Hoffmann A, Spengler D
Biallelic expression of the imprinted gene ZAC1/PLAGL1 underlies ∼60% of all cases of transient neonatal diabetes mellitus (TNDM) which present with low perinatal insulin secretion. Molecular targets of ZAC1 misexpression in pancreatic β-cells are so far unknown.Here, we identified the guanine nucleotide exchange factor Rasgrf1 as a direct Zac1/Plagl1 target gene in murine β-cells. Doubling Zac1 expression reduced Rasgrf1 expression, stimulus-induced activation of Mitogen-Activated Protein Kinase (MAPK) and Phosphoinositide 3-Kinase (PI3K) pathways and ultimately, insulin secretion. Normalizing Rasgrf1 expression reversed this phenotype. Moreover, transplantation of Zac1 overexpressing β-cells failed to reinstate euglycemia in experimental diabetic mice. In contrast, Zac1 expression did not interfere with signaling of the Glucagon-like Peptide-1 receptor (GLP-1R) and the GLP-1 analog liraglutide improved hyperglycemia in transplanted experimental diabetic mice. This study unravels a mechanism contributing to insufficient perinatal insulin secretion in TNDM and raises new prospects for therapy.