Transient Neonatal Diabetes Mellitus Gene Zac1 Impairs Insulin Secretion in Mice through Rasgrf1

Abstract

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.

SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.06637-11.

ACKNOWLEDGMENTS

We are thankful to Alexandre Patchev, Albin Varga, Guillaume Daniel, and Udo Schmidt for help in animal experiments and discussions. INS-1, Min6, and R7T1 β cells were kindly provided by Claes Wollheim (University of Geneva, Geneva, Switzerland), Sabine Senkel (University Duisburg-Essen, Essen, Germany), Jun-ichi Miyazaki (Osaka University, Osaka, Japan), Annette Schuermann (German Institute of Human Nutrition, Nuthetal, Germany), and Norman Fleischer (Albert Einstein College of Medicine, New York, New York). The Rasgrf1 promoter and cDNA were kindly provided by Paul Soloway (Cornell University, Ithaca, New York) and Renata Zippel (University of Milan, Milan, Italy).

This study was funded by the Deutsche Forschungsgemeinschaft (SP 386/5-1) to D.S.