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Endothelial TFEB improves glucose intolerance via upregulation of IRS1 and IRS2

ABSTRACT: To determine whether endothelial TFEB is critical for glucose metabolism in vivo, we utilized EC-selective TFEB knockout mice and EC selective TFEB transgenic mice fed a high fat diet (HFD). EC-TFEB knockout mice exhibited significantly impaired glucose tolerance compared with control mice. Consistently, EC-TFEB transgenic mice showed improved glucose intolerance. In primary human ECs, small interfering RNA-mediated TFEB knockdown blunts the Akt signaling. adenovirus-mediated overexpression of TFEB consistently activates Akt signaling and significantly increases glucose uptake in ECs. Mechanically, TFEB upregulates insulin receptor substrate 1 and 2 (IRS1 and IRS2). TFEB increases IRS2 transcription measured by reporter gene and chromatin immunoprecipitation assays. Furthermore, we found that TFEB increases IRS1 protein via downregulation of microRNAs (miR-335, miR-495 and miR548o). In vivo, Akt signaling in the skeletal muscle and adipose tissue was significantly impaired in EC-TFEB knockout mice and consistently improved in EC-TFEB transgenic mice on HFD

ORGANISM(S): Homo sapiens

PROVIDER: GSE148026 | GEO | 2021/03/01

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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Endothelial TFEB improves glucose intolerance via upregulation of IRS1 and IRS2

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