학술논문
Dominant PDX1 deficiency causes highly penetrant diabetes at different ages, associated with obesity and exocrine pancreatic deficiency: Lessons for precision medicine.
Document Type
Academic Journal
Author
Kouidrat Y; Department of Rehabilitation, Nutrition and Obesity, Berck Maritime Hospital, Greater Paris University Hospitals, AP-HP, Berck, France.; Le Collen L; Inserm UMR1283, CNRS UMR8199, Pasteur Institute of Lille, European Genomic Institute for Diabetes, Université de Lille, Lille University Hospital, Cedex, Lille 59045, France; Department of Endocrinology Diabetology, University Hospital Center of Reims, Reims, France; Department of Clinical Genetic, University Hospital Center of Reims, Reims, France. Electronic address: laurianelecollen@wanadoo.fr.; Vaxillaire M; Inserm UMR1283, CNRS UMR8199, Pasteur Institute of Lille, European Genomic Institute for Diabetes, Université de Lille, Lille University Hospital, Cedex, Lille 59045, France; University of Lille, Lille University Hospital, Lille, France.; Dechaume A; Inserm UMR1283, CNRS UMR8199, Pasteur Institute of Lille, European Genomic Institute for Diabetes, Université de Lille, Lille University Hospital, Cedex, Lille 59045, France; University of Lille, Lille University Hospital, Lille, France.; Toussaint B; Inserm UMR1283, CNRS UMR8199, Pasteur Institute of Lille, European Genomic Institute for Diabetes, Université de Lille, Lille University Hospital, Cedex, Lille 59045, France; University of Lille, Lille University Hospital, Lille, France.; Vaillant E; Inserm UMR1283, CNRS UMR8199, Pasteur Institute of Lille, European Genomic Institute for Diabetes, Université de Lille, Lille University Hospital, Cedex, Lille 59045, France; University of Lille, Lille University Hospital, Lille, France.; Amanzougarene S; Inserm UMR1283, CNRS UMR8199, Pasteur Institute of Lille, European Genomic Institute for Diabetes, Université de Lille, Lille University Hospital, Cedex, Lille 59045, France; University of Lille, Lille University Hospital, Lille, France.; Derhourhi M; Inserm UMR1283, CNRS UMR8199, Pasteur Institute of Lille, European Genomic Institute for Diabetes, Université de Lille, Lille University Hospital, Cedex, Lille 59045, France; University of Lille, Lille University Hospital, Lille, France.; Delemer B; Department of Endocrinology Diabetology, University Hospital Center of Reims, Reims, France.; Azahaf M; Department of Radiology, Groupement des Hôpitaux de l'Institut Catholique de Lille, Saint Philibert Hospital, Lille, France.; Froguel P; Inserm UMR1283, CNRS UMR8199, Pasteur Institute of Lille, European Genomic Institute for Diabetes, Université de Lille, Lille University Hospital, Cedex, Lille 59045, France; University of Lille, Lille University Hospital, Lille, France; Department of Metabolism, Imperial College London, Hammersmith Hospital, London, UK. Electronic address: p.froguel@imperial.ac.uk.; Bonnefond A; Inserm UMR1283, CNRS UMR8199, Pasteur Institute of Lille, European Genomic Institute for Diabetes, Université de Lille, Lille University Hospital, Cedex, Lille 59045, France; University of Lille, Lille University Hospital, Lille, France; Department of Metabolism, Imperial College London, Hammersmith Hospital, London, UK. Electronic address: amelie.bonnefond@inserm.fr.
Source
Publisher: Masson Country of Publication: France NLM ID: 9607599 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-1780 (Electronic) Linking ISSN: 12623636 NLM ISO Abbreviation: Diabetes Metab Subsets: MEDLINE
Subject
Language
English
Abstract
Objective: Heterozygous pathogenic or likely pathogenic (P/LP) PDX1 variants cause monogenic diabetes. We comprehensively examined the phenotypes of carriers of P/LP PDX1 variants, and delineated potential treatments that could be efficient in an objective of precision medicine.
Methods: The study primarily involved a family harboring a novel P/LP PDX1 variant. We then conducted an analysis of documented carriers of P/LP PDX1 variants, from the Human Gene Mutation Database (HGMD), RaDiO study, and Type 2 Diabetes Knowledge Portal (T2DKP) including 87 K participants.
Results: Within the family, we identified a P/LP PDX1 variant encoding p.G232S in four relatives. All of them exhibited diabetes, albeit with very different ages of onset (10-40 years), along with caudal pancreatic agenesis and childhood-onset obesity. In the HGMD, 79 % of carriers of a P/LP PDX1 variant displayed diabetes (with differing ages of onset from eight days of life to 67 years), 63 % exhibited pancreatic insufficiency and surprisingly 40 % had obesity. The impact of P/LP PDX1 variants on increased risk of type 2 diabetes mellitus was confirmed in the T2DKP. Dipeptidyl peptidase 4 inhibitor (DPP4i) and glucagon-like peptide-1 receptor agonist (GLP1-RA), enabled good glucose control without hypoglycemia and weight management.
Conclusions: This study reveals diverse clinical presentations among the carriers of a P/LP PDX1 variant, highlighting strong variations in diabetes onset, and unexpectedly high prevalence of obesity and pancreatic development abnormalities. Clinical data suggest that DPP4i and GLP1-RA may be the best effective treatments to manage both glucose and weight controls, opening new avenue in precision diabetic medicine.
Competing Interests: Declaration of competing interest Authors declare that they have no competing interests.
(Copyright © 2023 Elsevier Masson SAS. All rights reserved.)
Methods: The study primarily involved a family harboring a novel P/LP PDX1 variant. We then conducted an analysis of documented carriers of P/LP PDX1 variants, from the Human Gene Mutation Database (HGMD), RaDiO study, and Type 2 Diabetes Knowledge Portal (T2DKP) including 87 K participants.
Results: Within the family, we identified a P/LP PDX1 variant encoding p.G232S in four relatives. All of them exhibited diabetes, albeit with very different ages of onset (10-40 years), along with caudal pancreatic agenesis and childhood-onset obesity. In the HGMD, 79 % of carriers of a P/LP PDX1 variant displayed diabetes (with differing ages of onset from eight days of life to 67 years), 63 % exhibited pancreatic insufficiency and surprisingly 40 % had obesity. The impact of P/LP PDX1 variants on increased risk of type 2 diabetes mellitus was confirmed in the T2DKP. Dipeptidyl peptidase 4 inhibitor (DPP4i) and glucagon-like peptide-1 receptor agonist (GLP1-RA), enabled good glucose control without hypoglycemia and weight management.
Conclusions: This study reveals diverse clinical presentations among the carriers of a P/LP PDX1 variant, highlighting strong variations in diabetes onset, and unexpectedly high prevalence of obesity and pancreatic development abnormalities. Clinical data suggest that DPP4i and GLP1-RA may be the best effective treatments to manage both glucose and weight controls, opening new avenue in precision diabetic medicine.
Competing Interests: Declaration of competing interest Authors declare that they have no competing interests.
(Copyright © 2023 Elsevier Masson SAS. All rights reserved.)