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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.

ORGANISM(S): synthetic construct Mus musculus

PROVIDER: GSE83241 | GEO | 2016/06/30

SECONDARY ACCESSION(S): PRJNA325351

REPOSITORIES: GEO

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

Project description: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.

2016-06-30 | E-GEOD-83241 | biostudies-arrayexpress

A Transcriptomic and Proteomic Atlas of Obesity and Type 2 Diabetes in Cynomolgus Monkeys

Project description:Obesity and type 2 diabetes (T2D) remain major global healthcare challenges and developing therapeutics necessitate using nonhuman primate models. Here, we present transcriptomic and proteomic analyses of all the major organs of cynomolgus monkeys with spontaneous obesity or T2D in comparison to healthy controls. Molecular changes occur predominantly in the adipose tissues of obesity individuals, while extensive expression perturbations of T2D individuals are observed in many tissues, such as liver, kidney, brain, and heart. Immune response-related pathways are upregulated in obesity and T2D, whereas metabolism and mitochondrial pathways are downregulated. Incorporating human single-cell RNA sequencing findings corroborates the role of macrophages and monocytes in obesity. Moreover, we highlight some potential therapeutic targets including SLC2A1 and PCSK1 in obesity as well as SLC30A8 and SLC2A2 in T2D. Our findings provide insights into the tissue-specific molecular foundations of obesity and T2D and reveal the mechanistic links between these two metabolic disorders.

2023-06-22 | GSE188418 | GEO

Comparison of gene expression in mouse placentas with different combination of MT1-MMP and MT2-MMP alleles

Project description:MT1-MMP and MT2-MMP double deficiency in mice leads to development of a placental defect resulting in embryonic death after E10.5. The protein substrate for these two proteases in placenta is unknown, which poses an obstacle in uncovering of molecular mechanism behind the observed placental defect. In search for a potential substrate for these two proteases in placenta we have employed whole genome microarray expression profiling as a discovery platform to identify genes, expression of which might be affected by double MMP deficiency. Fetal parts of mouse placentas were isolated from E10.5 placentas of different genotypes for MT1- and MT2-MMP.

2010-03-09 | E-GEOD-18604 | biostudies-arrayexpress

The genomic response of human granulosa cells (KGN) to melatonin and specific agonists/antagonists to the melatonin receptors

Project description:Melatonin is a known modulator of follicle development, it acts through several molecular cascades via binding to its two high-affinity, G-protein coupled receptors MT1 and MT2. Even though it is believed that melatonin can modulate granulosa cell (GC) functions, there is still limited knowledge of how it can act in human GC through MT1 and MT2 and which one is the major receptor implicated in the effects of melatonin on the metabolic processes in the dominant follicle. To better characterize the roles of the MT1 and MT2 receptors on the effects of melatonin on follicular atresia and the regulation of proliferation and differentiation of granulosa cells during the antral stage, human granulosa-like tumor cells (KGN) were treated with specific melatonin receptor agonists and antagonists, and gene expression was analyzed with RNA-seq technology. Following appropriate normalization and the application of a fold change cut-off of 1.5 (FC 1.5, p ≤ 0.05) for each treatment, lists of the principal differentially expressed genes (DEGs) are generated. Analysis of major upstream regulators suggested that the MT1 receptor may be involved in the melatonin antiproliferative effect by reprogramming the metabolism of human GC by activating the PKB signaling pathway. Our data suggest that melatonin may act complementary through both MT1 and MT2 receptors to modulate human GC steroidogenesis, proliferation, and differentiation. However, MT2 receptors may be the ones implicated in transducing the effects of melatonin on the prevention of GC luteinization and follicle atresia at the antral follicular stage through stimulating the PKA pathway.

2022-10-26 | GSE201943 | GEO

Transcription profiling of lung from wild type and Mt1(-/-)Mt2(-/-) double knock-out mice after nickel aerosol exposure for 3, 8, 24, 48, and 72 hrs

Project description:Wildtype and Mt1(-/-)Mt2(-/-) double knockout 129S1/SvImJ strain mouse lungs were compared in their response to nickel aerosol exposure at 3, 8, 24, 48, and 72 hrs.

2006-08-02 | E-MEXP-816 | biostudies-arrayexpress

Expression array of early postnatal Mt2-mmp-targeted mammary glands

Project description:Mammary gland branching morphogenesis is thought to depend on the mobilization of the membrane-anchored matrix metalloproteinases, MT1-MMP and MT2-MMP, that drive epithelial cell invasion by remodeling the extracellular matrix and triggering associated signaling cascades. However, the roles that these proteinases play during mammary gland development in vivo remains undefined. A mammary gland branching program that occurs during the first 10 days of early postnatal development was used to characterize the impact of global Mt1-mmp or Mt2-mmp targeting on mammary gland morphogenesis. Transcriptome profiling of ductal networks and associated stroma was used to investigate the functional roles of MT2-MMP in the early postnatal mammary gland in an unbiased fashion.

2016-10-05 | GSE77678 | GEO

Expression array of early postnatal Mt1-mmp-targeted mammary glands

Project description:Mammary gland branching morphogenesis is thought to depend on the mobilization of the membrane-anchored matrix metalloproteinases, MT1-MMP and MT2-MMP, that drive epithelial cell invasion by remodeling the extracellular matrix and triggering associated signaling cascades. However, the roles that these proteinases play during mammary gland development in vivo remains undefined. A mammary gland branching program that occurs during the first 10 days of early postnatal development was used to characterize the impact of global Mt1-mmp or Mt2-mmp targeting on mammary gland morphogenesis. Transcriptome profiling of ductal networks and associated stroma was used to investigate the functional roles of MT1-MMP in the early postnatal mammary gland in an unbiased fashion.

2016-10-05 | GSE77677 | GEO

Gene expression profile of isolated splenic NK cells from mice treated with ptaquiloside and/or selenium

Project description:To better understand the immunosuppressor mechanism of ptaquiloside in splenic NK cells and the reversion of this effect by selenium, we have employed whole genome microarray expression profile to identify genes associated with immunosuppression. Among 89 genes induced by ptaquiloside treatment in splenic NK cells only two genes (Mt1 and Mt2) were identified as related with its immunosuppressor effect. Moreover this augmented expression of Mt1 and Mt2 was totally abrogated by selenium co-treatment. These results were confirmed by flow cytometry in splenic cells harvested from other six mice and treated in vitro for 1 hour with ptaquiloside and/or selenium.

2013-07-24 | GSE30629 | GEO

Understanding the role of GLUT2 in dysglycemia associated with Fanconi-Bickel syndrome (RNA-Seq)

Project description:Fanconi–Bickel Syndrome (FBS) is a rare disorder of carbohydrate metabolism that is characterized by the accumulation of glycogen mainly in the liver. It is inherited in an autosomal recessive manner due to mutations in the SLC2A2 gene. SLC2A2 encodes for the glucose transporter GLUT2 and is expressed in tissues that are involved in glucose homeostasis. The molecular mechanisms of dysglycemia in FBS are still not clearly understood. In this study, we report two cases of FBS with classical phenotypes of FBS associated with dysglycemia. Genomic DNA was extracted and analyzed by whole-genome and Sanger sequencing, and patient PBMCs were used for molecular analysis. One patient had an exonic SLC2A2 mutation (c.1093C > T in exon 9, R365X), while the other patient had a novel intronic SLC2A2 mutation (c.613-7T>G). Surprisingly, the exonic mutation resulted in the overexpression of dysfunctional GLUT2, resulting in the dysregulated expression of other glucose transporters. The intronic mutation did not affect the coding sequence of GLUT2, its expression, or glucose transport activity. However, it was associated with the expression of miRNAs correlated with type 1 diabetes mellitus, with a particular significant overexpression of hsa-miR-29a-3p implicated in insulin production and secretion. Our findings suggest that SLC2A2 mutations cause dysglycemia in FBS either by a direct effect on GLUT2 expression and/or activity or, indirectly, by the dysregulated expression of miRNAs implicated in glucose homeostasis.

2022-09-28 | GSE198676 | GEO

Mice Harboring the Human SLC30A8 R138X Loss-of-Function Mutation Have Increased Insulin Secretory Capacity

Project description:SLC30A8 encodes a zinc transporter that is primarily expressed in the pancreatic islets of Langerhans. In beta-cells it transports zinc into insulin-containing secretory granules. Loss-of-function (LOF) mutations in SLC30A8 protect against type 2 diabetes in humans. In this study, we generated a mouse model carrying one of the most common human LOF mutations for SLC30A8, R138X. The R138X mice had normal body weight, glucose tolerance and pancreatic beta-cell mass. Interestingly, in hyperglycemic conditions induced by the insulin receptor antagonist S961, the R138X mice showed a 50% increase in insulin secretion. This effect was not associated with enhanced beta-cell proliferation or beta-cell mass. Our data suggest that the SLC30A8 R138X LOF mutation in humans may protect from type 2 diabetes in part by increasing the capacity of beta-cells to secrete insulin.

2018-11-01 | GSE114207 | GEO

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