Diabetes Genetics

Our group is involved in understanding the molecular mechanisms underlying Diabetes. Both Type I Diabetes (insulinodependent) and Type II (non insulinodependent) diabetes ultimately result in the selective loss of insulin-producing beta-cells in the endocrine pancreas (Figure 1). The subsequent lack in insulin hormone induces a blood hyperglycemia that may be attenuated by daily injection of exogenous insulin hormone. Nevertheless, due to variations in glycemia, vascular damages, blindness, amputation or even death may occur.


Figure 1: Type I diabetes in mouse and human

Aiming to overcome these complications, the in vitro generation of pancreatic beta cells from stem or progenitor cells appears as a promising alternative. However, to design rational protocols that will allow the differentiation of beta cells, it is imperative to uncover the molecular determinant controlling their genesis.

Using the Mouse to study diabetes
We belong to a NIH-funded consortium whose goal is to gain further insight into the mechanisms regulating the genesis of the mouse pancreas and apply this knowledge to improve the treatment of diabetes in human. Toward this aim, we have identified two transcription factors, Arx and Pax4, playing a crucial role in the genesis of the different endocrine cell subtypes, including insulin-secreting beta-cells. Specifically, we demonstrated that Arx controls the development of alpha- and PP-cells, whereas Pax4 regulates the genesis of beta- and delta-cell (Animated Figure 2). Importantly, our latest results indicate that these factors are sufficient to literally transform adult alpha-cells into beta-cells and vice versa.


Figure 2: Diaporama auto-animé représentant les modifications du pancréas endocrine observées dans les animaux transgéniques pour Arx ou Pax4.

Generating beta-cells from other pancreatic cells
Building upon these findings, we recently discovered that duct cells can also be transformed into beta cells in vivo and that such cells can cure diabetes in mice. To further understand the genetic determinants implicated in these multiple conversions, we use transcriptome analysis, gain- and loss-of-function approaches and small molecule screens. This work is funded by Juvenile Diabetes research foundation and is performed in tight collaboration with the pharmaceutical company Novonordisk (Copenhagen-Denmark) and the Broad Institute of Harward and MIT (Boston-USA).


Figure 3

 

 

Last publications

Long-Term GABA Administration Induces Alpha Cell-Mediated Beta-like Cell Neogenesis. - 2017 - Cell - 168 P73-85.e11 - Ben-Othman N, Vieira A, Courtney M, Record F, Gjernes E, Avolio F, Hadzic B, Druelle N, Napolitano T, Navarro-Sanz S, Silvano S, Al-Hasani K, Pfeifer A, Lacas-Gervais S, Leuckx G, Marroquí L, Thévenet J, Madsen OD, Eizirik DL, Heimberg H, Kerr-Conte J, Pattou F, Mansouri A, and Collombat,P

Artemisinins Target GABAA Receptor Signaling and Impair alpha Cell Identity. - 2017 - Cell - 168 P86-100.e15 - Li J, Casteels T, Frogne T, Ingvorsen C, Honoré C, Courtney M, Huber KV, Schmitner N, Kimmel RA, Romanov RA, Sturtzel C, Lardeau CH, Klughammer J, Farlik M, Sdelci S, Vieira A, Avolio F, Briand F, Baburin I, Májek P, Pauler FM, Penz T, Stukalov A, Gridling M, Parapatics K, Barbieux C, Berishvili E, Spittler A, Colinge J, Bennett KL, Hering S, Sulpice T, Bock C, Distel M, Harkany T, Meyer D, Superti-Furga G, Collombat P, Hecksher-Sørensen J, and Kubicek,S

GABA triggers pancreatic beta-like cell neogenesis. - 2017 - Cell cycle (Georgetown, Tex.) - 16 P727-728 - Vieira A, Ben-Othman N, and Collombat,P

beta-Cell Replacement Strategies: The Increasing Need for a "beta-Cell Dogma". - 2017 - Frontiers in genetics - 8 P75 - Vieira A, Druelle N, Avolio F, Napolitano T, Navarro-Sanz S, Silvano S, and Collombat,P

Ectopic expression of Pax4 in pancreatic delta-cells results in beta-like cell neogenesis. - 2017 - The Journal of cell biology - Druelle N, Vieira A, Shabro A, Courtney M, Mondin M, Rekima S, Napolitano T, Silvano S, Navarro-Sanz S, Hadzic B, Avolio F, Rassoulzadegan M, Schmid HA, Mansouri A, and Collombat,P

GABA signaling stimulates alpha-cell-mediated beta-like cell neogenesis. - 2017 - Communicative & integrative biology - 10 Pe1300215 - Napolitano T, Avolio F, Vieira A, Ben-Othman N, Courtney M, Gjernes E, Hadzic B, Druelle N, Navarro Sanz S, Silvano S, Mansouri A, and Collombat,P

Pax6 Inactivation in the Adult Pancreas Reveals Ghrelin as Endocrine Cell Maturation Marker. - 2015 - PloS one - 10 Pe0144597 - Ahmad Z, Rafeeq M, Collombat P, and Mansouri,A

Pax4 acts as a key player in pancreas development and plasticity. - 2015 - Seminars in cell & developmental biology - Napolitano T, Avolio F, Courtney M, Vieira A, Druelle N, Ben-Othman N, Hadzic B, Navarro S, and Collombat,P

Embryonic stem cell-derived neural progenitors as non-tumorigenic source for dopaminergic neurons. - 2014 - World journal of stem cells - 6 P248-55 - Liao MC, Diaconu M, Monecke S, Collombat P, Timaeus C, Kuhlmann T, Paulus W, Trenkwalder C, Dressel R, and Mansouri,A

A genetic mouse model for progressive ablation and regeneration of insulin producing beta-cells. - 2014 - Cell cycle (Georgetown, Tex.) - 13 P3948-57 - Shamsi F, Parlato R, Collombat P, and Mansouri,A

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Collombat Patrick
Group Leader

2015 Prix Auguste Loubatières

2014 Prix G. B. Morgagni

2013 CG06 Medal

2013 A. Bouchardat Award

2013 FG de Santé Award

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Members Team
Postdocs
   Avolio Fabio
   Balaji Shruti
   Vieira Andhira
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   Garrido Utrilla Anna
   Napolitano Tiziana
   Silvano Serena
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   Navarro Sanz Sergi
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    May 2017 - P. Collombat Team
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    November 2015 - P. Collombat Team
   1 POST-DOC position 2 years   Closed

    October 2014 - P. Collombat Team
   1 CDD Technicien AI 3 ans   Closed

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