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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 ? cells are unknown. Here, we identified the guanine nucleotide exchange factor Rasgrf1 as a direct Zac1/Plagl1 target gene in murine ? 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 ? 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.

SUBMITTER: Hoffmann A

PROVIDER: S-EPMC3434484 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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

Hoffmann Anke A Spengler Dietmar D

Molecular and cellular biology 20120430 13

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 kin ...[more]

PMID: 22547676

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Project description:Dysregulation in expression of microRNAs (miRNAs) in various tissues has been linked to a wide spectrum of diseases, including Type 2 Diabetes mellitus (T2D). In this study, we compared the expression profiles of miRNAs in blood samples from Impaired Fasting Glucose (IFG) and T2D male patients with tissues from T2D rat models. Healthy adult males with no past history of T2D (n=158) and with desirable cholesterol and blood pressure profiles were enrolled in this study. They were then classified according to fasting glucose levels to have T2D, IFG or as healthy controls (CTL), for comparison of miRNA expression profiles. Employing miRNA microarray, we identified ‘signature miRNAs’ in peripheral blood samples that distinguished IFG and T2D. Eight selected miRNAs were further validated using stem-loop real-time RT-PCR. miR-144 expression was found to be dysregulated in Type 2 Diabetes, wherein its expression was significantly higher than in healthy controls. Insulin receptor substrate 1 (IRS1) has been predicted to be a potential target of miR-144. Consistent with this observation, IRS1 mRNA and protein levels, verified by quantitative real-time PCR and western blotting respectively, were found to be down-regulated. Using luciferase assay, we further demonstrated that miR-144 directly targets IRS1 and showed its effects on protein expression via immunocytochemistry. From this cross-sectional study in humans, we have identified signature miRNAs which could explain the pathogenesis of T2D. Whether miRNAs like miR-144 could be potential therapeutic targets for management of T2D will need to be explored by further mechanistic and functional studies. miRNA profiling of tissues from T2D rat models. Total RNA (plus miRNAs) was isolated using a modification of the RiboPure™-Blood kit from Ambion (Austin,TX) according to the manufacturer’s protocol. The concentration of total RNA and integrity were determined by using Nano-Drop ND-1000 Spectrophotometry (NanoDrop Tech, Rockland, Del) and gel electrophoresis respectively.

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

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

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