AccueilAccueil>La recherche>Les équipes>Nicolas VENTECLEF

Nicolas VENTECLEF

 

 

 Métabolic inflammation in Diabetes and its complications
(MiDiab Team)

 

 

 

The increased incidence of diabetes worldwide has greatly augmented the risk for numerous associated complications that lead to reduced quality of life and increased mortality. A high percentage of patients with T2D develop micro-vascular complications (53.5 %) such as diabetic retinopathy, nephropathy and neuropathy, as well as life-threatening macro-vascular diseases (27.3 %) such as atherosclerosis, stroke and hypertension. Interestingly, all of these complications are associated with inflammation, which is characterized at the tissue and systemic levels by activation of immune cells and more particularly resident macrophages and blood monocytes. Indeed, macrophages and monocytes are responsible for sensing, integrating, and responding to a myriad of stimuli in their microenvironment. Persistence or abnormal activation of macrophages or monocytes might contribute to pathogenesis of T2D and its complications linked to inflammation such as nephropathy, cardiovascular events and retinopathy. Although inflammation is not a disease in itself, a better understanding of the mechanisms linking inflammation and T2D pathogenesis and progression is nevertheless crucial for the prevention and the development of new, efficient, and personalized therapeutic approaches.
It is increasingly evident that, because of the influences of gene-environment interactions, epigenetic mechanisms may also play a key role in the pathogenesis of diabetes and of its vascular complications. Our recent studies, proposed that epigenetic mechanisms are involved in pathogenesis of diabetes and of its complications trough the modulation of the immune response. The epigenetic regulatory machinery is highly responsive to metabolic cues, as, for example, key metabolites are the substrates for the enzymes that catalyze the deposition of covalent modifications on histones, DNA and RNA.
The main focus of our team is to identify relevant epigenemic  and metabolic pathways that control macrophage responsiveness influencing T2D pathogenesis and its vascular and liver complications. We believe that metabolic pathways may drive aberrant epigenetic marks, provoking abnormal activation of macrophages.
To reach our aims, we are developing large-scale approaches using innovative bioinformatics and complex system modeling tools. Investigations are carried out in well-phenotyped diabetic subjects with vascular complications and at various disease stages, from whom clinical datasets and biobanks are being constructed. This strategy generates hypotheses of putative novel cellular and molecular pathophysiological actors, which are then tested through in vitro and ex vivo modeling and in various in vivo models (genetically modified mice, targeted knockouts, diet-induced obesity and T2D models). Very active recruitment of new patient cohorts, lead by clinical team members, allows the efficient return from bench-to-bedside, testing back hypotheses driven by the in vitro and in vivo models.

Websites:

MiDiab.com (To be created)

http://hopital-lariboisiere.aphp.fr/plus-de-details-sur-les-services-de-soins/diabetologie-centre-du-diabete-de-ses-complications/

 

Team Leader : Nicolas VENTECLEF (DR INSERM)

Team Members : GAUTIER Jean-François (PU-PH), RIVELINE Jean-Pierre (PU-PH), ALZAID Fawaz (CR INSERM),   
BALLAIRE Raphaëlle (IE CDD), EJLALMANESH Tina (AI CDD), KONDILI Maria (IE CDD),  DALMAS Elise (Post-doc), DRARENI Karima (Doc.), FANIDI Anouar (Post-doc), JULLA Jean-Baptiste (Doc.), MATHEW J Mano (Post-doc), ORLIAGUET Lucie (Doc.)

Administration :    Valérie RESVE

Contact details : 33 1 44 27 63 93 / Fax : 33 1 44 27 64 21

Selected Publications

  • Alzaid F, Lagadec F, Albuquerque M, Ballaire R, Orliaguet L, Hainault I, Blugeon C, Lemoine S, Lehuen A, Saliba DG, Udalova IA, Paradis V, Foufelle F, Venteclef N. IRF5 governs liver macrophage activation that promotes hepatic fibrosis in mice and humans. JCI Insight. 2016 Dec 8;1(20):e88689. PubMed PMID:27942586; PubMed Central PMCID: PMC5135279.
  • Fan R, Toubal A, Goñi S, Drareni K, Huang Z, Alzaid F, Ballaire R, Ancel P, Liang N, Damdimopoulos A, Hainault I, Soprani A, Aron-Wisnewsky J, Foufelle F, Lawrence T, Gautier JF, Treuter E* and Venteclef N*. Loss of the co-repressor GPS2 sensitizes macrophage activation upon metabolic stress induced by obesity and type 2 diabetes. Nat Med. 2016 Jul;22(7):780-91. doi: 10.1038/nm.4114. Epub 2016 Jun 6. PubMed PMID: 27270589. (*Co-corresponding authors)
  • Dalmas E, Toubal A, Alzaid F, Blazek K, Eames HL, Lebozec K, Pini M, Hainault  I, Montastier E, Denis RG, Ancel P, Lacombe A, Ling Y, Allatif O, Cruciani-Guglielmacci C, André S, Viguerie N, Poitou C, Stich V, Torcivia A, Foufelle F, Luquet S, Aron-Wisnewsky J, Langin D, Clément K, Udalova IA, Venteclef N. Irf5 deficiency in macrophages promotes beneficial adipose tissue expansion and insulin sensitivity during obesity. Nat Med. 2015 Jun;21(6):610-8.  doi: 10.1038/nm.3829. Epub 2015 May 4. PubMed PMID: 25939064.
  • Dos Santos RS, Daures M, Philippi A, Romero S, Marselli L, Marchetti P, Senée  V, Bacq D, Besse C, Baz B, Marroquí L, Ivanoff S, Masliah-Planchon J, Nicolino M, Soulier J, Socié G, Eizirik DL, Gautier JF*, Julier C*. dUTPase (DUT) Is Mutated in a Novel Monogenic Syndrome With Diabetes and Bone Marrow Failure. Diabetes. 2017  Apr;66(4):1086-1096. doi: 10.2337/db16-0839. Epub 2017 Jan 10. PubMed PMID:28073829. (*Co-corresponding authors)
  • Gautier JF, Porcher R, Abi Khalil C, Bellili-Munoz N, Fetita LS, Travert F, Choukem SP, Riveline JP, Hadjadj S, Larger E, Boudou P, Blondeau B, Roussel R, Ferré P, Ravussin E, Rouzet F, Marre M. Kidney Dysfunction in Adult Offspring Exposed In Utero to Type 1 Diabetes Is Associated with Alterations in Genome-Wide DNA Methylation. PLoS One. 2015 Aug 10;10(8):e0134654. doi: 10.1371/journal.pone.0134654. eCollection 2015. PubMed PMID: 26258530; PubMed Central PMCID: PMC4530883.

Link to PubMed

 

Les Outils