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

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

From pancreatic islet formation to beta-cell regeneration. - 2013 - Diabetes research and clinical practice - Ben-Othman N, Courtney M, Vieira A, Pfeifer A, Druelle N, Gjernes E, Faurite B, Avolio F, and Collombat,P

Adult duct-lining cells can reprogram into β-like cells able to counter repeated cycles of toxin-induced diabetes. - 2013 - Developmental cell - 26 P86-100 - Al-Hasani K, Pfeifer A, Courtney M, Ben-Othman N, Gjernes E, Vieira A, Druelle N, Avolio F, Ravassard P, Leuckx G, Lacas-Gervais S, Ambrosetti D, Benizri E, Hecksher-Sorensen J, Gounon P, Ferrer J, Gradwohl G, Heimberg H, Mansouri A, and Collombat,P

Gastrin: a distinct fate of neurogenin3 positive progenitor cells in the embryonic pancreas. - 2013 - PloS one - 8 Pe70397 - Suissa Y, Magenheim J, Stolovich-Rain M, Hija A, Collombat P, Mansouri A, Sussel L, Sosa-Pineda B, McCracken K, Wells JM, Heller RS, Dor Y, and Glaser,B

The inactivation of Arx in pancreatic α-cells triggers their neogenesis and conversion into functional β-like cells. - 2013 - PLoS genetics - 9 Pe1003934 - Courtney M, Gjernes E, Druelle N, Ravaud C, Vieira A, Ben-Othman N, Pfeifer A, Avolio F, Leuckx G, Lacas-Gervais S, Burel-Vandenbos F, Ambrosetti D, Hecksher-Sorensen J, Ravassard P, Heimberg H, Mansouri A, and Collombat,P

From pancreas morphogenesis to β-cell regeneration. - 2013 - Current topics in developmental biology - 106 P217-38 - Avolio F, Pfeifer A, Courtney M, Gjernes E, Ben-Othman N, Vieira A, Druelle N, Faurite B, and Collombat,P

Induction of multiple cycles of pancreatic β-cell replacement. - 2013 - Cell cycle (Georgetown, Tex.) - 12 P3243-4 - Pfeifer A, Courtney M, Ben-Othman N, Al-Hasani K, Gjernes E, Vieira A, Druelle N, Avolio F, Faurite B, Mansouri A, and Collombat,P

A regulatory path associated with X-linked intellectual disability and epilepsy links KDM5C to the polyalanine expansions in ARX. - 2013 - American journal of human genetics - 92 P114-25 - Poeta L, Fusco F, Drongitis D, Shoubridge C, Manganelli G, Filosa S, Paciolla M, Courtney M, Collombat P, Lioi MB, Gecz J, Ursini MV, and Miano,MG

The homeodomain-containing transcription factors Arx and Pax4 control enteroendocrine subtype specification in mice. - 2012 - PloS one - 7 Pe36449 - Beucher A, Gjernes E, Collin C, Courtney M, Meunier A, Collombat P, and Gradwohl,G

Generation of animals allowing the conditional inactivation of the Pax4 gene. - 2012 - Transgenic research - 21 P1215-20 - Kordowich S, Serup P, Collombat P, and Mansouri,A

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Collombat Patrick
Group Leader

2014 Prix G. B. Morgagni

2013 A. Bouchardat Award

2013 FG de Santé Award

2013 CG06 Medal

2011 ERC Starting Grant

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   Avolio Fabio
   Courtney Monica
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   Druelle Noémie
   Leclerc Justine
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   Vieira Andhira
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   Gjernes Elisabet
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