COLLOMBAT

The pancreas can be subdivided into two distinct structures: the exocrine and the endocrine tissues. The exocrine compartment secretes and transports digestive enzymes to the duodenum, whereas the endocrine tissue is organized into small clusters of cells termed islets of Langerhans. The latter contain four main different hormone-secreting cell subtypes: alpha-, beta-, delta-, and PP-cells producing glucagon, insulin, somatostatin, and pancreatic polypeptide (PP), respectively.

Both type I and type II diabetes conditions may ultimately result in pancreatic beta-cell loss and chronic hyperglycemia. While current therapies (insulin supplementation, transplantation) provide a measure of control of the glycemia, treated diabetic patients still display a shortened life expectancy and worsened quality of life as compared to their healthy counterparts.

Our research therefore aims at finding alternative ways to treat type 1 diabetes through the induction of beta-cell regeneration.

Using the mouse as a model, we have initially focused our research on the Arx and Pax4 transcription factors. Importantly, we demonstrated that :

- both factors control endocrine cell development during pancreas morphogenesis, Arx inducing the alpha-cell lineage, whereas Pax4 promotes the beta- and delta-cell fates.
- the forced expression of the Arx gene in adult beta-cells convert these into cells displaying an alpha- or PP-cell phenotype in vivo.
- the misexpression of Pax4 gene in embryonic (Collombat et al., Cell, 2009) or adult alpha-cells induces their continued regeneration and conversion into beta-like cells, such cells being able to reverse several rounds of chemically-induced diabetes in vivo.

Importantly, through a collaborative screening effort, we recently identified several chemical compounds of interest for diabetes research (Ben-Othman et al, Cell, 2017 - Li et al, Cell, 2017). Among these, GABA (γ-aminobutyric acid - a well know neurotransmitter also produced in the pancreas) was found able to induce alpha-cell-mediated beta-like cell neogenesis. Indeed, when provided to animals rendered diabetics, GABA could literally induce the regeneration of a functional beta-cell mass and thereby reverse the consequences of diabetes (multiple times) in vivo.

We are currently deciphering the genetic cascade underlying GABA signalling and running a pilot clinical trial aiming to determine whether GABA could potentially help diabetic patients.