title: 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.
authors.affiliation: Max Planck Institute of Psychiatry, Molecular Neuroendocrinology, Munich, Germany.
authors.forename: Anke
authors.initials: A
authors.lastname: Hoffmann
authors.forename: Dietmar
authors.initials: D
authors.lastname: Spengler
mesh_terms: D000818:Animals; D001483:Base Sequence; D001786:Blood Glucose / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology; D016381:Islets of Langerhans Transplantation; D000069450:Liraglutide; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D018027:Receptors, Glucagon / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology; D020666:ras-GRF1 / Q000235:genetics / Q000502:physiology*
chemical_list: D001786:Blood Glucose; D018797:Cell Cycle Proteins; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; C106464:PLAGL1 protein, human; C498423:Plagl1 protein, mouse; C513039:RASGRF1 protein, human; D034741:RNA, Small Interfering; C513037:Rasgrf1 protein, mouse; D018027:Receptors, Glucagon; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D020666:ras-GRF1; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D019869:Phosphatidylinositol 3-Kinases