GLP-1 Controls Pancreatic Endocrine Development

Glucagon-like peptide 1 (GLP-1) has been successfully leveraged as a treatment of type 2 diabetes mellitus. Its beneficial effects on β-cell growth and function are documented in the adult rodents but its role during pancreatic organogenesis remains unexplored. GLP-1 has numerous targets in vivo and has been shown to regulate key signaling pathways in β-cells. In the mature islets, GLP-1 modulates the MAPK and Akt signaling pathways, controls glucose sensing and responsiveness and increases Pdx-1 levels. All these processes are also known to be instrumental in the regulation of the proper growth, differentiation and maturation of the early endocrine progenitors. A few studies indirectly implied that GLP-1 could also have some impact on pancreatic organogenesis, promoting endocrine development in in vitro models. However, adult GLP-1 receptor (GLP-1R) knock out mice only display mild metabolic impairments mostly triggered by exposure to high-fat diet, but the phenotype of these animals had not been studied during early development. Using our total body knockout of the GLP-1 receptor, we found that total size of the pancreas of the newborn knocked-out animals appears to be reduced at birth and the β-cell mass is diminished by 89%. These results support that GLP-1R signaling is crucial for normal pancreatic development but that catch up growth can takes place between birth and adulthood to compensate for reduced GLP-1R signaling. These data illustrate that in addition to its insulinotropic effects in mature islets, GLP-1 signaling plays a central role during pancreatic development and the acquisition of a normal β-cell mass. Disclosure C.M.H. Cras-Meneur: None. R.J. Seeley: Research Support; Self; Novo Nordisk Inc., Novo Nordisk Inc., Ethicon US, LLC.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Research Support; Self; Zafgen, MedImmune. Consultant; Self; Kallyope, Scohia.