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Molecular and cellular biology
Jul, 2012;32 (13): 2549-60.

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

Anke Hoffmann, Dietmar Spengler
Author Information
  1. Anke Hoffmann: Max Planck Institute of Psychiatry, Molecular Neuroendocrinology, Munich, Germany.
PMID: 22547676 DOI: 10.1128/MCB.06637-11

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.

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MeSH Term

Animals
Base Sequence
Blood Glucose
Cell Cycle Proteins
Cell Line
Diabetes Mellitus, Experimental
Genes, Tumor Suppressor
Glucagon-Like Peptide 1
Glucagon-Like Peptide-1 Receptor
Humans
Infant, Newborn
Insulin
Insulin Secretion
Insulin-Secreting Cells
Islets of Langerhans Transplantation
Liraglutide
MAP Kinase Signaling System
Male
Mice
Phosphatidylinositol 3-Kinases
RNA, Small Interfering
Receptors, Glucagon
Transcription Factors
Tumor Suppressor Proteins
ras-GRF1

Chemicals

Blood Glucose
Cell Cycle Proteins
GLP1R protein, human
Glp1r protein, mouse
Glucagon-Like Peptide-1 Receptor
Insulin
PLAGL1 protein, human
Plagl1 protein, mouse
RASGRF1 protein, human
RNA, Small Interfering
Rasgrf1 protein, mouse
Receptors, Glucagon
Transcription Factors
Tumor Suppressor Proteins
ras-GRF1
Liraglutide
Glucagon-Like Peptide 1
Phosphatidylinositol 3-Kinases
Journal Article Research Support, Non-U.S. Gov't

Word Cloud

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