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

ROMERO, AGUSTÍN; ROMÁN, CAROLINA L. ; GAGLIARDINO, JUAN J. ; MAIZTEGUI, BÁRBARA; FLORES, LUIS E.; RODRÍGUEZ SEGUÍ, S.A.

Bariloche

Simposio; Fourth South American Symposium in Signal Transduction and Molecular Medicine (SISTAM); 2018

International Union of Biochemistry and Molecular Biology (IUBMB).

DiabetesMellitus (DM) is a disease characterized by the lost or reduction ofthe pancreatic β cell mass and theconsequent diminution of insulin production. Nowadays, one of themost attractive therapeutic treatments is trying to leverage theinnate regenerative potential of the pancreas. A pancreatic protein,INGAP (homologous to REG3γin mouse) increases the β cell mass andthe insulin secretion. The same effect is achieved with apentadecapeptide, INGAP-PP, containing an inner sequence of INGAP.Here we will present our ongoing work to characterize thetranscriptomic and epigenomic effects of INGAP-PP, as well as thepotential effects of INGAP (and more widely REG3 proteins) in otherregenerative settings of the pancreas.Toprofile the transcriptomic response of rat pancreatic islets to theINGAP-PP treatment, we performed RNA-seq assays on rat pancreaticislets treated in vitrowith INGAP-PP. Our preliminary results suggest that the INGAP-PPactivates pathways associated with GABA signaling and interactionswith cells of the immune system,among others. In this context, INGAP-PPcould reduce the immunoregulatory interactions between islet- andlymphoid-cells, reducing the activation of cytokine-mediated pathwaysand leading the tissue regeneration through an anti-inflammatoryenvironment. Interestingly,a re-analysis of public RNA-seq datasets, profiled in purifiedpancreatic cell populations throughout β cell development, revealedthat the expression of genes coding for proteins of the REG3 familyis strongly enhanced in 12-day-postnatal βcells. This coincides with the expansion and maturation period ofthese cells, and suggests an important role of REG3 proteins duringthe neonatal period. Thus, the effects of the REG3/INGAP proteinsmight have more functions than initially expected, opening newavenues of research. Gaining furtherinsights into the molecular mechanisms through which the INGAP-PPexcerpts its effects is expected to help developing an improvedtreatment for diabetic patients.p { margin-bottom: 0.1in; direction: ltr; line-height: 115%; text-align: left; }a:link { color: rgb(0, 0, 255); }