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Bhattacharya S, Fernandez CJ, Kamrul-Hasan ABM, Pappachan JM. Monogenic diabetes: An evidence-based clinical approach. World J Diabetes 2025; 16:104787. [DOI: 10.4239/wjd.v16.i5.104787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2024] [Revised: 02/20/2025] [Accepted: 03/11/2025] [Indexed: 04/25/2025] Open
Abstract
Monogenic diabetes is a heterogeneous disorder characterized by hyperglycemia arising from defects in a single gene. Maturity-onset diabetes of the young (MODY) is the most common type with 14 subtypes, each linked to specific mutations affecting insulin synthesis, secretion and glucose regulation. Common traits across MODY subtypes include early-onset diabetes, a family history of autosomal dominant diabetes, lack of features of insulin resistance, and absent islet cell autoimmunity. Many cases are misdiagnosed as type 1 and type 2 diabetes mellitus. Biomarkers and scoring systems can help identify candidates for genetic testing. GCK-MODY, a common subtype, manifests as mild hyperglycemia and doesn’t require treatment except during pregnancy. In contrast, mutations in HNF4A, HNF1A, and HNF1B genes lead to progressive beta-cell failure and similar risks of complications as type 2 diabetes mellitus. Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes that usually presents within the first six months. Half of the cases are lifelong, while others experience transient remission. Permanent NDM is most commonly due to activating mutations in genes encoding the adenosine triphosphate-sensitive potassium channel (KCNJ11 or ABCC8) and can be transitioned to sulfonylurea after confirmation of diagnosis. Thus, in many cases, monogenic diabetes offers an opportunity to provide precision treatment. The scope has broadened with next-generation sequencing (NGS) technologies, replacing older methods like Sanger sequencing. NGS can be for targeted gene panels, whole-exome sequencing (WES), or whole-genome sequencing. Targeted gene panels offer specific information efficiently, while WES provides comprehensive data but comes with bioinformatic challenges. The surge in testing has also led to an increase in variants of unknown significance (VUS). Deciding whether VUS is disease-causing or benign can be challenging. Computational models, functional studies, and clinical knowledge help to determine pathogenicity. Advances in genetic testing technologies offer hope for improved diagnosis and personalized treatment but also raise concerns about interpretation and ethics.
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Affiliation(s)
| | - Cornelius J Fernandez
- Department of Endocrinology and Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, Boston PE21 9QS, Lincolnshire, United Kingdom
| | | | - Joseph M Pappachan
- Faculty of Science, Manchester Metropolitan University, Manchester M15 6BH, Greater Manchester, United Kingdom
- Department of Endocrinology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal 576104, India
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Cobry EC, Steck AK. Review of Monogenic Diabetes: Clinical Features and Precision Medicine in Genetic Forms of Diabetes. Diabetes Technol Ther 2025. [PMID: 40176772 DOI: 10.1089/dia.2024.0602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/04/2025]
Abstract
Monogenic diabetes is a group of diseases that encompasses a growing number of genetic abnormalities affecting pancreatic function/development leading to glycemic dysregulation. This includes conditions that have historically been referred to as maturity onset diabetes of the young or MODY in addition to neonatal diabetes mellitus. While recognition of a genetic or inherited form of diabetes has been known for decades, advances in molecular genetic testing have resulted in identification of specific forms of monogenic diabetes. Despite this, these genetic forms of diabetes remain widely underreported. It is important to be able to identify genetic forms of diabetes as treatment, monitoring for microvascular and macrovascular complications, and overall management varies for the different forms of monogenic diabetes. Furthermore, the identification of a specific monogenic form of diabetes can significantly impact the person's quality of life and other family members, as well as health care costs. This article highlights the identification, treatment, and management for various forms of monogenic diabetes and addresses some unmet needs in caring for people with monogenic forms of diabetes.
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Affiliation(s)
- Erin C Cobry
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora CO, USA
| | - Andrea K Steck
- Barbara Davis Center for Diabetes, University of Colorado Anschutz Medical Campus, Aurora CO, USA
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Holder M, Kamrath C, Lange K, Kummer S, Ziegler R. Diagnosis, Therapy and Follow-Up of Type 1 Diabetes Mellitus in Children and Adolescents. Exp Clin Endocrinol Diabetes 2025; 133:205-223. [PMID: 40328265 DOI: 10.1055/a-2490-5096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/08/2025]
Affiliation(s)
- Martin Holder
- Olgahospital, Stuttgart Hospital, Stuttgart, Germany
| | | | - Karin Lange
- Hannover Medical School (MHH), Hannover, Germany
| | | | - Ralph Ziegler
- Diabetological Practice for Children and Adolescents, Münster, Germany
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Tagawa K, Matsui K, Tsukamura A, Shibata M, Tsutsui H, Nagai S, Maruo Y. Use of a long-term continuous glucose monitor for predicting sulfonylurea dose in patients with neonatal diabetes mellitus: a case series. Clin Pediatr Endocrinol 2025; 33:131-138. [PMID: 38993723 PMCID: PMC11234181 DOI: 10.1297/cpe.2023-0062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Accepted: 02/17/2024] [Indexed: 07/13/2024] Open
Abstract
Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes that presents with uncontrolled hyperglycemia during the first 6 months of life. NDM is a rare disease in which gene variants mainly cause β-cell loss or dysfunction (6q24 duplication, KCNJ11, and ABCC8). Although NDM is primarily treated through insulin therapy, it is highly challenging to manage blood glucose levels using insulin therapy during infancy. In contrast, KCNJ11 and ABCC8 mutant patients received oral sulfonylureas (SU) instead of insulin injections; however, the dose and frequency differ among individuals. Continuous glucose monitoring (CGM) is useful in patients with type 1 diabetes; but reports on patients with NDM are lacking. Herein, we report two cases of NDM with the KCNJ11 variant. We used CGM not only during insulin injection therapy but also after switching to oral SU therapy. The CGM data can also be used to determine the dose and frequency of SU. Furthermore, long-term CGM may be useful for adjusting SU dose and frequency, and maintaining good glycemic control not only during insulin injection but also during oral SU therapy.
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Affiliation(s)
- Koji Tagawa
- Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan
- Department of Pediatrics, Sapporo Tokushukai Hospital, Hokkaido, Japan
| | - Katsuyuki Matsui
- Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan
- Division of Endocrinology, Metabolism & Diabetes, Shiga Medical Center for Children, Shiga, Japan
| | - Atsushi Tsukamura
- Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan
| | - Masami Shibata
- Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan
- Department of Pediatrics, Ogaki Municipal Hospital, Gifu, Japan
| | - Hidemi Tsutsui
- Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan
| | - Shizuyo Nagai
- Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan
| | - Yoshihiro Maruo
- Department of Pediatrics, Shiga University of Medical Science, Shiga, Japan
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De Silva Y, Birt S. The complexities of managing a newborn with 6q24 transient neonatal diabetes mellitus: a case report. J Pediatr Endocrinol Metab 2024; 37:995-998. [PMID: 39279438 DOI: 10.1515/jpem-2024-0258] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Accepted: 08/24/2024] [Indexed: 09/18/2024]
Abstract
OBJECTIVES This case report delves into the intricate management of a newborn with transient neonatal diabetes mellitus (TNDM), shedding light on the complexities and challenges in treatment decisions. CASE PRESENTATION Born prematurely with a low birth weight and a maternal background of gestational diabetes, the infant developed hyperglycaemia necessitating intravenous insulin therapy. Subsequent genetic testing confirmed 6q24-TNDM, due to the uniparental disomy of the whole of chromosome 6. Glibenclamide, a second-generation sulfonylurea, was cautiously introduced but discontinued due to adverse effects. Despite post-meal hyperglycaemia, blood glucose levels stabilised over subsequent weeks. Regular follow-ups demonstrated appropriate growth and development and the resolution of diabetes. CONCLUSIONS This unique case highlights the need for multidisciplinary collaboration, tailored treatment strategies, and vigilant monitoring in managing 6q24-TNDM.
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Affiliation(s)
- Yannick De Silva
- Central Coast Clinical School, 5982 The University of Newcastle , Gosford, Australia
| | - Stewart Birt
- Central Coast Specialist Centre, Gosford Hospital, Gosford, Australia
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Ba T, Ren Q, Gong S, Li M, Cai X, Liu W, Luo Y, Zhang S, Zhang R, Zhou L, Zhu Y, Zhang X, Chen J, Wu J, Zhou X, Li Y, Wang X, Wang F, Zhong L, Han X, Ji L. Phenotypic features, prevalence of KCNJ11-MODY in Chinese patients with early-onset diabetes and a literature review. Clin Endocrinol (Oxf) 2024; 101:466-474. [PMID: 39190464 DOI: 10.1111/cen.15126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Accepted: 07/29/2024] [Indexed: 08/28/2024]
Abstract
OBJECTIVE Gain-of-function (GOF) variants of KCNJ11 cause neonate diabetes and maturity-onset diabetes of the young (KCNJ11-MODY), while loss-of-function (LOF) variants lead to hyperinsulinemia hypoglycemia and subsequent diabetes. Given the limited research of KCNJ11-MODY, we aimed to analyse its phenotypic features and prevalence in Chinese patients with early-onset type 2 diabetes (EOD). DESIGN, PATIENTS AND MEASUREMENTS We performed next-generation sequencing on 679 Chinese EOD patients to screen for KCNJ11 exons variants. Bioinformatics prediction and the American College of Medical Genetics and Genomics guidelines was used to determine the pathogenicity and diagnosed KCNJ11-MODY. A literature review was conducted to investigate the phenotypic features of KCNJ11-MODY. RESULTS We identified six predicted deleterious rare variants in six EOD patients (0.88%). They were classified as uncertain significance (variant of uncertain significance [VUS]), but more common in this EOD cohort than a general Chinese population database, however, without significant difference (53/10,588, 0.50%) (p = .268). Among 80 previously reported patients with KCNJ11-MODY, 23.8% (19/80) carried 9 (32.1%) LOF variants, who had significantly older age at diagnosis, higher birthweight and higher fasting C-peptide compared to patients with GOF variants. Many patients carrying VUS were not correctly diagnosed. CONCLUSIONS Some rare variants of KCNJ11 might contribute to the development of Chinese EOD, although available evidence has not enough power to support them as cause of KCNJ11-MODY. The clinical features of LOF variants were different from GOF variants in KCNJ11-MODY patients. It is necessary to evaluate the pathogenicity of VUS through function experiments.
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Affiliation(s)
- Tianhao Ba
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Qian Ren
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Siqian Gong
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Meng Li
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Wei Liu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Yingying Luo
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Simin Zhang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Rui Zhang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Lingli Zhou
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Yu Zhu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xiuying Zhang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Jing Chen
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Jing Wu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xianghai Zhou
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Yufeng Li
- Department of Endocrinology and Metabolism, Beijing Pinggu Hospital, Beijing, China
| | - Xirui Wang
- Department of Endocrinology and Metabolism, Beijing Airport Hospital, Beijing, China
| | - Fang Wang
- Department of Endocrinology and Metabolism, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Liyong Zhong
- Department of Endocrinology and Metabolism, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Xueyao Han
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
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Serbis A, Kantza E, Siomou E, Galli-Tsinopoulou A, Kanaka-Gantenbein C, Tigas S. Monogenic Defects of Beta Cell Function: From Clinical Suspicion to Genetic Diagnosis and Management of Rare Types of Diabetes. Int J Mol Sci 2024; 25:10501. [PMID: 39408828 PMCID: PMC11476815 DOI: 10.3390/ijms251910501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/25/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Monogenic defects of beta cell function refer to a group of rare disorders that are characterized by early-onset diabetes mellitus due to a single gene mutation affecting insulin secretion. It accounts for up to 5% of all pediatric diabetes cases and includes transient or permanent neonatal diabetes, maturity-onset diabetes of the young (MODY), and various syndromes associated with diabetes. Causative mutations have been identified in genes regulating the development or function of the pancreatic beta cells responsible for normal insulin production and/or release. To date, more than 40 monogenic diabetes subtypes have been described, with those caused by mutations in HNF1A and GCK genes being the most prevalent. Despite being caused by a single gene mutation, each type of monogenic diabetes, especially MODY, can appear with various clinical phenotypes, even among members of the same family. This clinical heterogeneity, its rarity, and the fact that it shares some features with more common types of diabetes, can make the clinical diagnosis of monogenic diabetes rather challenging. Indeed, several cases of MODY or syndromic diabetes are accurately diagnosed in adulthood, after having been mislabeled as type 1 or type 2 diabetes. The recent widespread use of more reliable sequencing techniques has improved monogenic diabetes diagnosis, which is important to guide appropriate treatment and genetic counselling. The current review aims to summarize the latest knowledge on the clinical presentation, genetic confirmation, and therapeutic approach of the various forms of monogenic defects of beta cell function, using three imaginary clinical scenarios and highlighting clinical and laboratory features that can guide the clinician in reaching the correct diagnosis.
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Affiliation(s)
- Anastasios Serbis
- Department of Pediatrics, University of Ioannina, 45110 Ioannina, Greece; (E.K.); (E.S.)
- Department of Endocrinology & Diabetes Center, University of Ioannina, 45110 Ioannina, Greece;
- 2nd Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University General Hospital, 54636 Thessaloniki, Greece;
| | - Evanthia Kantza
- Department of Pediatrics, University of Ioannina, 45110 Ioannina, Greece; (E.K.); (E.S.)
| | - Ekaterini Siomou
- Department of Pediatrics, University of Ioannina, 45110 Ioannina, Greece; (E.K.); (E.S.)
| | - Assimina Galli-Tsinopoulou
- 2nd Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University General Hospital, 54636 Thessaloniki, Greece;
| | - Christina Kanaka-Gantenbein
- Division of Endocrinology, Diabetes and Metabolism and Aghia Sophia ENDO-ERN Center for Rare Pediatric Endocrine Disorders, First Department of Pediatrics, Medical School, Aghia Sophia Children’s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Stelios Tigas
- Department of Endocrinology & Diabetes Center, University of Ioannina, 45110 Ioannina, Greece;
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Wang S, Liu Y, Zhang Y, Zhang K, Song X, Zhang Y, Pang S. CHL-DTI: A Novel High-Low Order Information Convergence Framework for Effective Drug-Target Interaction Prediction. Interdiscip Sci 2024; 16:568-578. [PMID: 38483753 DOI: 10.1007/s12539-024-00608-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Revised: 01/05/2024] [Accepted: 01/07/2024] [Indexed: 09/19/2024]
Abstract
Recognizing drug-target interactions (DTI) stands as a pivotal element in the expansive field of drug discovery. Traditional biological wet experiments, although valuable, are time-consuming and costly as methods. Recently, computational methods grounded in network learning have demonstrated great advantages by effective topological feature extraction and attracted extensive research attention. However, most existing network-based learning methods only consider the low-order binary correlation between individual drug and target, neglecting the potential higher-order correlation information derived from multiple drugs and targets. High-order information, as an essential component, exhibits complementarity with low-order information. Hence, the incorporation of higher-order associations between drugs and targets, while adequately integrating them with the existing lower-order information, could potentially yield substantial breakthroughs in predicting drug-target interactions. We propose a novel dual channels network-based learning model CHL-DTI that converges high-order information from hypergraphs and low-order information from ordinary graph for drug-target interaction prediction. The convergence of high-low order information in CHL-DTI is manifested in two key aspects. First, during the feature extraction stage, the model integrates both high-level semantic information and low-level topological information by combining hypergraphs and ordinary graph. Second, CHL-DTI fully fuse the innovative introduced drug-protein pairs (DPP) hypergraph network structure with ordinary topological network structure information. Extensive experimentation conducted on three public datasets showcases the superior performance of CHL-DTI in DTI prediction tasks when compared to SOTA methods. The source code of CHL-DTI is available at https://github.com/UPCLyy/CHL-DTI .
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Affiliation(s)
- Shudong Wang
- College of Computer Science and Technology, China University of Petroleum (East China), Qingdao, 266580, China
| | - Yingye Liu
- College of Computer Science and Technology, China University of Petroleum (East China), Qingdao, 266580, China
| | - Yuanyuan Zhang
- College of Information and Control Engineering, Qingdao University of Technology, Qingdao, 266520, China.
| | - Kuijie Zhang
- College of Computer Science and Technology, China University of Petroleum (East China), Qingdao, 266580, China
| | - Xuanmo Song
- College of Computer Science and Technology, China University of Petroleum (East China), Qingdao, 266580, China
| | - Yu Zhang
- College of Computer Science and Technology, China University of Petroleum (East China), Qingdao, 266580, China
| | - Shanchen Pang
- College of Computer Science and Technology, China University of Petroleum (East China), Qingdao, 266580, China
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Mӓnnikkӧ R, Kullmann DM. Structure-function and pharmacologic aspects of ion channels relevant to neurologic channelopathies. HANDBOOK OF CLINICAL NEUROLOGY 2024; 203:1-23. [PMID: 39174242 DOI: 10.1016/b978-0-323-90820-7.00009-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/24/2024]
Abstract
Ion channels are membrane proteins that allow the passage of ions across the membrane. They characteristically contain a pore where the selectivity of certain ion species is determined and gates that open and close the pore are found. The pore is often connected to additional domains or subunits that regulate its function. Channels are grouped into families based on their selectivity for specific ions and the stimuli that control channel opening and closing, such as voltage or ligands. Ion channels are fundamental to the electrical properties of excitable tissues. Dysfunction of channels can lead to abnormal electrical signaling of neurons and muscle cells, accompanied by clinical manifestations, known as channelopathies. Many naturally occurring toxins target ion channels and affect excitable cells where the channels are expressed. Furthermore, ion channels, as membrane proteins and key regulators of a number of physiologic functions, are an important target for drugs in clinical use. In this chapter, we give a general overview of the classification, genetics and structure-function features of the main ion channel families, and address some pharmacologic aspects relevant to neurologic channelopathies.
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Affiliation(s)
- Roope Mӓnnikkӧ
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
| | - Dimitri M Kullmann
- Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
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Hattori A, Okuhara K, Shimizu Y, Ohta T, Suzuki S. A Japanese school urine screening program led to the diagnosis of KCNJ11-MODY: A case report. Clin Pediatr Endocrinol 2023; 33:12-16. [PMID: 38299173 PMCID: PMC10825650 DOI: 10.1297/cpe.2023-0037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 08/15/2023] [Indexed: 02/02/2024] Open
Abstract
Although KCNJ11 mutation is the main cause of neonatal diabetes mellitus, reports of maturity-onset diabetes in the young (MODY) related to KCNJ11 are rare. Here, we report a case of KCNJ11-MODY in a 12-yr-old Japanese female. Hyperglycemia was initially detected during a school urine screening program. Subsequent laboratory examinations revealed impaired insulin secretion; however, no islet autoantibodies were detected. Genetic testing of KCNJ11 revealed a novel heterozygous variant, c.153G>C, p.Glu51Asp. The patient's father had the same mutation and was diagnosed with diabetes at 46 yr of age. KCNJ11-MODY was suspected, and sulfonylurea administration resulted in adequate glycemic control in the patient. The American College of Medical Genetics and Genomics guidelines classify this variant as likely pathogenic, and the effectiveness of sulfonylureas supports its pathogenicity. The patient could be treated with 0.02-0.03 mg/kg/d of glibenclamide, as this mutation may be responsive to only a small amount of sulfonylurea. A detailed family history and sequencing of causative genes, including KCNJ11, may help diagnose diabetes in school-aged patients.
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Affiliation(s)
- Akito Hattori
- Department of Pediatrics, Tenshi Hospital, Hokkaido, Japan
| | - Koji Okuhara
- Department of Pediatrics, Tenshi Hospital, Hokkaido, Japan
| | | | - Tohru Ohta
- Department of Pediatrics, Tenshi Hospital, Hokkaido, Japan
- Advanced Research Promotion Center, Health Sciences University of Hokkaido, Hokkaido, Japan
| | - Shigeru Suzuki
- Department of Pediatrics, Asahikawa Medical University, Hokkaido, Japan
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Xiao B, Yi H, Zhang M, Wang R, Hu Y, Xu Y, Shao Z, Zhang S, Peng N. MODY in China: two families carrying the KCNJ11 E229K variant. Acta Diabetol 2023; 60:1287-1289. [PMID: 37296241 DOI: 10.1007/s00592-023-02114-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 05/05/2023] [Indexed: 06/12/2023]
Affiliation(s)
- Banghui Xiao
- Department of Endocrinology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Hongmei Yi
- Department of Endocrinology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Miao Zhang
- Department of Endocrinology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Rui Wang
- Department of Endocrinology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Ying Hu
- Department of Endocrinology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Yi Xu
- Department of Endocrinology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Zhijuan Shao
- Department of Endocrinology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China
| | - Song Zhang
- Department of Endocrinology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
| | - Nianchun Peng
- Department of Endocrinology, Affiliated Hospital of Guizhou Medical University, Guiyang, 550004, China.
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Ashcroft FM. KATP Channels and the Metabolic Regulation of Insulin Secretion in Health and Disease: The 2022 Banting Medal for Scientific Achievement Award Lecture. Diabetes 2023; 72:693-702. [PMID: 37815796 PMCID: PMC10202764 DOI: 10.2337/dbi22-0030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Accepted: 02/28/2023] [Indexed: 10/11/2023]
Abstract
Diabetes is characterized by elevation of plasma glucose due to an insufficiency of the hormone insulin and is associated with both inadequate insulin secretion and impaired insulin action. The Banting Medal for Scientific Achievement Commemorates the work of Sir Frederick Banting, a member of the team that first used insulin to treat a patient with diabetes almost exactly one hundred years ago on 11 January 1922. This article is based on my Banting lecture of 2022 and concerns the mechanism of glucose-stimulated insulin secretion from pancreatic β-cells, with an emphasis on the metabolic regulation of the KATP channel. This channel plays a central role in insulin release. Its closure in response to metabolically generated changes in the intracellular concentrations of ATP and MgADP stimulates β-cell electrical activity and insulin granule exocytosis. Activating mutations in KATP channel genes that impair the ability of the channel to respond to ATP give rise to neonatal diabetes. Impaired KATP channel regulation may also play a role in type 2 diabetes. I conjecture that KATP channel closure in response to glucose is reduced because of impaired glucose metabolism, which fails to generate a sufficient increase in ATP. Consequently, glucose-stimulated β-cell electrical activity is less. As ATP is also required for insulin granule exocytosis, both reduced exocytosis and less β-cell electrical activity may contribute to the reduction in insulin secretion. I emphasize that what follows is not a definitive review of the topic but a personal account of the contribution of my team to the field that is based on my Banting lecture.
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Affiliation(s)
- Frances M. Ashcroft
- Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, U.K
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Abstract
Monogenic diabetes includes several clinical conditions generally characterized by early-onset diabetes, such as neonatal diabetes, maturity-onset diabetes of the young (MODY) and various diabetes-associated syndromes. However, patients with apparent type 2 diabetes mellitus may actually have monogenic diabetes. Indeed, the same monogenic diabetes gene can contribute to different forms of diabetes with early or late onset, depending on the functional impact of the variant, and the same pathogenic variant can produce variable diabetes phenotypes, even in the same family. Monogenic diabetes is mostly caused by impaired function or development of pancreatic islets, with defective insulin secretion in the absence of obesity. The most prevalent form of monogenic diabetes is MODY, which may account for 0.5-5% of patients diagnosed with non-autoimmune diabetes but is probably underdiagnosed owing to insufficient genetic testing. Most patients with neonatal diabetes or MODY have autosomal dominant diabetes. More than 40 subtypes of monogenic diabetes have been identified to date, the most prevalent being deficiencies of GCK and HNF1A. Precision medicine approaches (including specific treatments for hyperglycaemia, monitoring associated extra-pancreatic phenotypes and/or following up clinical trajectories, especially during pregnancy) are available for some forms of monogenic diabetes (including GCK- and HNF1A-diabetes) and increase patients' quality of life. Next-generation sequencing has made genetic diagnosis affordable, enabling effective genomic medicine in monogenic diabetes.
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14
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Ashcroft FM, Lloyd M, Haythorne EA. Glucokinase activity in diabetes: too much of a good thing? Trends Endocrinol Metab 2023; 34:119-130. [PMID: 36586779 DOI: 10.1016/j.tem.2022.12.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 12/15/2022] [Indexed: 12/31/2022]
Abstract
Type 2 diabetes (T2D) is a global health problem characterised by chronic hyperglycaemia due to inadequate insulin secretion. Because glucose must be metabolised to stimulate insulin release it was initially argued that drugs that stimulate glucokinase (the first enzyme in glucose metabolism) would enhance insulin secretion in diabetes. However, in the long term, glucokinase activators have been largely disappointing. Recent studies show it is hyperactivation of glucose metabolism, not glucose itself, that underlies the progressive decline in beta-cell function in diabetes. This perspective discusses if glucokinase activators exacerbate this decline (by promoting glucose metabolism) and, counterintuitively, if glucokinase inhibitors might be a better therapeutic strategy for preserving beta-cell function in T2D.
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Affiliation(s)
- Frances M Ashcroft
- Department of Physiology, Anatomy and Genetics, Parks Road, Oxford, OX1 3PT, UK.
| | - Matthew Lloyd
- Department of Physiology, Anatomy and Genetics, Parks Road, Oxford, OX1 3PT, UK
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15
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Wu B, Xu W. Case report: Neonatal diabetes mellitus caused by KCNJ11 mutation presenting with intracranial hemorrhage. Front Neurol 2023; 14:1072078. [PMID: 36937531 PMCID: PMC10022729 DOI: 10.3389/fneur.2023.1072078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Accepted: 02/06/2023] [Indexed: 03/06/2023] Open
Abstract
Neonatal diabetes mellitus (NDM) is a rare type of monogenic diabetes. At present, most published studies have focused on the types of gene mutations associated with NDM and the therapeutic effect of sulfonylureas (SUs) on the disease; few studies on NDM-associated intracranial hemorrhage (ICH) exist. In addition, p.V59M mutations generally lead to intermediate DEND (iDEND: intermediate developmental delay and neonatal diabetes) syndrome without epilepsy. Here, we present a case of a 1-month-old male infant who was diagnosed with NDM caused by a KCNJ11 missense mutation (p.V59M), presenting with cerebral injury. In the early stage of the disease, continuous insulin dose adjustment did not achieve an ideal level of blood glucose. Although blood glucose was subsequently controlled by oral SUs, which were administered after the genetic test result, the patient still displayed epilepsy and developmental delay. In this case report, we present our experience in the treatment of the infant, switching from insulin to oral SUs and we thought that SUs have limited effects on improving the prognosis of neurodevelopmental disturbances in NDM with foci of encephalomalacia. In addition, there may be a relationship between KCNJ11 missense mutations and cerebral injury, and further research must be carried out to confirm these points.
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16
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Stankute I, Dobrovolskiene R, Danyte E, Steponaviciute R, Schwitzgebel VM, Verkauskiene R. Pancreatic beta-cell function dynamics in youth with GCK, HNF1A, and KCNJ11 genes mutations during mixed meal tolerance test. Pediatr Diabetes 2022; 23:1009-1016. [PMID: 36068963 PMCID: PMC9826376 DOI: 10.1111/pedi.13404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 06/21/2022] [Accepted: 08/14/2022] [Indexed: 01/11/2023] Open
Abstract
OBJECTIVE The aims were (1) to assess beta-cell function in GCK diabetes patients over 2-year period; (2) to evaluate the dynamics of beta-cell function in HNF1A and KCNJ11 patients after treatment optimization; using mixed meal tolerance test (MMTT) as a gold standard for non-invasive beta-cell function assessment. RESEARCH DESIGN AND METHODS Twenty-two GCK diabetes patients, 22 healthy subjects, 4 patients with HNF1A and 2 with KCNJ11 were recruited. Firstly, beta-cell function was compared between GCK patients versus controls; the dynamics of beta-cell function were assessed in GCK patients with two MMTTs in 2-year period. Secondly, the change of beta-cell function was evaluated in HNF1A and KCNJ11 patients after successful treatment optimization in 2-year period. RESULTS GCK diabetes patients had lower area under the curve (AUC) of C-peptide (CP), average CP and peak CP compared to controls. Also, higher levels of fasting, average, peak and AUC of glycemia during MMTT were found in GCK patients compared to healthy controls. No significant changes in either CP or glycemia dynamics were observed in GCK diabetes group comparing 1st and 2nd MMTTs. Patients with HNF1A and KCNJ11 diabetes had significantly improved diabetes control 2 years after the treatment was optimized (HbA1c 7.1% vs. 5.9% [54 mmol/mol vs. 41 mmol/mol], respectively, p = 0.028). Higher peak CP and lower HbA1c were found during 2nd MMTT in patients with targeted treatment compared to the 1st MMTT before the treatment change. CONCLUSION In short-term perspective, GCK diabetes group revealed no deterioration of beta-cell function. Individualized treatment in monogenic diabetes showed improved beta-cell function.
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Affiliation(s)
- Ingrida Stankute
- Institute of EndocrinologyLithuanian University of Health SciencesKaunasLithuania,Medical AcademyLithuanian University of Health SciencesKaunasLithuania
| | | | - Evalda Danyte
- Institute of EndocrinologyLithuanian University of Health SciencesKaunasLithuania
| | - Rasa Steponaviciute
- Department of Laboratory MedicineLithuanian University of Health SciencesKaunasLithuania
| | - Valerie M. Schwitzgebel
- Pediatric Endocrine and Diabetes Unit, Department of Pediatrics, Gynecology and ObstetricsUniversity Hospitals of GenevaGenevaSwitzerland,Diabetes Center of the Faculty of MedicineUniversity of GenevaGenevaSwitzerland
| | - Rasa Verkauskiene
- Institute of EndocrinologyLithuanian University of Health SciencesKaunasLithuania
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17
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Colclough K, van Heugten R, Patel K. An update on the diagnosis and management of monogenic diabetes. PRACTICAL DIABETES 2022. [DOI: 10.1002/pdi.2410] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Kevin Colclough
- Exeter Genomics Laboratory, Royal Devon & Exeter NHS Foundation Trust Exeter UK
| | - Rachel van Heugten
- Exeter Genomics Laboratory, Royal Devon & Exeter NHS Foundation Trust Exeter UK
| | - Kashyap Patel
- Institute of Biomedical and Clinical Science University of Exeter Medical School Exeter UK
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18
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Mouler M, Lebenthal Y, de Vries L, Yackobovitch-Gavan M, Averbuch NS, Fauret-Amsellem AL, Cavé H, Beltrand J, Polak M, Phillip M, Nimri R. Clinical characteristics, growth patterns, and long-term diabetes complications of 24 patients with neonatal diabetes mellitus: A single center experience. Pediatr Diabetes 2022; 23:45-54. [PMID: 34837310 DOI: 10.1111/pedi.13295] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/29/2021] [Accepted: 11/15/2021] [Indexed: 11/30/2022] Open
Abstract
OBJECTIVES Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes, diagnosed before age 6 months. We aimed to describe the clinical characteristics, molecular genetics, and long-term follow-up of NDM patients from a single pediatric endocrine center in Israel. METHODS Retrospective study (1975-2020) of all patients diagnosed with diabetes before 6 months of age, who tested negative for pancreatic autoantibodies. Medical records were reviewed for demographic, familial and medical history, and clinical and biochemical features; a genetic analysis was performed. RESULTS Of 24 patients, nine had transient neonatal diabetes (TNDM) and 15 permanent neonatal diabetes (PNDM), of whom five had rare syndromic causes. Genetic etiology was revealed in 87.5% of the NDM cohort, and the most common causes were ABCC8 mutations in TNDM and KCNJ11 and insulin gene mutations in PNDM. The switch from insulin to off-label sulfonylurea therapy was successful for 5/9 (56%) of the qualifying candidates. Severe hypoglycemia and diabetic ketoacidosis developed in 2 (8%) patients, and chronic diabetes complications in 5 (21%) patients with more than 10 years NDM. At last follow-up, weight and height of all but two syndromic PNDM patients were normal. The median height-SDS of the TNDM subgroup was significantly taller and the mean weight-SDS significantly heavier than those of the PNDM subgroup (-0.52 (-0.67, -0.09) vs. -0.9 (-1.42, -0.3) (p = 0.035) and 0.22 ± 0.69 vs. -0.89 ± 1.21 (p = 0.02), respectively). PNDM patients showed no incremental change in mean weight SDS over the time. CONCLUSION The Israeli NDM cohort has clinical and genetic characteristics comparable with other populations. Patients with TNDM were taller and heavier than those diagnosed with PNDM, although both show rapid catch-up growth and reached normal growth parameters. Chronic diabetes complications developed in patients with long-standing NDM.
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Affiliation(s)
- Marie Mouler
- The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
| | - Yael Lebenthal
- The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Liat de Vries
- The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Michal Yackobovitch-Gavan
- The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
| | - Noa Shefer Averbuch
- The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
| | - Anne Laure Fauret-Amsellem
- Department of Genetics, Hôpital Universitaire Robert Debré, Assistance Publique-Hôpitaux de Paris, Université Paris-Diderot, Paris, France
| | - Helene Cavé
- Department of Genetics, Hôpital Universitaire Robert Debré, Assistance Publique-Hôpitaux de Paris, Université Paris-Diderot, Paris, France
| | - Jacques Beltrand
- Department of Paediatric Endocrinology, Gynaecology, and Diabetology, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, IMAGINE Institute, INSERM U1016, Paris, France
| | - Michel Polak
- Department of Paediatric Endocrinology, Gynaecology, and Diabetology, Hôpital Universitaire Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, IMAGINE Institute, INSERM U1016, Paris, France
| | - Moshe Phillip
- The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tikva, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Revital Nimri
- The Jesse Z. and Sara Lea Shafer Institute for Endocrinology and Diabetes, National Center for Childhood Diabetes, Schneider Children's Medical Center of Israel, Petah Tikva, Israel
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19
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Houtman MJC, Friesacher T, Chen X, Zangerl-Plessl EM, van der Heyden MAG, Stary-Weinzinger A. Development of I KATP Ion Channel Blockers Targeting Sulfonylurea Resistant Mutant K IR6.2 Based Channels for Treating DEND Syndrome. Front Pharmacol 2022; 12:814066. [PMID: 35095528 PMCID: PMC8795863 DOI: 10.3389/fphar.2021.814066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 12/23/2021] [Indexed: 11/13/2022] Open
Abstract
Introduction: DEND syndrome is a rare channelopathy characterized by a combination of developmental delay, epilepsy and severe neonatal diabetes. Gain of function mutations in the KCNJ11 gene, encoding the KIR6.2 subunit of the IKATP potassium channel, stand at the basis of most forms of DEND syndrome. In a previous search for existing drugs with the potential of targeting Cantú Syndrome, also resulting from increased IKATP, we found a set of candidate drugs that may also possess the potential to target DEND syndrome. In the current work, we combined Molecular Modelling including Molecular Dynamics simulations, with single cell patch clamp electrophysiology, in order to test the effect of selected drug candidates on the KIR6.2 WT and DEND mutant channels. Methods: Molecular dynamics simulations were performed to investigate potential drug binding sites. To conduct in vitro studies, KIR6.2 Q52R and L164P mutants were constructed. Inside/out patch clamp electrophysiology on transiently transfected HEK293T cells was performed for establishing drug-channel inhibition relationships. Results: Molecular Dynamics simulations provided insight in potential channel interaction and shed light on possible mechanisms of action of the tested drug candidates. Effective IKIR6.2/SUR2a inhibition was obtained with the pore-blocker betaxolol (IC50 values 27-37 μM). Levobetaxolol effectively inhibited WT and L164P (IC50 values 22 μM) and Q52R (IC50 55 μM) channels. Of the SUR binding prostaglandin series, travoprost was found to be the best blocker of WT and L164P channels (IC50 2-3 μM), while Q52R inhibition was 15-20% at 10 μM. Conclusion: Our combination of MD and inside-out electrophysiology provides the rationale for drug mediated IKATP inhibition, and will be the basis for 1) screening of additional existing drugs for repurposing to address DEND syndrome, and 2) rationalized medicinal chemistry to improve IKATP inhibitor efficacy and specificity.
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Affiliation(s)
- Marien J C Houtman
- Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands
| | - Theres Friesacher
- Department of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
| | - Xingyu Chen
- Department of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
| | - Eva-Maria Zangerl-Plessl
- Department of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
| | - Marcel A G van der Heyden
- Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands
| | - Anna Stary-Weinzinger
- Department of Pharmaceutical Sciences, Division of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
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20
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Role of Actionable Genes in Pursuing a True Approach of Precision Medicine in Monogenic Diabetes. Genes (Basel) 2022; 13:genes13010117. [PMID: 35052457 PMCID: PMC8774614 DOI: 10.3390/genes13010117] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/04/2022] [Accepted: 01/05/2022] [Indexed: 12/16/2022] Open
Abstract
Monogenic diabetes is a genetic disorder caused by one or more variations in a single gene. It encompasses a broad spectrum of heterogeneous conditions, including neonatal diabetes, maturity onset diabetes of the young (MODY) and syndromic diabetes, affecting 1-5% of patients with diabetes. Some of these variants are harbored by genes whose altered function can be tackled by specific actions ("actionable genes"). In suspected patients, molecular diagnosis allows the implementation of effective approaches of precision medicine so as to allow individual interventions aimed to prevent, mitigate or delay clinical outcomes. This review will almost exclusively concentrate on the clinical strategy that can be specifically pursued in carriers of mutations in "actionable genes", including ABCC8, KCNJ11, GCK, HNF1A, HNF4A, HNF1B, PPARG, GATA4 and GATA6. For each of them we will provide a short background on what is known about gene function and dysfunction. Then, we will discuss how the identification of their mutations in individuals with this form of diabetes, can be used in daily clinical practice to implement specific monitoring and treatments. We hope this article will help clinical diabetologists carefully consider who of their patients deserves timely genetic testing for monogenic diabetes.
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21
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Barash G, Bassan H, Livne A, Benyamini L, Heyman E, Bowman P, Rachmiel M. Novel perspectives of super-high dose sulfonylurea and high-dose oral prednisolone in an infant with DEND syndrome due to V64M heterozygote KCNJ11 mutation. Acta Diabetol 2021; 58:1665-1672. [PMID: 34272607 DOI: 10.1007/s00592-021-01763-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2021] [Accepted: 06/11/2021] [Indexed: 12/25/2022]
Abstract
AIMS To report a novel mutation associated with developmental delay, epilepsy, and neonatal diabetes-DEND Syndrome, responsive to a novel management combination. METHODS We describe the investigation, treatment, and genetic diagnosis of a newborn diagnosed with DEND syndrome. RESULTS The patient was found to be de-novo heterozygous for pathogenic KCNJ11 missense variant: c.190G > A, p. (Val64Met), associated with DEND syndrome, responsive to a combination of super high doses of sulfonylurea (SU) and oral high-dose steroids. A single case was reported so far due to this mutation, presenting with severe DEND syndrome, treated by insulin only. His phenotypic description and management during 18 months, demonstrates this mutation is responsive to super-high doses of SU combined with high dose 6 weeks steroids protocol. CONCLUSIONS We have identified a heterozygous missense mutation as the etiology for severe DEND syndrome in a one-day old neonate, presenting with asymptomatic hyperglycemia, responsive to a novel management combination.
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Affiliation(s)
- Galia Barash
- Pediatric Endocrinology and Diabetes Institute Shamir Medical Center, 70300, Zerifin, Israel
| | - Haim Bassan
- Pediatric Neurology and Development Center Shamir Medical Center, Tel Aviv, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ayelet Livne
- Neonatal Intensive Care Unit Shamir Medical Center, Tel Aviv, Israel
| | | | - Eli Heyman
- Pediatric Neurology and Development Center Shamir Medical Center, Tel Aviv, Israel
| | | | - Marianna Rachmiel
- Pediatric Endocrinology and Diabetes Institute Shamir Medical Center, 70300, Zerifin, Israel.
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
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22
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Ramzy A, Kieffer TJ. Altered islet prohormone processing: A cause or consequence of diabetes? Physiol Rev 2021; 102:155-208. [PMID: 34280055 DOI: 10.1152/physrev.00008.2021] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Peptide hormones are first produced as larger precursor prohormones that require endoproteolytic cleavage to liberate the mature hormones. A structurally conserved but functionally distinct family of nine prohormone convertase enzymes (PCs) are responsible for cleavage of protein precursors of which PC1/3 and PC2 are known to be exclusive to neuroendocrine cells and responsible for prohormone cleavage. Differential expression of PCs within tissues define prohormone processing; whereas glucagon is the major product liberated from proglucagon via PC2 in pancreatic α-cells, proglucagon is preferentially processed by PC1/3 in intestinal L cells to produce glucagon-like peptides 1 and 2 (GLP-1, GLP-2). Beyond our understanding of processing of islet prohormones in healthy islets, there is convincing evidence that proinsulin, proIAPP, and proglucagon processing is altered during prediabetes and diabetes. There is predictive value of elevated circulating proinsulin or proinsulin : C-peptide ratio for progression to type 2 diabetes and elevated proinsulin or proinsulin : C-peptide is predictive for development of type 1 diabetes in at risk groups. After onset of diabetes, patients have elevated circulating proinsulin and proIAPP and proinsulin may be an autoantigen in type 1 diabetes. Further, preclinical studies reveal that α-cells have altered proglucagon processing during diabetes leading to increased GLP-1 production. We conclude that despite strong associative data, current evidence is inconclusive on the potential causal role of impaired prohormone processing in diabetes, and suggest that future work should focus on resolving the question of whether altered prohormone processing is a causal driver or merely a consequence of diabetes pathology.
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Affiliation(s)
- Adam Ramzy
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada
| | - Timothy J Kieffer
- Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, BC, Canada.,Department of Surgery, University of British Columbia, Vancouver, BC, Canada.,School of Biomedical Engineering, University of British Columbia, Vancouver, BC, Canada
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23
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Abstract
ATP-sensitive K+ channels (KATP) are inwardly-rectifying potassium channels, broadly expressed throughout the body. KATP is regulated by adenine nucleotides, characteristically being activated by falling ATP and rising ADP levels thus playing an important physiological role by coupling cellular metabolism with membrane excitability. The hetero-octameric channel complex is formed of 4 pore-forming inward rectifier Kir6.x subunits (Kir6.1 or Kir6.2) and 4 regulatory sulfonylurea receptor subunits (SUR1, SUR2A, or SUR2B). These subunits can associate in various tissue-specific combinations to form functional KATP channels with distinct electrophysiological and pharmacological properties. KATP channels play many important physiological roles and mutations in channel subunits can result in diseases such as disorders of insulin handling, cardiac arrhythmia, cardiomyopathy, and neurological abnormalities. The tissue-specific expression of KATP channel subunits coupled with their rich and diverse pharmacology makes KATP channels attractive therapeutic targets in the treatment of endocrine and cardiovascular diseases.
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24
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Oshiro A, Ohkuma T, Sakamoto W, Komorita Y, Oku Y, Hirakawa Y, Kitazono T. An adult patient with permanent neonatal diabetes successfully discontinued insulin therapy after initiating sitagliptin added to sulphonylurea. Diabetes Obes Metab 2021; 23:1213-1214. [PMID: 33464705 DOI: 10.1111/dom.14318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/09/2021] [Accepted: 01/14/2021] [Indexed: 11/28/2022]
Affiliation(s)
- Ayaka Oshiro
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Toshiaki Ohkuma
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Wakako Sakamoto
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuji Komorita
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yutaro Oku
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoichiro Hirakawa
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Takanari Kitazono
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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25
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Hajji S, Aljenaee K, Garrahy A, Byrne M. Successful transition from insulin to sulfonylurea, on second attempt, in a 24-year-old female with neonatal diabetes secondary to KCNJ11 gene mutation. BMJ Case Rep 2021; 14:14/4/e239973. [PMID: 33837025 PMCID: PMC8043004 DOI: 10.1136/bcr-2020-239973] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/04/2022] Open
Abstract
Neonatal diabetes (NDM) is defined as diabetes that occurs in the first 6 months of life, the majority of cases are due to sporadic mutations. ATP-sensitive potassium channels located in the beta cells of the pancreas play a major role in insulin secretion and blood glucose homeostasis. Mutations that alter the function of these channels may lead to NDM. We report a case of a 26-year-old Irish woman who was diagnosed with NDM at the age of 4 weeks and treated as type 1 diabetes mellitus, with multiple daily injections of insulin with suboptimal glycaemic control and frequent episodes of hypoglycaemic. She underwent genetic testing for NDM and was diagnosed with a KCNJ11 gene mutation. She was transitioned to high dose glibenclamide at the age of 16 years, but the trial failed due to poor glycaemic control and patient preference, and she was restarted on insulin. At 24 years of age, she was successfully transitioned from insulin (total daily dose 50 units) to high dose sulfonylurea (SU) (glibenclamide 15 mg twice daily). This resulted in optimal control of blood glucose (HbA1C fell from 63 to 44 mmol/mol), lower rates of hypoglycaemic and better quality of life. This case demonstrates that a second trial of SU in later life may be successful.
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Affiliation(s)
- Sulaiman Hajji
- Endocrinology, Mater Misericordiae University Hospital, Dublin, Ireland
| | - Khaled Aljenaee
- Endocrine and Diabetes, Saint James's Hospital, Dublin, Ireland
| | - Aoife Garrahy
- Endocrinology and Diabetes, South Infirmary Victoria University Hospital, Cork, Ireland
| | - Maria Byrne
- Endocrinology, Mater Misericordiae University Hospital, Dublin, Ireland
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26
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Öngen YD, Eren E, Demirbaş Ö, Sobu E, Ellard S, De Franco E, Tarım Ö. Genotype and Phenotype Heterogeneity in Neonatal Diabetes: A Single Centre Experience in Turkey. J Clin Res Pediatr Endocrinol 2021; 13:80-87. [PMID: 32820876 PMCID: PMC7947723 DOI: 10.4274/jcrpe.galenos.2020.2020.0093] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
OBJECTIVE Neonatal diabetes mellitus (NDM) may be transient or permanent, and the majority is caused by genetic mutations. Early diagnosis is essential to select the patients who will respond to oral treatment. In this investigation, we aimed to present the phenotype and genotype of our patients with NDM and share our experience in a single tertiary center METHODS A total of 16 NDM patients from 12 unrelated families are included in the study. The clinical presentation, age at diagnosis, perinatal and family history, consanguinity, gender, hemoglobin A1c, C-peptide, insulin, insulin autoantibodies, genetic mutations, and response to treatment are retrospectively evaluated. RESULTS The median age at diagnosis of diabetes was five months (4 days-18 months) although six patients with a confirmed genetic diagnosis were diagnosed >6 months. Three patients had KCNJ11 mutations, six had ABCC8 mutations, three had EIF2AK3 mutations, and one had a de novo INS mutation. All the permanent NDM patients with KCNJ11 and ABCC8 mutations were started on sulfonylurea treatment resulting in a significant increase in C-peptide level, better glycemic control, and discontinuation of insulin. CONCLUSION Although NDM is defined as diabetes diagnosed during the first six months of life, and a diagnosis of type 1 diabetes is more common between the ages of 6 and 24 months, in rare cases NDM may present as late as 12 or even 24 months of age. Molecular diagnosis in NDM is important for planning treatment and predicting prognosis. Therefore, genetic testing is essential in these patients.
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Affiliation(s)
- Yasemin Denkboy Öngen
- Bursa Uludağ University Faculty of Medicine, Department of Pediatric Endocrinology, Bursa, Turkey,* Address for Correspondence: Bursa Uludağ University Faculty of Medicine, Department of Pediatric Endocrinology, Bursa, Turkey Phone: +90 224 295 05 33 E-mail:
| | - Erdal Eren
- Bursa Uludağ University Faculty of Medicine, Department of Pediatric Endocrinology, Bursa, Turkey
| | - Özgecan Demirbaş
- Bursa Uludağ University Faculty of Medicine, Department of Pediatric Endocrinology, Bursa, Turkey
| | - Elif Sobu
- Bursa Uludağ University Faculty of Medicine, Department of Pediatric Endocrinology, Bursa, Turkey
| | - Sian Ellard
- University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom,Royal Devon and Exeter NHS Foundation Trust, Genomics Laboratory, Exeter, United Kingdom
| | - Elisa De Franco
- University of Exeter Medical School, Institute of Biomedical and Clinical Science, Exeter, United Kingdom
| | - Ömer Tarım
- Bursa Uludağ University Faculty of Medicine, Department of Pediatric Endocrinology, Bursa, Turkey
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27
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Zhang H, Colclough K, Gloyn AL, Pollin TI. Monogenic diabetes: a gateway to precision medicine in diabetes. J Clin Invest 2021; 131:142244. [PMID: 33529164 PMCID: PMC7843214 DOI: 10.1172/jci142244] [Citation(s) in RCA: 92] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Monogenic diabetes refers to diabetes mellitus (DM) caused by a mutation in a single gene and accounts for approximately 1%-5% of diabetes. Correct diagnosis is clinically critical for certain types of monogenic diabetes, since the appropriate treatment is determined by the etiology of the disease (e.g., oral sulfonylurea treatment of HNF1A/HNF4A-diabetes vs. insulin injections in type 1 diabetes). However, achieving a correct diagnosis requires genetic testing, and the overlapping of the clinical features of monogenic diabetes with those of type 1 and type 2 diabetes has frequently led to misdiagnosis. Improvements in sequencing technology are increasing opportunities to diagnose monogenic diabetes, but challenges remain. In this Review, we describe the types of monogenic diabetes, including common and uncommon types of maturity-onset diabetes of the young, multiple causes of neonatal DM, and syndromic diabetes such as Wolfram syndrome and lipodystrophy. We also review methods of prioritizing patients undergoing genetic testing, and highlight existing challenges facing sequence data interpretation that can be addressed by forming collaborations of expertise and by pooling cases.
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Affiliation(s)
- Haichen Zhang
- University of Maryland School of Medicine, Department of Medicine, Baltimore, Maryland, USA
| | - Kevin Colclough
- Exeter Genomics Laboratory, Royal Devon and Exeter Hospital, Exeter, United Kingdom
| | - Anna L. Gloyn
- Department of Pediatrics, Division of Endocrinology, and,Stanford Diabetes Research Center, Stanford School of Medicine, Stanford, California, USA
| | - Toni I. Pollin
- University of Maryland School of Medicine, Department of Medicine, Baltimore, Maryland, USA
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He B, Li X, Zhou Z. Continuous spectrum of glucose dysmetabolism due to the KCNJ11 gene mutation-Case reports and review of the literature. J Diabetes 2021; 13:19-32. [PMID: 32935446 DOI: 10.1111/1753-0407.13114] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 07/20/2020] [Accepted: 09/03/2020] [Indexed: 12/01/2022] Open
Abstract
The KCNJ11 gene encodes the Kir6.2 subunit of the adenosine triphosphate-sensitive potassium (KATP ) channel, which plays a key role in insulin secretion. Monogenic diseases caused by KCNJ11 gene mutation are rare and easily misdiagnosed. It has been shown that mutations in the KCNJ11 gene are associated with neonatal diabetes mellitus (NDM), maturity-onset diabetes of the young 13 (MODY13), type 2 diabetes mellitus (T2DM), and hyperinsulinemic hypoglycemia. We report four patients with KCNJ11 gene mutations and provide a systematic review of the literature. A boy with diabetes onset at the age of 1 month was misdiagnosed as type 1 diabetes mellitus (T1DM) for 12 years and received insulin therapy continuously, resulting in poor glycemic control. He was diagnosed as NDM with KCNJ11 E322K gene mutation, and glibenclamide was given to replace exogenous insulin. The successful transfer time was 4 months, much longer than the previous unsuccessful standard of 4 weeks. The other three patients were two sisters and their mother; the younger sister was misdiagnosed with T1DM at 13 years old, while the elder sister was diagnosed with diabetes (type undefined) at 16 years old. They were treated with insulin for 3 years, with poor glycemic control. Their mother was diagnosed with T2DM and achieved good glycemia control with glimepiride. They were diagnosed as MODY13 because of the autosomal dominant inheritance of two generations, early onset of diabetes before 25 years of age in the two sisters, and the presence of the KCNJ11 N48D gene mutation. All patients successfully transferred to sulfonylureas with excellent glycemic control. Therefore, the wide spectrum of clinical phenotypes of glucose dysmetabolism caused by KCNJ11 should be recognized to reduce misdiagnosis and implement appropriate treatment.
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Affiliation(s)
- Binbin He
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Xia Li
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education; National Clinical Research Center for Metabolic Diseases, Changsha, China
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29
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Qin X, Zhong J, Lan D. The use of glimepiride for the treatment of neonatal diabetes mellitus caused by a novel mutation of the ABCC8 gene. J Pediatr Endocrinol Metab 2020; 33:1605-1608. [PMID: 33035187 DOI: 10.1515/jpem-2020-0030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 08/06/2020] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Neonatal diabetes mellitus (NDM) is a rare form of monogenic diabetes that is usually diagnosed in the first six months of life. CASE PRESENTATION We report on a male infant with neonatal diabetes who presented with diabetic ketoacidosis at two months and 16 days. A novel homozygous missense mutation (c.259T>G) was identified in the ABCC8 gene. In this case, insulin was replaced with glimepiride at a dosage of 0.49 mg/kg/day at five months, and this achieved metabolic control and satisfactory growth as observed at follow-up. CONCLUSIONS This report improves our understanding of the mutational spectrum of ABCC8, which is normally associated with NDM, and shows that the treatment regimen for this condition can be successfully switched from insulin therapy to the use of sulfonylurea.
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Affiliation(s)
- Xiao Qin
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Jingzi Zhong
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Dan Lan
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
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30
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Pipatpolkai T, Usher S, Stansfeld PJ, Ashcroft FM. New insights into K ATP channel gene mutations and neonatal diabetes mellitus. Nat Rev Endocrinol 2020; 16:378-393. [PMID: 32376986 DOI: 10.1038/s41574-020-0351-y] [Citation(s) in RCA: 78] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/17/2020] [Indexed: 12/12/2022]
Abstract
The ATP-sensitive potassium channel (KATP channel) couples blood levels of glucose to insulin secretion from pancreatic β-cells. KATP channel closure triggers a cascade of events that results in insulin release. Metabolically generated changes in the intracellular concentrations of adenosine nucleotides are integral to this regulation, with ATP and ADP closing the channel and MgATP and MgADP increasing channel activity. Activating mutations in the genes encoding either of the two types of KATP channel subunit (Kir6.2 and SUR1) result in neonatal diabetes mellitus, whereas loss-of-function mutations cause hyperinsulinaemic hypoglycaemia of infancy. Sulfonylurea and glinide drugs, which bind to SUR1, close the channel through a pathway independent of ATP and are now the primary therapy for neonatal diabetes mellitus caused by mutations in the genes encoding KATP channel subunits. Insight into the molecular details of drug and nucleotide regulation of channel activity has been illuminated by cryo-electron microscopy structures that reveal the atomic-level organization of the KATP channel complex. Here we review how these structures aid our understanding of how the various mutations in the genes encoding Kir6.2 (KCNJ11) and SUR1 (ABCC8) lead to a reduction in ATP inhibition and thereby neonatal diabetes mellitus. We also provide an update on known mutations and sulfonylurea therapy in neonatal diabetes mellitus.
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Affiliation(s)
- Tanadet Pipatpolkai
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
- Department of Biochemistry, University of Oxford, Oxford, UK
| | - Samuel Usher
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
| | - Phillip J Stansfeld
- Department of Biochemistry, University of Oxford, Oxford, UK
- School of Life Sciences, University of Warwick, Coventry, UK
- Department of Chemistry, University of Warwick, Coventry, UK
| | - Frances M Ashcroft
- Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
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31
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Torbjörnsdotter T, Marosvari‐Barna E, Henckel E, Corrias M, Norgren S, Janson A. Successful treatment of a cohort of infants with neonatal diabetes using insulin pumps including data on genetics and estimated incidence. Acta Paediatr 2020; 109:1131-1137. [PMID: 31746017 DOI: 10.1111/apa.15100] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 11/11/2019] [Accepted: 11/18/2019] [Indexed: 11/29/2022]
Abstract
AIM Neonatal diabetes is rare, and treatment is challenging. We present aspects on treatment, genetics and incidence. METHOD This was a prospective cohort study including all cases in our study area in Sweden. We compared with data from the National Diabetes Registry, the Neonatal Quality Register and the National Patient Register. RESULTS In the 19-year study period January 1, 1998 to December 31, 2016, we treated seven infants, five of them boys. Six patients used a subcutaneous insulin pump, and the smallest patient started at a weight of 938 g. Most important was for the pump to deliver minute doses of insulin and the design of cannulas and tubing. All patients could stop insulin treatment at 17-145 days of age. One patient relapsed at age 4.5 years. Four patients used the insulin pump after discharge. A mutation was identified in five patients, and this included all patients born after 30 weeks of gestation. The incidence of neonatal diabetes was 2/1 00 000, higher than previously estimated for Europe. Similar but lower incidences were reported in the registries. CONCLUSION Insulin pumps were safe in neonatal diabetes. All seven cases were transient. Neonatal diabetes was more common in our area than reported from Europe.
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Affiliation(s)
| | | | - Ewa Henckel
- Neonatal Intensive Care Unit Karolinska University Hospital Huddinge Sweden
- Division of Pediatrics Department of Clinical Science, Intervention and Technology Karolinska Institutet Huddinge Sweden
| | - Martino Corrias
- Neonatal Intensive Care Unit Karolinska University Hospital Huddinge Sweden
| | - Svante Norgren
- Pediatric Diabetes Unit Karolinska University Hospital Huddinge Sweden
- Division of Pediatric Endocrinology Department of Women´s and Children´s Health Karolinska Institutet Stockholm Sweden
| | - Annika Janson
- Pediatric Diabetes Unit Karolinska University Hospital Huddinge Sweden
- Division of Pediatric Endocrinology Department of Women´s and Children´s Health Karolinska Institutet Stockholm Sweden
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32
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Nicolaides NC, Kanaka-Gantenbein C, Papadopoulou-Marketou N, Sertedaki A, Chrousos GP, Papassotiriou I. Emerging technologies in pediatrics: the paradigm of neonatal diabetes mellitus. Crit Rev Clin Lab Sci 2020; 57:522-531. [PMID: 32356495 DOI: 10.1080/10408363.2020.1752141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
In the era of precision medicine, the tremendous progress in next-generation sequencing technologies has allowed the identification of an ever-increasing number of genes associated with known Mendelian disorders. Neonatal diabetes mellitus is a rare, genetically heterogeneous endocrine disorder diagnosed before 6 months of age. It may occur alone or in the context of genetic syndromes. Neonatal diabetes mellitus has been linked with genetic defects in at least 26 genes to date. Novel mutations in these disease-causing genes are being reported, giving us a better knowledge of the molecular events that occur upon insulin biosynthesis and secretion from the pancreatic β-cell. Of great importance, some of the identified genes encode proteins that can be therapeutically targeted by drugs per os, leading to transitioning from insulin to sulfonylureas. In this review, we provide an overview of pancreatic β-cell physiology, present the clinical manifestations and the genetic causes of the different forms of neonatal diabetes, and discuss the application of next-generation sequencing methods in the diagnosis and therapeutic management of neonatal diabetes and on research in this area.
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Affiliation(s)
- Nicolas C Nicolaides
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece.,Division of Endocrinology and Metabolism, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.,University Research Institute of Maternal and Child Health and Precision Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Christina Kanaka-Gantenbein
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - Nektaria Papadopoulou-Marketou
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - Amalia Sertedaki
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece
| | - George P Chrousos
- Division of Endocrinology, Metabolism and Diabetes, First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, "Aghia Sophia" Children's Hospital, Athens, Greece.,Division of Endocrinology and Metabolism, Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.,University Research Institute of Maternal and Child Health and Precision Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece
| | - Ioannis Papassotiriou
- Department of Clinical Biochemistry, "Aghia Sophia" Children's Hospital, Athens, Greece.,IFCC Emerging Technologies Division, Emerging Technologies in Pediatric Laboratory Medicine (C-ETPLM), Milano, Italy
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33
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De Franco E, Saint-Martin C, Brusgaard K, Knight Johnson AE, Aguilar-Bryan L, Bowman P, Arnoux JB, Larsen AR, Sanyoura M, Greeley SAW, Calzada-León R, Harman B, Houghton JAL, Nishimura-Meguro E, Laver TW, Ellard S, Del Gaudio D, Christesen HT, Bellanné-Chantelot C, Flanagan SE. Update of variants identified in the pancreatic β-cell K ATP channel genes KCNJ11 and ABCC8 in individuals with congenital hyperinsulinism and diabetes. Hum Mutat 2020; 41:884-905. [PMID: 32027066 PMCID: PMC7187370 DOI: 10.1002/humu.23995] [Citation(s) in RCA: 101] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 01/08/2020] [Accepted: 02/04/2020] [Indexed: 01/03/2023]
Abstract
The most common genetic cause of neonatal diabetes and hyperinsulinism is pathogenic variants in ABCC8 and KCNJ11. These genes encode the subunits of the β-cell ATP-sensitive potassium channel, a key component of the glucose-stimulated insulin secretion pathway. Mutations in the two genes cause dysregulated insulin secretion; inactivating mutations cause an oversecretion of insulin, leading to congenital hyperinsulinism, whereas activating mutations cause the opposing phenotype, diabetes. This review focuses on variants identified in ABCC8 and KCNJ11, the phenotypic spectrum and the treatment implications for individuals with pathogenic variants.
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Affiliation(s)
- Elisa De Franco
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Cécile Saint-Martin
- Department of Genetics, Pitié-Salpêtrière Hospital, AP-HP, Sorbonne University, Paris, France
| | - Klaus Brusgaard
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
| | - Amy E Knight Johnson
- Department of Human Genetics, University of Chicago Genetic Services Laboratory, The University of Chicago, Chicago, Illinois
| | | | - Pamela Bowman
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Jean-Baptiste Arnoux
- Reference Center for Inherited Metabolic Diseases, Necker-Enfants Malades Hospital, Paris, France
| | - Annette Rønholt Larsen
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark
| | - May Sanyoura
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, Kovler Diabetes Center, University of Chicago, Chicago, Illinois
| | - Siri Atma W Greeley
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, Kovler Diabetes Center, University of Chicago, Chicago, Illinois
| | - Raúl Calzada-León
- Pediatric Endocrinology, Endocrine Service, National Institute for Pediatrics, Mexico City, Mexico
| | - Bradley Harman
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Jayne A L Houghton
- Department of Molecular Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
| | - Elisa Nishimura-Meguro
- Department of Pediatric Endocrinology, Children's Hospital, National Medical Center XXI Century, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Thomas W Laver
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Sian Ellard
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.,Department of Molecular Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
| | - Daniela Del Gaudio
- Department of Human Genetics, University of Chicago Genetic Services Laboratory, The University of Chicago, Chicago, Illinois
| | - Henrik Thybo Christesen
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark.,Odense Pancreas Center, Odense University Hospital, Odense, Denmark
| | | | - Sarah E Flanagan
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
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Shidler KL, Letourneau LR, Novak LM. Uncommon Presentations of Diabetes: Zebras in the Herd. Clin Diabetes 2020; 38:78-92. [PMID: 31975755 PMCID: PMC6969666 DOI: 10.2337/cd19-0019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The majority of patients with diabetes are diagnosed as having either type 1 or type 2 diabetes. However, when encountered in clinical practice, some patients may not match the classic diagnostic criteria or expected clinical presentation for either type of the disease. Latent autoimmune, ketosis-prone, and monogenic diabetes are nonclassical forms of diabetes that are often misdiagnosed as either type 1 or type 2 diabetes. Recognizing the distinguishing clinical characteristics and understanding the diagnostic criteria for each will lead to appropriate treatment, facilitate personalized medicine, and improve patient outcomes.
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Affiliation(s)
- Karen L. Shidler
- North Central Indiana Area Health Education Center, Rochester, IN
| | | | - Lucia M. Novak
- Riverside Diabetes Center, Riverside Medical Associates, Riverdale, MD
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Abstract
Neonatal diabetes mellitus (DM) is defined by the onset of persistent hyperglycemia within the first six months of life but may present up to 12 months of life. A gene mutation affecting pancreatic beta cells or synthesis/secretion of insulin is present in more than 80% of the children with neonatal diabetes. Neonatal DM can be transient, permanent, or be a component of a syndrome. Genetic testing is important as a specific genetic mutation can significantly alter the treatment and outcome. Patients with mutations of either KCNJ11 or ABCC8 that encode subunits of the KATP channel gene mutation can be managed with sulfonylurea oral therapy while patients with other genetic mutations require insulin treatment.
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Affiliation(s)
- Amanda Dahl
- Division of Pediatric Endocrinology and Metabolism, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
| | - Seema Kumar
- Division of Pediatric Endocrinology and Metabolism, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
- Correspondence: Seema Kumar Division of Pediatric Endocrinology and Metabolism, Department of Pediatric and Adolescent Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN55590, USATel +1 507-284-3300Fax +1 507-284-0727 Email
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36
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Letourneau LR, Greeley SAW. Precision Medicine: Long-Term Treatment with Sulfonylureas in Patients with Neonatal Diabetes Due to KCNJ11 Mutations. Curr Diab Rep 2019; 19:52. [PMID: 31250216 PMCID: PMC6894166 DOI: 10.1007/s11892-019-1175-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
PURPOSE OF REVIEW The goal of this review is to provide updates on the safety and efficacy of long-term sulfonylurea use in patients with KCNJ11-related diabetes. Publications from 2004 to the present were reviewed with an emphasis on literature since 2014. RECENT FINDINGS Sulfonylureas, often taken at high doses, have now been utilized effectively in KCNJ11 patients for over 10 years. Mild-moderate hypoglycemia can occur, but in two studies with a combined 975 patient-years on sulfonylureas, no severe hypoglycemic events were reported. Improvements in neurodevelopment and motor function after transition to sulfonylureas continue to be described. Sulfonylureas continue to be an effective, sustainable, and safe treatment for KCNJ11-related diabetes. Ongoing follow-up of patients in research registries will allow for deeper understanding of the facilitators and barriers to long-term sustainability. Further understanding of the effect of sulfonylurea on long-term neurodevelopmental outcomes, and the potential for adjunctive therapies, is needed.
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Affiliation(s)
- Lisa R Letourneau
- Section of Pediatric and Adult Endocrinology, Diabetes, and Metabolism Kovler Diabetes Center, University of Chicago, 5841 S. Maryland Ave., MC1027-N235, Chicago, IL, 60637, USA
| | - Siri Atma W Greeley
- Section of Pediatric and Adult Endocrinology, Diabetes, and Metabolism Kovler Diabetes Center, University of Chicago, 5841 S. Maryland Ave., MC1027-N235, Chicago, IL, 60637, USA.
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37
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Ion Transporters, Channelopathies, and Glucose Disorders. Int J Mol Sci 2019; 20:ijms20102590. [PMID: 31137773 PMCID: PMC6566632 DOI: 10.3390/ijms20102590] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 05/21/2019] [Accepted: 05/22/2019] [Indexed: 01/19/2023] Open
Abstract
Ion channels and transporters play essential roles in excitable cells including cardiac, skeletal and smooth muscle cells, neurons, and endocrine cells. In pancreatic beta-cells, for example, potassium KATP channels link the metabolic signals generated inside the cell to changes in the beta-cell membrane potential, and ultimately regulate insulin secretion. Mutations in the genes encoding some ion transporter and channel proteins lead to disorders of glucose homeostasis (hyperinsulinaemic hypoglycaemia and different forms of diabetes mellitus). Pancreatic KATP, Non-KATP, and some calcium channelopathies and MCT1 transporter defects can lead to various forms of hyperinsulinaemic hypoglycaemia (HH). Mutations in the genes encoding the pancreatic KATP channels can also lead to different types of diabetes (including neonatal diabetes mellitus (NDM) and Maturity Onset Diabetes of the Young, MODY), and defects in the solute carrier family 2 member 2 (SLC2A2) leads to diabetes mellitus as part of the Fanconi–Bickel syndrome. Variants or polymorphisms in some ion channel genes and transporters have been reported in association with type 2 diabetes mellitus.
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38
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Chen X, Garon A, Wieder M, Houtman MJC, Zangerl-Plessl EM, Langer T, van der Heyden MAG, Stary-Weinzinger A. Computational Identification of Novel Kir6 Channel Inhibitors. Front Pharmacol 2019; 10:549. [PMID: 31178728 PMCID: PMC6543810 DOI: 10.3389/fphar.2019.00549] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Accepted: 05/01/2019] [Indexed: 12/25/2022] Open
Abstract
KATP channels consist of four Kir6.x pore-forming subunits and four regulatory sulfonylurea receptor (SUR) subunits. These channels couple the metabolic state of the cell to membrane excitability and play a key role in physiological processes such as insulin secretion in the pancreas, protection of cardiac muscle during ischemia and hypoxic vasodilation of arterial smooth muscle cells. Abnormal channel function resulting from inherited gain or loss-of-function mutations in either the Kir6.x and/or SUR subunits are associated with severe diseases such as neonatal diabetes, congenital hyperinsulinism, or Cantú syndrome (CS). CS is an ultra-rare genetic autosomal dominant disorder, caused by dominant gain-of-function mutations in SUR2A or Kir6.1 subunits. No specific pharmacotherapeutic treatment options are currently available for CS. Kir6 specific inhibitors could be beneficial for the development of novel drug therapies for CS, particular for mutations, which lack high affinity for sulfonylurea inhibitor glibenclamide. By applying a combination of computational methods including atomistic MD simulations, free energy calculations and pharmacophore modeling, we identified several novel Kir6.1 inhibitors, which might be possible candidates for drug repurposing. The in silico predictions were confirmed using inside/out patch-clamp analysis. Importantly, Cantú mutation C166S in Kir6.2 (equivalent to C176S in Kir6.1) and S1020P in SUR2A, retained high affinity toward the novel inhibitors. Summarizing, the inhibitors identified in this study might provide a starting point toward developing novel therapies for Cantú disease.
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Affiliation(s)
- Xingyu Chen
- Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
| | - Arthur Garon
- Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria
| | - Marcus Wieder
- Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria
| | - Marien J. C. Houtman
- Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands
| | | | - Thierry Langer
- Department of Pharmaceutical Chemistry, University of Vienna, Vienna, Austria
| | - Marcel A. G. van der Heyden
- Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria
- Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands
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39
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Ang SF, Tan CSH, Fong JCW, Lim SC. Precision medicine for a man presented with diabetes at 2-month old. Eur J Hum Genet 2019; 27:989-993. [PMID: 30890782 DOI: 10.1038/s41431-019-0371-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2018] [Revised: 01/31/2019] [Accepted: 02/16/2019] [Indexed: 10/27/2022] Open
Abstract
A 22-year-old man was referred for continuation of diabetes mellitus treatment. He was first diagnosed with diabetes mellitus 2 months after birth, when he failed to thrive and showed symptoms of diabetic ketoacidosis. There was no family history of diabetes mellitus. The patient did not exhibit the full set of features to be qualified for any developmental delay, epilepsy and neonatal diabetes mellitus (DEND) syndrome. Insulin replacement therapy was initiated; however, management was challenged by wide glycemic excursion, hypoglycemic unawareness and insulin-associated cutaneous lipo-hypertrophy. Re-evaluation, including genetic testing, revealed a heterozygous missense p.Arg201Cys variation in the KCNJ11 gene encoding the potassium channel subunit Kir6.2. Successful treatment conversion from insulin to glibenclamide was achieved over an extended period of 2 months (up-titrating to a dose of 1.0 mg/kg) in this patient despite his long diabetes duration of 27 years with elimination of hypoglycemia unawareness and achievement of excellent glycemic control sustained over more than 5 years. This case highlights the importance of after having secured a firm genetic diagnosis, to undertake conversion to sulphonylurea with careful dose titration and perseverance over months. Confirmation of variants with functional implications by genetic testing in patients suspected of neonatal diabetes is important for accurate molecular diagnosis and precision-treatment strategy with optimal outcome.
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Affiliation(s)
- Su Fen Ang
- Clinical Research Unit, Khoo Teck Puat Hospital (KTPH), Singapore, Singapore
| | - Clara Si Hua Tan
- Clinical Research Unit, Khoo Teck Puat Hospital (KTPH), Singapore, Singapore
| | | | - Su Chi Lim
- Clinical Research Unit, Khoo Teck Puat Hospital (KTPH), Singapore, Singapore. .,Diabetes Centre, , Khoo Teck Puat Hospital (KTPH), Singapore, Singapore. .,Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
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Abstract
PURPOSE OF REVIEW Monogenic forms of diabetes have specific treatments that differ from the standard care provided for type 1 and type 2 diabetes, making the appropriate diagnosis essential. In this review, we discuss current clinical challenges that remain, including improving case-finding strategies, particularly those that have transethnic applicability, and understanding the interpretation of genetic variants as pathogenic, with clinically meaningful impacts. RECENT FINDINGS Biomarker approaches to the stratification for genetic testing now appear to be most effective in identifying cases of monogenic diabetes, and use of genetic risk scores may also prove useful. However, applicability in all ethnic groups is lacking. Challenges remain in the classification of genes as diabetes-causing and the interpretation of genetic variants at the clinical interface. Since the discovery that genetic defects can cause neonatal or young-onset diabetes, multiple causal genes have been identified and there have been many advances in strategies to detect genetic forms of diabetes and their treatments. Approaches learnt from monogenic diabetes are now being translated to polygenic diabetes.
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Affiliation(s)
- Shivani Misra
- Diabetes, Endocrinology & Metabolism, Imperial College London, Ground Floor Medical School, St Mary’s Campus, Norfolk Place, London, W2 1PG UK
| | - Katharine R. Owen
- Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, OX3 7LJ UK
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41
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Hattersley AT, Greeley SAW, Polak M, Rubio-Cabezas O, Njølstad PR, Mlynarski W, Castano L, Carlsson A, Raile K, Chi DV, Ellard S, Craig ME. ISPAD Clinical Practice Consensus Guidelines 2018: The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes 2018; 19 Suppl 27:47-63. [PMID: 30225972 DOI: 10.1111/pedi.12772] [Citation(s) in RCA: 195] [Impact Index Per Article: 27.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2018] [Accepted: 08/07/2018] [Indexed: 02/06/2023] Open
Affiliation(s)
- Andrew T Hattersley
- Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, UK
| | - Siri A W Greeley
- The University of Chicago Medicine, Comer Children's Hospital, Chicago, Illinois
| | - Michel Polak
- Hôpital Universitaire Necker-Enfants Malades, Université Paris Descartes, Paris, France
| | - Oscar Rubio-Cabezas
- Department of Paediatric Endocrinology, Hospital Infantil Universitario Niño Jesús, Madrid, Spain
| | - Pål R Njølstad
- Department of Clinical Science, University of Bergen, Bergen, Norway.,Department of Pediatrics, Haukeland University Hospital, Bergen, Norway
| | - Wojciech Mlynarski
- Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland
| | - Luis Castano
- Endocrinology and Diabetes Research Group, BioCruces Health Research Institute, Cruces University Hospital, Barakaldo, Spain
| | - Annelie Carlsson
- Department of Clinical Sciences, Skåne University Hospital, Lund University, Lund, Sweden
| | - Klemens Raile
- Department of Paediatric Endocrinology and Diabetology, Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Dung V Chi
- Department of Endocrinology, Metabolism & Genetics, National Children's Hospital, Hanoi, Vietnam.,Department of Pediatrics, Hanoi Medical University, Hanoi, Vietnam
| | - Sian Ellard
- Institute of Biomedical and Clinical Sciences, University of Exeter Medical School, Exeter, UK
| | - Maria E Craig
- The Children's Hospital at Westmead and Discipline of Child Health and Adolescent Health, University of Sydney, Sydney, Australia.,School of Women's and Children's Health, University of New South Wales, Sydney, Australia
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42
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Chen T, Zhang D, Bai Z, Wu S, Wu H, Xie R, Li Y, Wang F, Chen X, Sun H, Wang X, Chen L. Successful Treatment of Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar Status in an Infant with KCNJ11-Related Neonatal Diabetes Mellitus via Continuous Renal Replacement Therapy. Diabetes Ther 2018; 9:2179-2184. [PMID: 30094785 PMCID: PMC6167281 DOI: 10.1007/s13300-018-0484-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2018] [Indexed: 12/20/2022] Open
Abstract
Neonatal diabetes mellitus (NDM) is a rare monogenic disorder presenting as uncontrolled hyperglycemia during the first 6 months of life. Hyperglycemic hyperosmolar state (HHS) is quite rare in NDM patients, and reported experience with this condition is limited. Continuous renal replacement therapy (CRRT) is frequently used as a mode of dialytic treatment in critically ill patients with acute renal failure, but has seldom been used in patients with diabetic ketoacidosis (DKA) and HHS. We report the case of a 2-month-old infant admitted to our hospital presenting with dyspnea and lethargy. Blood gas showed severe hyperosmotic DKA. After 21 h of fluid and insulin therapy, the baby presented with increased drowsiness and irregular respiration, which suggested cerebral edema. Moreover, the DKA and HHS were exacerbated. After 18 h of CRRT, the patient gradually recovered from DKA and HHS. The gene analysis revealed a de novo mutation (c.602G > A (p.R201H)) of the KCNJ11 gene, and oral glibenclamide successfully replaced insulin treatment in the patient.
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Affiliation(s)
- Ting Chen
- Department of Endocrinology, Metabolism and Genetic Disorders, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Dandan Zhang
- Department of Endocrinology, Metabolism and Genetic Disorders, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Zhenjiang Bai
- Department of Intensive Care Unit, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Shuiyan Wu
- Department of Intensive Care Unit, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Haiying Wu
- Department of Endocrinology, Metabolism and Genetic Disorders, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Rongrong Xie
- Department of Endocrinology, Metabolism and Genetic Disorders, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Ying Li
- Department of Intensive Care Unit, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Fengyun Wang
- Department of Endocrinology, Metabolism and Genetic Disorders, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Xiuli Chen
- Department of Endocrinology, Metabolism and Genetic Disorders, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Hui Sun
- Department of Endocrinology, Metabolism and Genetic Disorders, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Xiaoyan Wang
- Department of Endocrinology, Metabolism and Genetic Disorders, Children's Hospital of Soochow University, Suzhou, Jiangsu, China
| | - Linqi Chen
- Department of Endocrinology, Metabolism and Genetic Disorders, Children's Hospital of Soochow University, Suzhou, Jiangsu, China.
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43
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Ioacara S, Sava E, Barosan A, Cojocaru F, Gutan A, Fica S. To diet or not to diet in neonatal diabetes responding to sulfonylurea treatment. J Pediatr Endocrinol Metab 2018; 31:1053-1056. [PMID: 30016278 DOI: 10.1515/jpem-2017-0155] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Accepted: 06/18/2018] [Indexed: 11/15/2022]
Abstract
Background Neonatal diabetes mellitus (NDM) is defined as a monogenic form of diabetes that occurs in the first 6 months of life. As information on diet in NDM patients successfully treated with sulfonylurea is not yet available, we aimed to investigate the hypothesis that a carb-restricted diet is not needed in such cases. Case presentation In this case report, we present a successful implementation of a completely liberalized diet in a young patient with NDM, developmental delay and epilepsy (DEND syndrome), who was also switched to sulfonylurea treatment. The excellent metabolic control during follow-up despite completely ignoring any diet suggests that at least in some patients this approach might work. Conclusions If our proposed hypothesis is also confirmed by other reports, it might add significantly to the quality of life of these patients and broaden the knowledge in this medical field.
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Affiliation(s)
- Sorin Ioacara
- "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania.,"Elias" University Emergency Hospital, Bucharest, Romania
| | - Elisabeta Sava
- "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania.,"Elias" University Emergency Hospital, Bucharest, Romania
| | | | | | - Adelina Gutan
- "Elias" University Emergency Hospital, Bucharest, Romania
| | - Simona Fica
- "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania.,"Elias" University Emergency Hospital, Bucharest, Romania
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44
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Tinker A, Aziz Q, Li Y, Specterman M. ATP‐Sensitive Potassium Channels and Their Physiological and Pathophysiological Roles. Compr Physiol 2018; 8:1463-1511. [DOI: 10.1002/cphy.c170048] [Citation(s) in RCA: 72] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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45
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Breidbart E, Golden L, Gonzaga-Jauregui C, Deng L, Lanzano P, LeDuc C, Guo J, Overton JD, Reid J, Shuldiner A, Chung WK. KCNJ11 Mutation in One Family is Associated with Adult-Onset Rather than Neonatal-Onset Diabetes Mellitus. AACE Clin Case Rep 2018. [DOI: 10.4158/accr-2018-0007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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46
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Barbetti F, D'Annunzio G. Genetic causes and treatment of neonatal diabetes and early childhood diabetes. Best Pract Res Clin Endocrinol Metab 2018; 32:575-591. [PMID: 30086875 DOI: 10.1016/j.beem.2018.06.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Diabetes mellitus and impaired fasting glucose associated with single gene mutations are less rare than previously thought and may account for more than 6% of patients attending a pediatric diabetes clinic. The number of loci involved in monogenic diabetes exceed 25, and appropriate genetic diagnosis is crucial to direct therapy, for genetic counseling and for prognosis of short- and long-term complications. Among patients with neonatal diabetes (i.e. with onset within first 6 months of life) and patients with Maturity Onset Diabetes of the Young (MODY; an autosomal dominant form of diabetes), those carrying mutations in KCNJ11, ABCC8, HNF1A and HNF4A genes usually respond to oral therapy with sulphonylurea, while those bearing GCK mutations do not necessitate any treatment. Sensor-augmented continuous subcutaneous insulin infusion has been successfully employed in neonatal diabetes, and long-lasting effectiveness of sulfonylurea in KCNJ11 mutation carriers with neonatal diabetes well documented.
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Affiliation(s)
- Fabrizio Barbetti
- Department of Experimental Medicine and Surgery, University of Rome Tor Vergata, Via Montpellier, 100133 Rome, Italy; S. Pietro Fatebenefratelli Hospital, 00189 Rome, Italy.
| | - Giuseppe D'Annunzio
- Pediatric Clinic, Regional Center for Pediatric Diabetes, IRCCS Istituto Giannina Gaslini, Via Gaslini 5, 16147, Genoa, Italy.
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47
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Misra S, Vedovato N, Cliff E, De Franco E, Hattersley AT, Ashcroft FM, Oliver NS. Permanent neonatal diabetes: combining sulfonylureas with insulin may be an effective treatment. Diabet Med 2018; 35:1291-1296. [PMID: 29896782 DOI: 10.1111/dme.13758] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/11/2018] [Indexed: 10/14/2022]
Abstract
BACKGROUND Permanent neonatal diabetes caused by mutations in the KCNJ11 gene may be managed with high-dose sulfonylureas. Complete transfer to sulfonylureas is not successful in all cases and can result in insulin monotherapy. In such cases, the outcomes of combining sulfonylureas with insulin have not been fully explored. We present the case of a woman with diabetes due to a KCNJ11 mutation, in whom combination therapy led to clinically meaningful improvements. CASE A 22-year-old woman was found to have a KCNJ11 mutation (G334V) following diagnosis with diabetes at 3 weeks. She was treated with insulin-pump therapy, had hypoglycaemia unawareness and suboptimal glycaemic control. We assessed the in vitro response of the mutant channel to tolbutamide in Xenopus oocytes and undertook sulfonylurea dose-titration with C-peptide assessment and continuous glucose monitoring. In vitro studies predicted the G334V mutation would be sensitive to sulfonylurea therapy [91 ± 2% block (n = 6) with 0.5 mM tolbutamide]. C-peptide increased following a glibenclamide test dose (from 5 to 410 pmol/l). Glibenclamide dose-titration was undertaken: a lower glibenclamide dose did not reduce blood glucose levels, but at 1.2 mg/kg/day insulin delivery was reduced to 0.1 units/h. However, when insulin was stopped, hyperglycaemia ensued. Glibenclamide was further increased (2 mg/kg/day), but once-daily long-acting insulin was still required to maintain glycaemia. This resulted in improved HbA1c of 52 mmol/mol (6.9%), restoration of hypoglycaemia awareness and reduced glycaemic variability. CONCLUSION In people with KCNJ11 mutations causing permanent neonatal diabetes, and where complete transfer is not possible, consideration should be given to dual insulin and sulfonylurea therapy. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- S Misra
- Department of Diabetes, Endocrinology, Metabolism, Imperial College, London
| | - N Vedovato
- Department of Physiology, Anatomy& Genetics, Oxford University, Oxford
| | - E Cliff
- Department of Physiology, Anatomy& Genetics, Oxford University, Oxford
| | - E De Franco
- Department of Molecular Genetics, Royal Devon and Exeter NHS Foundation Trust
| | - A T Hattersley
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - F M Ashcroft
- Department of Physiology, Anatomy& Genetics, Oxford University, Oxford
| | - N S Oliver
- Department of Diabetes, Endocrinology, Metabolism, Imperial College, London
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48
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Letourneau LR, Greeley SAW. Congenital Diabetes: Comprehensive Genetic Testing Allows for Improved Diagnosis and Treatment of Diabetes and Other Associated Features. Curr Diab Rep 2018; 18:46. [PMID: 29896650 PMCID: PMC6341981 DOI: 10.1007/s11892-018-1016-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
PURPOSE OF REVIEW The goal of this review is to provide updates on congenital (neonatal) diabetes from 2011 to present, with an emphasis on publications from 2015 to present. RECENT FINDINGS There has been continued worldwide progress in uncovering the genetic causes of diabetes presenting within the first year of life, including the recognition of nine new causes since 2011. Management has continued to be refined based on underlying molecular cause, and longer-term experience has provided better understanding of the effectiveness, safety, and sustainability of treatment. Associated conditions have been further clarified, such as neurodevelopmental delays and pancreatic insufficiency, including a better appreciation for how these "secondary" conditions impact quality of life for patients and their families. While continued research is essential to understand all forms of congenital diabetes, these cases remain a compelling example of personalized genetic medicine.
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Affiliation(s)
- Lisa R Letourneau
- Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, Kovler Diabetes Center, The University of Chicago, MC 1027/N235; 5841 S. Maryland Ave., Chicago, IL, 60637, USA
| | - Siri Atma W Greeley
- Section of Adult and Pediatric Endocrinology, Diabetes and Metabolism, Kovler Diabetes Center, The University of Chicago, MC 1027/N235; 5841 S. Maryland Ave., Chicago, IL, 60637, USA.
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49
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Garcin L, Kariyawasam D, Busiah K, Fauret-Amsellem AL, Le Bourgeois F, Vaivre-Douret L, Cavé H, Polak M, Beltrand J. Successful off-label sulfonylurea treatment of neonatal diabetes mellitus due to chromosome 6 abnormalities. Pediatr Diabetes 2018; 19:663-669. [PMID: 29504184 DOI: 10.1111/pedi.12635] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Revised: 11/22/2017] [Accepted: 12/11/2017] [Indexed: 11/28/2022] Open
Abstract
Chromosome 6 abnormalities such as paternal uniparental isodisomy, paternal 6q24 duplication, and maternal DMR (differentially methylated region) hypomethylation are a common cause of transient neonatal diabetes mellitus (TNDM). Oral sulfonylurea (SU) is used off-label to treat permanent neonatal diabetes mellitus owing to potassium channel mutation but has not been evaluated in TNDM. Our objective was to evaluate the efficacy and safety of SU therapy in chromosome 6-related TNDM. Description of 3 case reports and literature review was the subject of the study. SU therapy was successful in 2 patients (initiated during neonatal life in 1 patient and during relapse in the other) but failed in the other despite the use of high dosage. The literature review identified 11 cases of patients with chromosome 6-related TNDM treated with SU, including 4 treated before remission and 7 after the relapse. SU therapy was consistently effective, although 4 patients treated after the relapse required multiple oral medications. None of the patients needed associated insulin therapy. No side effects of SU or complications of diabetes were reported. SU seems effective and safe in chromosome 6-related TNDM treatment when used to treat the initial episode of diabetes or the relapse. It improves patients' and families' quality of life. SU is available only as oral tablets. A pediatric dosage form would facilitate the treatment of neonates and infants.
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Affiliation(s)
- Laure Garcin
- Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, France
| | - Dulanjalee Kariyawasam
- Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, France.,Faculté de Médecine Paris Descartes, Université Sorbonne Paris Cité, Paris, France.,Inserm U1016, Institut Cochin, Paris, France
| | - Kanetee Busiah
- Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, France
| | - Anne-Laure Fauret-Amsellem
- Département de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Robert Debré, Paris, France
| | - Fleur Le Bourgeois
- Service de Réanimation et Surveillance Continues de Pédiatrie, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Robert Debré, Paris, France
| | - Laurence Vaivre-Douret
- Faculté de Médecine Paris Descartes, Université Sorbonne Paris Cité, Paris, France.,UMR 1018 INSERM-CESP, Universités Paris Sud-Paris Saclay UVSQ et Paris Descartes SPC, Paris, France.,Service de Pédiatrie, Hôpitaux Universitaires Paris Centre Port-Royal Cochin, Assistance Publique-Hôpitaux de Paris, et Hôpital Universitaire Necker Enfants Malades, Paris, France.,Institut Universitaire de France, Paris, France
| | - Hélène Cavé
- Département de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Universitaire Robert Debré, Paris, France.,Faculté de Médecine Paris-Diderot, Université Sorbonne-Paris-Cité, Paris, France
| | - Michel Polak
- Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, France.,Faculté de Médecine Paris Descartes, Université Sorbonne Paris Cité, Paris, France.,Inserm U1016, Institut Cochin, Paris, France.,Institut Imagine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France
| | - Jacques Beltrand
- Service Endocrinologie, Gynécologie et Diabétologie Pédiatrique, Hôpital Universitaire Necker Enfants Malades Paris, Assistance Publique-Hôpitaux de Paris, France.,Faculté de Médecine Paris Descartes, Université Sorbonne Paris Cité, Paris, France.,Inserm U1016, Institut Cochin, Paris, France.,Institut Imagine, Paris Descartes-Université Sorbonne Paris Cité, Paris, France
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50
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Ando A, Nagasaka S, Ishibashi S. A case with relapsed transient neonatal diabetes mellitus treated with sulfonylurea, ending chronic insulin requirement. Endocrinol Diabetes Metab Case Rep 2018; 2018:EDM180005. [PMID: 29675256 PMCID: PMC5900458 DOI: 10.1530/edm-18-0005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Accepted: 03/16/2018] [Indexed: 11/08/2022] Open
Abstract
Summary
We report a case of a woman with diabetes mellitus caused by a genetic defect in ABCC8-coding sulfonylurea receptor 1 (SUR1), a subunit of the ATP-sensitive potassium (KATP) channel protein. She was diagnosed with diabetes at 7 days after birth. After intravenous insulin drip for 1 month, her hyperglycaemia remitted. At the age of 13 years, her diabetes relapsed, and after that she had been treated by intensive insulin therapy for 25 years with relatively poor glycaemic control. She was switched to oral sulfonylurea therapy and attained euglycaemia. In addition, her insulin secretory capacity was ameliorated gradually.
Learning points:
Genetic testing should be considered in any individuals or family with diabetes that occurred within the first year or so of life.
Sulfonylurea can achieve good glycaemic control in patients with KATP channel mutations by restoring endogenous insulin secretion, even if they were treated with insulin for decades.
Early screening and genetic testing are important to improve the prognosis of patients with neonatal diabetes mellitus arising from ABCC8 or KCNJ11 mutation.
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Affiliation(s)
- Akihiko Ando
- 1Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan
| | - Shoichiro Nagasaka
- 1Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan
- 2Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Showa University Fujigaoka Hospital, Kanagawa Japan
| | - Shun Ishibashi
- 1Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan
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