Unknown,Transcriptomics,Genomics,Proteomics

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Integrative analysis of pathology, mRNA and microRNA in a polygenic diabetes model, NONcNZO10/LtJ mice

ABSTRACT: The NONcNZO10/LtJ mouse is a polygenic model of type-2 diabetes (T2D) that shows moderate obesity and diabetes, and is regarded as a good model reflective of the conditions of human T2D. In this study, we analyzed pathological changes of pancreases with the progress of time by using histopathology and gene expression analysis, including microRNA. A number of gene expression changes associated with decreased insulin secretion (possibly regulated by miR-29a/b) were observed, and zinc homeostasis (Slc30a8, Mt1 and Mt2) or glucose metabolism (Slc2a2) was suggested as being the candidate mechanism of pancreas failure in NONcNZO10/LtJ mice. These results demonstrate NONcNZO10/LtJ mice have a complex pathogenic mechanism of diabetes, and moreover, this fundamental information of NONcNZO10/LtJ mice would offer the opportunity for research and development of a novel antidiabetic drug. To identify the diabetes related genes that changed expression during the development of T2D in NONcNZO10/LtJ mice, we analyzed gene expression profiles of 7-, 13-, and 22-week old NONcNZO10/LtJ mice using GeneChip Mouse Gene 2.0 ST Arrays. On the other hand, we compared gene expression profiles of 7-week old NONcNZO10/LtJ mice with 7-week old NON/ShiLtJ mice to investigate the differences of gene expression before developing T2D. Furthermore, to validate the hypothesis generated by the results of mRNA analysis, we identified differentially expressed microRNAs in 13- and 22-week compared with 7-week old NONcNZO10/LtJ mice using Affymetrix miRNA GeneChip 3.0 Arrays.

ORGANISM(S): Mus musculus

SUBMITTER: Tsuyoshi Hirata

PROVIDER: E-GEOD-83241 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Relative beta cell deficit and increased beta cell apoptosis are hallmarks of type 2 diabetes (T2D). The Insulin/Insulin Growth Factor (Igf) signaling pathway is an established regulator of beta cell survival and is found downregulated in human T2D islets. The Insulin Receptor Substrate 2 (Irs2) plays a central role in the coordination of this pathway in beta cells. Thus, Irs2 knockout mice (Irs2 -/-) exhibit increased beta cell apoptosis that leads to a progressive decline of beta cell mass and hyperglycaemia. In this study, we sought to determine whether the anti-diabetic compound sodium tungstate could prevent the onset of diabetes in Irs2 -/- mice. Oral administration of tungstate resulted in an overall improvement in whole-body glucose tolerance in Irs2 -/- mice which correlated with increased beta cell mass. Enhanced beta cell mass was due to a dramatic reduction of beta cell apoptosis without changes in proliferation. Whole genome gene profiling analysis of islets isolated from treated Irs2 -/- mice confirmed a broad impact of tungstate on cell death pathways. Mechanistically, tungstate induced Erk1/2 phosphorylation in islets in vitro and, in agreement, treated Irs2 -/- islets exhibited increased basal Erk1/2 phosphorylation. Tungstate also downregulated expression of apoptosis-related genes in Irs2-/- islets in vitro, uncovering a direct effect of this compound in islets. All together, our data demonstrate that tungstate can restore beta cell mass and glucose homeostasis in a context of deficient Insulin/Igf signaling. This study underscores the importance of developing strategies specifically designed to arrest beta cell apoptosis as a means to prevent progressive beta cell failure in diabetes. 10-week old WT and Irs2 -/- mice were randomly divided into two treatment group, in a total of 4 experimental groups. For 21 days one group received distilled water as drinking water (untreated group) whilst the other received ad libitum a solution of 2mg/ml of sodium tungstate in distilled water (treated group). For each experimental group 2 independent samples were analysed, in a total of 8 samples.

Project description:The global prevalence of type 2 diabetes (T2D) is increasing, and it is contributing to the susceptibility to diabetes and its related epidemic in offspring. Although the impacts of paternal T2D on metabolism of offspring have been well established, the exact molecular and mechanistic basis that mediates these impacts remains largely unclear. Here we show that paternal T2D increases the susceptibility to diabetes in offspring through the gametic epigenetic alterations. Paternal T2D led to glucose intolerance and insulin resistance in offspring. Relative to controls, offspring of T2D fathers exhibited altered gene expression patterns in the pancreatic islets, with downregulation of several genes involved in glucose metabolism and insulin signaling pathway. Epigenomic profiling of offspring pancreatic islets revealed numerous changes in cytosine methylation depending on paternal T2D, including reproducible changes in methylation over several insulin signaling genes. Paternal T2D altered overall methylome patterns in sperm, with a large portion of differentially methylated genes overlapped with that of pancreatic islets in offspring. Our study revealed, for the first time, that T2D can be inherited transgenerationally through the mammalian germline by an epigenetic manner. For all comparisons shown, male F0 founders were weaned from mothers at 3 weeks of age, and sibling males were put into cages with high-fat diet (33% energy as fat) or control diet until 12 weeks of age, at which point mice fed with HFD were injected intraperitoneally with a low dose of STZ and kept on the same diet for 4 weeks. Fasting blood glucose was examined each week post-STZ for 4 weeks, and only glucose level at 7~11 mM was considered as type 2 diabetes. Females were always raised on standard diet. At 16 weeks, male F0 founders were mated with females. After 1 or 2 days, males were removed, and pregnant females were left alone until their litters were 3 weeks of age. Note that we always used virgin females to avoid confounding effects brought about by the females. At 3 weeks of age a portion of the offspring were sacrificed and islets were generated, each from an independent father.Samples from six control and six paternal type 2 diabetes offspring were chosen for microarray analysis.

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Integrative analysis of pathology, mRNA and microRNA in a polygenic diabetes model, NONcNZO10/LtJ mice

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