INGAP and the control of pancreatic B cell mass and function: transcriptional and epigenomic effects

ROMERO AGUSTÍN; ROMÁN, CAROLINA LISI; GAGLIARDINO, JUAN JOSÉ; MAIZTEGUI, BÁRBARA; FLORES, LUIS EMILIO; RODRÍGUEZ SEGUÍ, SANTIAGO A

Bariloche

Simposio; The Fourth South American Symposium in Signal Transduction and Molecular Medicine SISTAM2018; 2018

Diabetes Mellitus is a disease characterized by the loss or reduction of the pancreatic β cell mass, the consequent diminution of insulin production and the incapability of maintain glycaemia in a normal range. Nowadays, one of the most promising therapeutic treatments is trying to leverage the innate regenerative potential of the endocrine pancreas. A pancreatic protein, INGAP (homologous to REG3􀉶 in mouse)increases the β cells mass, vascular neogenesis and insulin secretion. The same effect is achieved with a pentadecapeptide, INGAP-PP, containing an inner sequence of INGAP. Here we will present our ongoing work to characterize the transcriptomic and epigenomic effects of INGAP-PP, as well as the potential effects of INGAP (and more widely REG3 proteins) in other regenerative settings of the pancreas.To profile the transcriptomic response of rat pancreatic islets to the INGAP-PPtreatment, we performed RNA-seq assays on INGAP-PP-treated-islets. Our preliminary results suggest that INGAP-PP activates pathways associated with GABA signaling and interacts with cells of the immune system, among others. In this context, INGAP-PP could reduce the immunoregulatory interactions between islet and lymphoid-cells, reducing the activation of cytokine-mediated pathways and leading the tissue regeneration through an anti-inflammatory environment.Interestingly, a re-analysis of public RNA-seq datasets, profiled in purified pancreatic cell populations throughout β cell development, revealed that the expression of genes coding for proteins of the REG3 family is strongly enhanced in 12-day postnatal β cells. This fact coincides with the expansion and maturation period of these cells, and suggests an important role of REG3 proteins during the neonatal period. Thus, the effects of the REG3/INGAP proteins might have more functions than initially expected, opening new avenues of research. Gaining further insights into the molecular mechanisms through which the INGAP-PP excerpts its effects is expected to help developing improved treatment strategies.