Viswambharan, H orcid.org/0000-0002-7616-5026, Yuldasheva, NY, Imrie, H et al. (22 more authors) (2021) Novel Paracrine Action of Endothelium enhances Glucose Uptake in Muscle and Fat. Circulation Research. ISSN 0009-7330
Abstract
Rationale: A hallmark of type 2 diabetes is insulin resistance, which leads to increased endothelial cell production of superoxide and a simultaneous reduction in availability of the vasoprotective signalling radical, nitric oxide (NO). We recently demonstrated in preclinical models that type 2 diabetes simultaneously causes resistance to insulin like growth factor-1 (IGF-1) mediated glucose lowering and endothelial NO release.
Objective: To examine the effect of insulin and IGF-1 resistance specifically in endothelial cells in vivo.
Methods and Results: We generated mice expressing mutant IGF-1 receptors (mIGF-1R), which form non-functioning hybrid receptors with native insulin receptors (IR) and IGF-1R, directed to endothelial cells under control of the Tie2 promoter-enhancer. Despite endothelial cell insulin and IGF-1 resistance, mutant IGF-1R endothelial cell over-expressing mice (mIGFREO) had enhanced insulin and IGF-1 mediated systemic glucose disposal, lower fasting free fatty acids and triglycerides. In hyperinsulinaemic-euglycaemic clamp studies, mIGFREO had increased glucose disposal and increased glucose uptake into muscle and fat, in response to insulin. mIGFREO had increased NADPH oxidase 4 (Nox4) expression due to reduced expression of the microRNA, miR-25. Consistent with increased Nox4, mIGFREO endothelial cells generated increased hydrogen peroxide (H2O2), with no increase in superoxide. Treatment with catalase, a dismutase restored insulin tolerance to wild type levels in mIGFREO.
Conclusions: Combined insulin and IGF-1 resistance restricted to the endothelium leads to a potentially favourable adaptation in contrast to pure insulin resistance, with increased Nox4-derived H2O2 generation mediating enhanced whole-body insulin sensitivity.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 The Authors. Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer Health, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited. |
Keywords: | Basic Science Research, Cell Signaling, Endothelium/Vascular Type/Nitric Oxide, Metabolism, Vascular Biology |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 24 Aug 2021 10:02 |
Last Modified: | 25 Jun 2023 22:44 |
Status: | Published online |
Publisher: | Lippincott, Williams & Wilkins |
Identification Number: | 10.1161/CIRCRESAHA.121.319517 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:177316 |