PROJET INDUCTION DES CELLULES B

Ce projet est porté par l’association Robert Debré pour la recherche médicale

CONTEXT

The pancreas plays a crucial role in nutritional homeostasis through the synthesis and secretion of hormones and enzymes. This organ includes three main tissue types: endocrine, acinar, and ductal cells. The exocrine pancreas is composed of acinar cells and a highly branched ductal epithelium, whereas endocrine cells are aggregated into islets of Langerhans. The latter correspond to specialized micro- organs consisting of four different cell subtypes, α-, b-, δ-, and PP cells, which produce the hormones glucagon, insulin, somatostatin, and PP (Pancreatic Polypeptide), respectively. Insulin and glucagon function coordinately to control glucose homeostasis, whereas somatostatin and PP regulate the secretion of other hormones and exocrine enzymes.

Diabetes is characterized by high blood glucose levels, which, in most cases, result from the inability of the pancreas to secrete sufficient amounts of insulin. While the autoimmune-mediated destruction of insulin-producing b-cells causes type 1 diabetes (T1D), type 2 diabetes (T2D) results from b-cell failure and eventual loss over time. Current treatments of diabetes fail to strictly restore normoglycemia and, in the case of T1D, even appear as rather palliative, replacing defective insulin secretion by exogenous insulin injections. Therefore, replenishing the pancreas with new functioning b-cells and/or maintaining the health of the remaining b-cells represent critical strategies for the treatment of both conditions. However, strategies aiming to restore new functional b-cells need to consider the underlying mechanisms of b-cell destruction or dysfunction and prevent diabetes recurrence. For T1D, any expansion of b-cells could trigger the autoimmune response responsible for their initial destruction and lead to the eventual loss of newly formed b-cells.

In this context, using the mouse as a model system, it was recently demonstrated that b-cell neogenesis can be forced using α-cells as a source. For instance, through the administration of GABA, it was shown that α-cells could be both regenerated and converted into b-like cells, such cells being able to reverse the consequences of chemically induced diabetes.

RESULTS

Building upon the previous results, we developed a bi-partite approach aiming at:

• Inducing α-cell-mediated b-like cell neogenesis using FDA-approved compound. Four hundred fifty compounds were thus screened for their ability to induce α-cell-mediated b-like cell conversion in a large number of conditions: five were found to be of high interest and are currently being validated in vivo with the eventual goals of testing them on human tissues and of gaining further insight into the molecular mechanisms involved.

• Assessing whether GABA can successfully counter autoimmune- mediated b-cell loss (as seen in T1D). Using animal models displaying an autoimmune-mediated attack of b-cells, we demonstrate that GABA significantly decreases diabetes incidence in two different genetic backgrounds, the NOD, and the YES mice. No differences were observed in the immune-cell phenotype in the periphery and pancreatic lymph node.

These experiments open the possibility that a treatment inducing the neoformation of b-cells may prevent the development of type 1 diabetes; whether it generates, a form of immune tolerance should be addressed.