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Mol Cell Biol. 2012 Jul;32(13):2549-60. doi: 10.1128/MCB.06637-11. Epub 2012 Apr 30.

Transient neonatal diabetes mellitus gene Zac1 impairs insulin secretion in mice through Rasgrf1.

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Max Planck Institute of Psychiatry, Molecular Neuroendocrinology, Munich, Germany.


The biallelic expression of the imprinted gene ZAC1/PLAGL1 underlies ≈ 60% of all cases of transient neonatal diabetes mellitus (TNDM) that present with low perinatal insulin secretion. Molecular targets of ZAC1 misexpression in pancreatic β cells are 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, the 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, the transplantation of Zac1-overexpressing β cells failed to reinstate euglycemia in experimental diabetic mice. In contrast, Zac1 expression did not interfere with the 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.

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