants in paediatric diabetes in Norway using functional and clinical investigations to unmask phenotype and monogenic diabetes.
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Svalastoga, Pernille, Kaci, Alba, Molnes, Janne, Solheim, Marie H., Johansson, Bente B., Krogvold, Lars, Skrivarhaug, Torild, Valen, Eivind, Johansson, Stefan, Molven, Anders, Sagen, Jørn V., Søfteland, Eirik, Bjørkhaug, Lise, Tjora, Erling, Aukrust, Ingvild, and Njølstad, Pål R.
- Abstract
Aims/hypothesis: Correctly diagnosing MODY is important, as individuals with this diagnosis can discontinue insulin injections; however, many people are misdiagnosed. We aimed to develop a robust approach for determining the pathogenicity of variants of uncertain significance in hepatocyte nuclear factor-1 alpha (HNF1A)-MODY and to obtain an accurate estimate of the prevalence of HNF1A-MODY in paediatric cases of diabetes. Methods: We extended our previous screening of the Norwegian Childhood Diabetes Registry by 830 additional samples and comprehensively genotyped HNF1A variants in autoantibody-negative participants using next-generation sequencing. Carriers of pathogenic variants were treated by local healthcare providers, and participants with novel likely pathogenic variants and variants of uncertain significance were enrolled in an investigator-initiated, non-randomised, open-label pilot study (ClinicalTrials.gov registration no. NCT04239586). To identify variants associated with HNF1A-MODY, we functionally characterised their pathogenicity and assessed the carriers' phenotype and treatment response to sulfonylurea. Results: In total, 615 autoantibody-negative participants among 4712 cases of paediatric diabetes underwent genetic sequencing, revealing 19 with HNF1A variants. We identified nine carriers with novel variants classified as variants of uncertain significance or likely to be pathogenic, while the remaining ten participants carried five pathogenic variants previously reported. Of the nine carriers with novel variants, six responded favourably to sulfonylurea. Functional investigations revealed their variants to be dysfunctional and demonstrated a correlation with the resulting phenotype, providing evidence for reclassifying these variants as pathogenic. Conclusions/interpretation: Based on this robust classification, we estimate that the prevalence of HNF1A-MODY is 0.3% in paediatric diabetes. Clinical phenotyping is challenging and functional investigations provide a strong complementary line of evidence. We demonstrate here that combining clinical phenotyping with functional protein studies provides a powerful tool to obtain a precise diagnosis of HNF1A-MODY. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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47. Modelling of Beta Cell Pathophysiology Using Stem Cell-Derived Islets
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Barsby, Tom, Montaser, Hossam, Lithovius, Väinö, Ibrahim, Hazem, Vähäkangas, Eliisa, Muralidharan, Sachin, Chandra, Vikash, Saarimäki-Vire, Jonna, Otonkoski, Timo, Piemonti, Lorenzo, editor, Odorico, Jon, editor, Kieffer, Timothy J ., editor, Sordi, Valeria, editor, and de Koning, Eelco, editor
- Published
- 2023
- Full Text
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48. The Etiological Diagnosis of Diabetes: Still a Challenge for the Clinician
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Danièle Dubois-Laforgue and José Timsit
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type 1 diabetes ,type 2 diabetes ,monogenic diabetes ,MODY ,phenotypic heterogeneity ,endotype ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
The etiological diagnosis of diabetes conveys many practical consequences for the care of patients, and often of their families. However, a wide heterogeneity in the phenotypes of all diabetes subtypes, including Type 1 diabetes, Type 2 diabetes, and monogenic diabetes, has been reported and contributes to frequent misdiagnoses. The recently revised WHO classification of diabetes mellitus includes two new classes, namely “hybrid forms” and “unclassified diabetes”, which also reflect the difficulties of this etiological diagnosis. During the last years, many studies aiming at identifying homogenous subgroups on refined phenotypes have been reported. Ultimately, such subtyping may improve the diagnosis, prognosis, and treatment of patients on a pathophysiological basis. Here, we discuss the concepts of typical vs. atypical diabetes in the context of autoimmune Type 1 diabetes, Type 2 diabetes, and its monogenic forms. We discuss the contributions of clinical markers, biological tests, particularly islet cell auto-antibodies, and genetics to improving accurate diagnoses. These data support a systematic evaluation of all newly diagnosed diabetes cases.
- Published
- 2023
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49. The application of droplet digital PCR technology to measure heteroplasmy levels of the mitochondrial DNA mutation m.3243A > G associated with maternally inherited diabetes and deafness
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Colclough, Kevin, Newman, William, and Morton, Cynthia
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MIDD ,monogenic diabetes ,heteroplasmy ,mitochondria ,digital PCR - Abstract
The pathogenic mitochondrial DNA mutation m.3243A > G causes two syndromes; maternally inherited diabetes and deafness (MIDD) and Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS). There is considerable clinical variation in these syndromes, and although clinically distinct patients can have overlapping features. m.3243A > G is highly heteroplasmic and mutation load varies significantly between different tissues and between individuals. Heteroplasmy levels have been shown to positively correlate with disease burden in MELAS, and very low levels of heteroplasmy (1%) have been considered diagnostic. However the effect of low level heteroplasmy on diagnostic test sensitivity is unknown and the association between heteroplasmy and clinical traits has rarely been studied in patients with MIDD. We developed a quantitative droplet digital PCR assay to measure m.3243A > G heteroplasmy to 0.01% in blood. We then tested 190 patients from suspected MIDD families previously tested by a TaqMan genotyping assay capable of detecting ≥5% heteroplasmy. The aim was to determine if cases had been missed by TaqMan due to low heteroplasmy, and to look for an association between heteroplasmy and clinical features in MIDD patients. We confirmed all previous positive TaqMan results and did not identify any additional low heteroplasmy cases in the negative patients. The mean heteroplasmy level was 24.9% ±13.9%. All positive patients had heteroplasmy >2% and all negative patients < 1%, thereby defining cut-offs for reporting a positive result and re-defining the true limit of detection of the TaqMan assay as 2%. A grey-zone between 1 and 2% heteroplasmy was identified representing clinical uncertainty that requires confirmatory testing of other tissues. No significant association was seen between age-adjusted heteroplasmy and age of diabetes diagnosis, HbA1c, diabetes status, deafness status and family history. Droplet digital PCR was considerably more expensive to perform compared to TaqMan genotyping (1.82 GBP per sample for TaqMan versus 39.60 GBP for ddPCR). The lack of a significant diagnostic and clinical benefit and the high cost of ddPCR suggests a low benefit to cost ratio in our cohort. It is therefore unlikely that ddPCR will replace the existing TaqMan genotyping assay as the Exeter laboratory's NHS funded routine diagnostic test for m.3243A > G. There may be a role for ddPCR in a research setting, although recent reconfigurations to NHS genomic testing services will likely result in the replacement of most single variant genotyping assays with next generation sequencing over time.
- Published
- 2021
50. Insulin regulates human pancreatic endocrine cell differentiation in vitro
- Author
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Perla Cota, Özüm Sehnaz Caliskan, Aimée Bastidas-Ponce, Changying Jing, Jessica Jaki, Lama Saber, Oliver Czarnecki, Damla Taskin, Anna Karolina Blöchinger, Thomas Kurth, Michael Sterr, Ingo Burtscher, Natalie Krahmer, Heiko Lickert, and Mostafa Bakhti
- Subjects
Insulin ,Endocrinogenesis ,β cell ,Monogenic diabetes ,iPSC differentiation ,Islet composition ,Internal medicine ,RC31-1245 - Abstract
Objective: The consequences of mutations in genes associated with monogenic forms of diabetes on human pancreas development cannot be studied in a time-resolved fashion in vivo. More specifically, if recessive mutations in the insulin gene influence human pancreatic endocrine lineage formation is still an unresolved question. Methods: To model the extremely reduced insulin levels in patients with recessive insulin gene mutations, we generated a novel knock-in H2B-Cherry reporter human induced pluripotent stem cell (iPSC) line expressing no insulin upon differentiation to stem cell-derived (SC-) β cells in vitro. Differentiation of iPSCs into the pancreatic and endocrine lineage, combined with immunostaining, Western blotting and proteomics analysis phenotypically characterized the insulin gene deficiency in SC-islets. Furthermore, we leveraged FACS analysis and confocal microscopy to explore the impact of insulin shortage on human endocrine cell induction, composition, differentiation and proliferation. Results: Interestingly, insulin-deficient SC-islets exhibited low insulin receptor (IR) signaling when stimulated with glucose but displayed increased IR sensitivity upon treatment with exogenous insulin. Furthermore, insulin shortage did not alter neurogenin-3 (NGN3)-mediated endocrine lineage induction. Nevertheless, lack of insulin skewed the SC-islet cell composition with an increased number in SC-β cell formation at the expense of SC-α cells. Finally, insulin deficiency reduced the rate of SC-β cell proliferation but had no impact on the expansion of SC-α cells. Conclusions: Using iPSC disease modelling, we provide first evidence of insulin function in human pancreatic endocrine lineage formation. These findings help to better understand the phenotypic impact of recessive insulin gene mutations during pancreas development and shed light on insulin gene function beside its physiological role in blood glucose regulation.
- Published
- 2024
- Full Text
- View/download PDF
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