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Next Generation Sequencing Facilitating Quantitative Analysis of Wild Type (Kcnj11fl/fl, WT) and β-cell Specific Kcnj11 -/- (βKcnj11 -/-, bKO) Mouse Islets' Transcriptomes

ABSTRACT: β-cell Specific Kcnj11 -/- mice and their islets exhibited a hirtherto unkown switch in the major signaling pathway of G-protein coulpled receptors from Gs to Gq, and overall enhanced Gq signaling. That the phenomeno was also observed in their isolated islets, and that the genetic manipulation of the mice was only in the pancreatic beta-cells, we reasoned that peharps knockout of Kcnj11 in beta cells could result to a general change in the expression of genes related to G-protein coupled receptor signaling. Since New-Generation Sequencing (NGS) has revolutionized cellular based pathway analysis, we extracted total RNA from WT and bKO islets, performed NGS and compared global changes in the expression of genes between WT and bKO islets.

ORGANISM(S): Mus musculus

PROVIDER: GSE156917 | GEO | 2021/04/24

REPOSITORIES: GEO

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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.

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Next Generation Sequencing Facilitating Quantitative Analysis of Wild Type (Kcnj11fl/fl, WT) and β-cell Specific Kcnj11 -/- (βKcnj11 -/-, bKO) Mouse Islets' Transcriptomes

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