Neonatal diabetes mellitus around the world: Update 2024

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Neonatal diabetes mellitus (NDM), defined as diabetes with an onset during the first 6 months of life, is a rare form of monogenic diabetes. The initial publications on this condition began appearing in the second half of the 1990s and quite surprisingly, the search for new NDM genes is still ongoing with great vigor. Between 2018 and early 2024, six brand new NDM‐genes have been discovered ( CNOT1, FICD, ONECUT1, PDIA6, YIPF5, ZNF808) and three genes known to cause different diseases were identified as NDM‐genes ( EIF2B1, NARS2, KCNMA1). In addition, NDM cases carrying mutations in three other genes known to give rise to diabetes during childhood have been also identified ( AGPAT2, BSCL2, PIK3R1). As a consequence, the list of NDM genes now exceeds 40. This genetic heterogeneity translates into many different mechanism(s) of disease that are being investigated with state‐of‐the‐art methodologies, such as induced pluripotent stem cells (iPSC) and human embryonic stem cells (hESC) manipulated with the CRISPR technique of genome editing. This diversity in genetic causes and the pathophysiology of diabetes dictate the need for a variety of therapeutic approaches. The aim of this paper is to provide an overview on recent achievements in all aspects of this area of research.

Abstract

Between 2018 and early 2024, six brand new NDM‐genes have been discovered and 3 genes known to cause different diseases were identified as NDM‐genes. Currently NDM genes' list exceeds forty.This genetic heterogeneity translates into many different mechanism(s) of disease that are investigated with state‐of‐the‐art methodologies, such as induced pluripotent stem cells (iPSC) manipulated with CRISPR technique of genome editing. This diversity in genetic causes and pathophysiology of diabetes dictate the need of a variety of therapeutic approaches.

Related collections

Most cited references 92

Record: found
Abstract: found
Article: found

Is Open Access

Insulin mutations impair beta-cell development in a patient-derived iPSC model of neonatal diabetes

Diego Balboa, Jonna Saarimäki-Vire, Daniel Borshagovski … (2018)

Insulin gene mutations are a leading cause of neonatal diabetes. They can lead to proinsulin misfolding and its retention in endoplasmic reticulum (ER). This results in increased ER-stress suggested to trigger beta-cell apoptosis. In humans, the mechanisms underlying beta-cell failure remain unclear. Here we show that misfolded proinsulin impairs developing beta-cell proliferation without increasing apoptosis. We generated induced pluripotent stem cells (iPSCs) from people carrying insulin (INS) mutations, engineered isogenic CRISPR-Cas9 mutation-corrected lines and differentiated them to beta-like cells. Single-cell RNA-sequencing analysis showed increased ER-stress and reduced proliferation in INS-mutant beta-like cells compared with corrected controls. Upon transplantation into mice, INS-mutant grafts presented reduced insulin secretion and aggravated ER-stress. Cell size, mTORC1 signaling, and respiratory chain subunits expression were all reduced in INS-mutant beta-like cells, yet apoptosis was not increased at any stage. Our results demonstrate that neonatal diabetes-associated INS-mutations lead to defective beta-cell mass expansion, contributing to diabetes development.

0 comments Cited 73 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis.

Intza Garin, Emma L Edghill, Ildem Akerman … (2010)

Heterozygous coding mutations in the INS gene that encodes preproinsulin were recently shown to be an important cause of permanent neonatal diabetes. These dominantly acting mutations prevent normal folding of proinsulin, which leads to beta-cell death through endoplasmic reticulum stress and apoptosis. We now report 10 different recessive INS mutations in 15 probands with neonatal diabetes. Functional studies showed that recessive mutations resulted in diabetes because of decreased insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, and altered mRNA stability because of the disruption of a polyadenylation signal. A subset of recessive mutations caused abnormal INS transcription, including the deletion of the C1 and E1 cis regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements. In keeping with an earlier and more severe beta-cell defect, patients with recessive INS mutations had a lower birth weight (-3.2 SD score vs. -2.0 SD score) and were diagnosed earlier (median 1 week vs. 10 weeks) compared to those with dominant INS mutations. Mutations in the insulin gene can therefore result in neonatal diabetes as a result of two contrasting pathogenic mechanisms. Moreover, the recessively inherited mutations provide a genetic demonstration of the essential role of multiple sequence elements that regulate the biosynthesis of insulin in man.

0 comments Cited 71 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: found

Is Open Access

Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study

Pamela Bowman, Åsta Sulen, Fabrizio Barbetti … (2018)

Summary Background KCNJ11 mutations cause permanent neonatal diabetes through pancreatic ATP-sensitive potassium channel activation. 90% of patients successfully transfer from insulin to oral sulfonylureas with excellent initial glycaemic control; however, whether this control is maintained in the long term is unclear. Sulfonylurea failure is seen in about 44% of people with type 2 diabetes after 5 years of treatment. Therefore, we did a 10-year multicentre follow-up study of a large international cohort of patients with KCNJ11 permanent neonatal diabetes to address the key questions relating to long-term efficacy and safety of sulfonylureas in these patients. Methods In this multicentre, international cohort study, all patients diagnosed with KCNJ11 permanent neonatal diabetes at five laboratories in Exeter (UK), Rome (Italy), Bergen (Norway), Paris (France), and Krakow (Poland), who transferred from insulin to oral sulfonylureas before Nov 30, 2006, were eligible for inclusion. Clinicians collected clinical characteristics and annual data relating to glycaemic control, sulfonylurea dose, severe hypoglycaemia, side-effects, diabetes complications, and growth. The main outcomes of interest were sulfonylurea failure, defined as permanent reintroduction of daily insulin, and metabolic control, specifically HbA1c and sulfonylurea dose. Neurological features associated with KCNJ11 permanent neonatal diabetes were also assessed. This study is registered with ClinicalTrials.gov, number NCT02624817. Findings 90 patients were identified as being eligible for inclusion and 81 were enrolled in the study and provided long-term (>5·5 years cut-off) outcome data. Median follow-up duration for the whole cohort was 10·2 years (IQR 9·3–10·8). At most recent follow-up (between Dec 1, 2012, and Oct 4, 2016), 75 (93%) of 81 participants remained on sulfonylurea therapy alone. Excellent glycaemic control was maintained for patients for whom we had paired data on HbA1c and sulfonylurea at all time points (ie, pre-transfer [for HbA1c], year 1, and most recent follow-up; n=64)—median HbA1c was 8·1% (IQR 7·2–9·2; 65·0 mmol/mol [55·2–77·1]) before transfer to sulfonylureas, 5·9% (5·4–6·5; 41·0 mmol/mol [35·5–47·5]; p<0·0001 vs pre-transfer) at 1 year, and 6·4% (5·9–7·3; 46·4 mmol/mol [41·0–56·3]; p<0·0001 vs year 1) at most recent follow-up (median 10·3 years [IQR 9·2–10·9]). In the same patients, median sulfonylurea dose at 1 year was 0·30 mg/kg per day (0·14–0·53) and at most recent follow-up visit was 0·23 mg/kg per day (0·12–0·41; p=0·03). No reports of severe hypoglycaemia were recorded in 809 patient-years of follow-up for the whole cohort (n=81). 11 (14%) patients reported mild, transient side-effects, but did not need to stop sulfonylurea therapy. Seven (9%) patients had microvascular complications; these patients had been taking insulin longer than those without complications (median age at transfer to sulfonylureas 20·5 years [IQR 10·5–24·0] vs 4·1 years [1·3–10·2]; p=0·0005). Initial improvement was noted following transfer to sulfonylureas in 18 (47%) of 38 patients with CNS features. After long-term therapy with sulfonylureas, CNS features were seen in 52 (64%) of 81 patients. Interpretation High-dose sulfonylurea therapy is an appropriate treatment for patients with KCNJ11 permanent neonatal diabetes from diagnosis. This therapy is safe and highly effective, maintaining excellent glycaemic control for at least 10 years. Funding Wellcome Trust, Diabetes UK, Royal Society, European Research Council, Norwegian Research Council, Kristian Gerhard Jebsen Foundation, Western Norway Regional Health Authority, Southern and Eastern Norway Regional Health Authority, Italian Ministry of Health, Aide aux Jeunes Diabetiques, Societe Francophone du Diabete, Ipsen, Slovak Research and Development Agency, and Research and Development Operational Programme funded by the European Regional Development Fund.

0 comments Cited 64 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Contributors

Fabrizio Barbetti:

ORCID: https://orcid.org/0000-0003-4687-980X

fabrizio.barbetti@uniroma2.it , mody.2@libero.it

Journal

Journal ID (nlm-ta): J Diabetes Investig

Journal ID (iso-abbrev): J Diabetes Investig

Journal ID (doi): 10.1111/(ISSN)2040-1124

Journal ID (publisher-id): JDI

Title: Journal of Diabetes Investigation

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Print): 2040-1116

ISSN (Electronic): 2040-1124

Publication date (Electronic): 30 September 2024

Publication date Collection: December 2024

Volume: 15

Issue: 12 ( doiID: 10.1111/jdi.v15.12 )

Pages: 1711-1724

Affiliations

[ ¹ ] Monogenic Diabetes Clinic, Endocrinology and Diabetes Unit Bambino Gesù Children's Hospital IRCCS Rome Italy

[ ² ] Pediatric Endocrine Division, Sheikh Shakhbout Medical City and College of Medicine and Health Science Khalifa University Abu Dhabi UAE

[ ³ ] Department of Pediatrics Asahikawa Medical University Asahikawa Japan

Author notes

[*] [* ] Correspondence

Fabrizio Barbetti

Tel.: +39 3473651265

E‐mail address: fabrizio.barbetti@ 123456uniroma2.it or mody.2@ 123456libero.it

Author information

Fabrizio Barbetti https://orcid.org/0000-0003-4687-980X

Asma Deeb https://orcid.org/0000-0003-4090-4672

Shigeru Suzuki https://orcid.org/0000-0002-5801-3088

Article

Publisher ID: JDI14312 Other ID: JDI-REV-2024-0480.R1

DOI: 10.1111/jdi.14312

PMC ID: 11615689

PubMed ID: 39344692

SO-VID: 4ae97398-6da5-46ba-8fdb-63b953f42eed

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

History

Date revision received : 22 August 2024

Date received : 05 August 2024

Date accepted : 29 August 2024

Page count

Figures: 2, Tables: 2, Pages: 14, Words: 11218

Funding

Funded by: JSPS KANKENHI

Award ID: JP18K07867

Funded by: Italian Ministry of Health , doi 10.13039/501100003196;

Custom metadata

source-schema-version-number 2.0

cover-date December 2024

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.5.1 mode:remove_FC converted:04.12.2024

Keywords: diabetes,mellitus,neonatal

Data availability:

Keywords: diabetes, mellitus, neonatal

Comments

Comment on this article

scite_

Smart Citations

Citing PublicationsSupportingMentioningContrasting

View Citations

See how this article has been cited at scite.ai

scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.

Most referenced authors 1,267

See all reference authors

- Version 1

Neonatal diabetes mellitus around the world: Update 2024

Read this article at

Abstract

Abstract

Related collections

Pediatric Pulse: Advancing Neonatal and Child Health

Most cited references 92

Insulin mutations impair beta-cell development in a patient-derived iPSC model of neonatal diabetes

Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis.

Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study

Author and article information

Contributors

Journal

Affiliations

Author notes

Author information

Article

History

Page count

Funding

Categories

Custom metadata

Comments

Comment on this article

Similar content 291

Most referenced authors 1,267