INSERM/CNRS UMR 1283/8199 – University of Lille – Lille University Hospital – Pasteur Institute of Lille
Type 2 diabetes (T2D) and associated disorders, including obesity, have reached pandemic proportions worldwide and are leading causes of morbidity and mortality, becoming a major public health burden. T2D results from the progressive impairment of insulin secretion by pancreatic beta cells (within the islets) against a background of impaired insulin action in sensitive organs and tissues. Obesity is clinically defined as a body mass index (BMI) greater than 30 kg/m². The failure to fully understand the multi-organ systemic pathophysiology of T2D and obesity has frustrated efforts to develop improved therapeutic and preventive strategies. While the environment is the primary determinant of T2D and obesity at the population level, a notable feature is the persistence of a substantial risk of disease among people sharing the same environment. Type 2 diabetes (T2D) and obesity are complex polygenic disorders, with an estimated heritability of 40–70%. To date, through genome-wide association studies (GWAS), we and others have identified several hundred genes associated with susceptibility to the risk of T2D and BMI. However, the main challenge is that >90% of GWAS loci are located in intronic or intergenic non-coding regions, making it difficult to obtain functional and mechanistic information on how these DNA variants affect disease risk. The team's primary goal is to improve the care and disability-free life expectancy of patients with T2D and other metabolic disorders, including obesity, by identifying novel pathways involved in the pathophysiology leading to the discovery of new therapeutic targets, and by identifying and characterizing specific genetic variants leading to precision and, where possible, personalized medicine.
News
- Obesity is a complex, multifactorial disease. In fewer than 5% of obese individuals, there is a monogenic form of obesity where a single mutation is sufficient to cause the disease. Until now, the genes found to be mutated in these monogenic forms have been part of the leptin/melanocortin pathway, which is primarily active in the hypothalamus and regulates satiety. The laboratory recently described a new monogenic form of obesity due to a deficiency in the MRAP2 gene. Unlike previously described forms, carriers of this form present with hyperglycemia and hypertension, suggesting that MRAP2 plays a systemic biological role in metabolic tissues in addition to its role in the hypothalamus. This study was published in December 2019 in Nature Medicine.
- Genome-wide association studies (GWAS) have identified 240 loci associated with the risk of type 2 diabetes (T2D), but these findings have not improved patient management. In contrast, the diagnosis of monogenic forms of diabetes (including MODY) has become a textbook case for genomic medicine. Using next-generation DNA sequencing data from nearly 75,000 individuals, we demonstrated a significant association between pathogenic mutations located in actionable MODY genes (i.e., those associated with precision medicine) and an increased risk of T2D. None of the carriers reported developing diabetes before the age of 25 (the historical criterion for diagnosing MODY). Ultimately, the team showed that more than 2% of patients with "classic" type 2 diabetes actually carried pathogenic mutations in actionable MODY genes, paving the way for intervention studies in these carriers with treatment changes tailored to their mutation. This study was published in 2020 in Nature Metabolism.
Cross-functional projects
PreciDIAB was recognized by an international jury and awarded the label by the French National Center for Precision Diabetes Medicine in December 2019. This project is supported by the European Metropolis of Lille, Amiens Métropole, the Hauts-de-France Region, the French National Research Agency (ANR), and the European Union. PreciDIAB brings together multidisciplinary specialists, researchers, and clinicians with a common goal: to develop new methods of prevention, care, and treatment for diabetic patients in order to combat the disease and its consequences and offer diabetic patients a quality of life and life expectancy equal to that of non-diabetics. PreciDIAB combines programs aimed at preventing the incidence of diabetes, childhood obesity and their comorbidities, by targeting the highest risk populations in the general population and the most vulnerable among diabetic patients, with the overall objective of developing optimal precision medicine based on the stratification of patients according to the most advanced markers (biomarkers and lifestyle markers).
OπO stems from the long-forgotten correlation between opioid use and metabolic trait abnormalities. Opioids classically act through the delta opioid receptor (DOP, encoded by OPRD1), as well as kappa and mu opioid receptors. Based on our preliminary data, including large-scale human functional genetics of OPRD1 mutations, we hypothesize that DOP is a major link between opioids and metabolism in humans. Specifically, we propose that DOP and opioid signaling play a crucial, direct role in insulin secretion by pancreatic β cells, making DOP a promising new therapeutic target for type 2 diabetes.
Obelisk is a five-year research project, and our ambition is to prevent childhood obesity and contribute to improving the health, quality of life, and life expectancy of people of all ages living in Europe. Treating obese and overweight adults is known to be challenging, and prevention and treatment have proven to be more effective in younger age groups. Obelisk has an ambitious research program to prevent childhood obesity and "cut the roots" of the pandemic. The core concept behind Obelisk is dedicated to understanding, predicting, and preventing childhood obesity and providing precision medicine for those affected.
Obelisk's 4P approach involves the active participation of all stakeholders, including families, scientific and medical communities, daycare centers, schools, policymakers and industry, to stimulate social innovation and achieve successful outcomes.
Members
Amna Khamis
Tenure track researcher
Frederic ALLEGAERT
AI, Biobank
Souhila AMANZOUGARENE
IE, Bioinformatics
Pascale BENLIAN
MCU-PH CHU of Lille – Genetics of cardiovascular diseases
N. ORCID: 0000-0002-3423-8979Raphaël BOUTRY
AI, Sequencing Technique
Hélène DE GRAVE
IE, HR
Aurélie DECHAUME
IE, Sequencing Technique
Jérôme DELPLANQUE
IR Functional Genetics
Mehdi DERHOURHI
IR, Bioinformatics
Marc-Emmanuel DUMAS
CNRS Research Director – Metabolomics and Systems Biology
N. ORCID: 0000-0001-9523-7024Mélanie HOCQUET
Secretary, HR
Lise FOLON
post-doc
Stefan Gaget
IR Software Engineering
Corentin GIRARD
AI, ISO1589 Quality Unit
Nicolas KUREZOBA
Technician, Purchasing
Anne-Sophie LEDOUX
IE, Computer Science
Audrey LELOIRE
AI Functional Genetics
Constance LOISELLE
EGID Assistant
Hélène LOISELLE
AI, Sequencing Technique
Vincent MASSY
IE, Computer Science
Sarah MEULEBROUCK
IR Functional Genetics
Lisa MOCHON
IE Communication EGID
Louise MONTAGNE
MCU-PH GHICL – Childhood Obesity
Inga PROKOPENKO
Visiting Professor – Systems Biology in Diabetes and Associated Cancers
N. ORCID: 0000-0003-1624-7457Sadia SAEED
post-doc
Victoria Scherrer
Functional Genetics
Anne VAMBERGUE
Professor of Medicine, University Hospital of Lille – Diabetology (particularly gestational diabetes)
N. ORCID: 0000-0003-4307-8695Bénédicte TOUSSAINT
IE, Sequencing Technique
Emmanuel VAILLANT
IE, Sequencing Technique
Matthias VANDESQUILLE
PreciDiab Project Manager
Nicolas VANEECHOUTTE
IE, Computer Science
Vincent VATIN
AI Purchase
Ines CASTRO
post-doc
Timothée BEKE
AI Biobank
Emmanuel BUSE FALAY
IE Bioinformatics
Christophe BRETON
PU Univ Lille; Animal Physiology – Metabolism
Shuangshuang GENG
IE Biostatistics
Hélène DE GAVRE
IE Purchase
Audrey Deprince
PhD student
Maxime DESLANDE
PhD student
Marie Fernandes
PhD student, University of Lille
Marie FOURCOT
Research Engineer, University of Lille
Xavier MARECHAL
Engineer, technician, University
Lucas MAURIN
PhD student
Emma Henriques
IE Biostatistics
Lauriane LE COLLEN
post-doc
Frédérik OGER
IR Genomics
Romina PACHECO TAPIA
post-doc
Judith Merrheim
IR Functional Genetics – Animal Physiology
Jessica Montaigne
Animal Physiology Technician
Gilles PULVERMULLER
IR Valuation Manager
Naomie RAMPHFT
LIGAN service technician
Vincent PASCAT
PhD student
Francesc PUIG CASTELLVI
post-doc
Fritz-Line VELAYOUDOM
MCU-PH CHU Guadeloupe; Diabetology
Louane SEYS
IE NGS
Chaima TOUAIBI
PhD student
Zhaojie WANG
PhD student
Nawel ZAIBI
post-doc
Keywords
Team contact
Publications
Nat Metab. 2020 Oct;2(10):1126-1134.
Pathogenic variants in actionable MODY genes are associated with type 2 diabetes.
Nat Med. 2019 Nov;25(11):1733-1738.
Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension.
Nat Genet. 2018 Feb;50(2):175-179. doi:10.1038/s41588-017-0023-6.
Loss-of-function mutations in ADCY3 cause monogenic severe obesity.
Nat Genet. 2014 May;46(5):492-7.
Low copy number of the salivary amylase gene predisposes to obesity.
Nat Genet. 2013 Sep;45(9):1040-3.
