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O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function

Although insulin mediated glucose uptake in skeletal muscle is a major mechanism ensuring glucose disposal in humans, glucose effectiveness, i.e., the ability of glucose itself to stimulate its own uptake independent of insulin, accounts for roughly half of the glucose disposed during an oral glucos...

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Autores principales: Norlin, Stefan, Axelsson, Jan, Ericsson, Madelene, Edlund, Helena
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10457357/
https://www.ncbi.nlm.nih.gov/pubmed/37626210
http://dx.doi.org/10.1038/s42003-023-05255-6
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author Norlin, Stefan
Axelsson, Jan
Ericsson, Madelene
Edlund, Helena
author_facet Norlin, Stefan
Axelsson, Jan
Ericsson, Madelene
Edlund, Helena
author_sort Norlin, Stefan
collection PubMed
description Although insulin mediated glucose uptake in skeletal muscle is a major mechanism ensuring glucose disposal in humans, glucose effectiveness, i.e., the ability of glucose itself to stimulate its own uptake independent of insulin, accounts for roughly half of the glucose disposed during an oral glucose tolerance test. Both insulin dependent and insulin independent skeletal muscle glucose uptake are however reduced in individuals with diabetes. We here show that AMPK activator O304 stimulates insulin independent glucose uptake and utilization in skeletal muscle and heart in vivo, while preventing glycogen accumulation. Combined glucose uptake and utilization requires an increased metabolic demand and we show that O304 acts as a mitochondrial uncoupler, i.e., generates a metabolic demand. O304 averts gene expression changes associated with metabolic inflexibility in skeletal muscle and heart of diabetic mice and reverts diabetic cardiomyopathy. In Type 2 diabetes, insulin resistance elicits compensatory insulin hypersecretion, provoking β-cell stress and eventually compensatory failure. In db/db mice O304 preserves β-cell function by preventing decline in insulin secretion, β-cell mass, and pancreatic insulin content. Thus, as a dual AMPK activator and mitochondrial uncoupler O304 mitigates two central defects of T2D; impaired glucose uptake/utilization and β-cell failure, which today lack effective treatment.
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spelling pubmed-104573572023-08-27 O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function Norlin, Stefan Axelsson, Jan Ericsson, Madelene Edlund, Helena Commun Biol Article Although insulin mediated glucose uptake in skeletal muscle is a major mechanism ensuring glucose disposal in humans, glucose effectiveness, i.e., the ability of glucose itself to stimulate its own uptake independent of insulin, accounts for roughly half of the glucose disposed during an oral glucose tolerance test. Both insulin dependent and insulin independent skeletal muscle glucose uptake are however reduced in individuals with diabetes. We here show that AMPK activator O304 stimulates insulin independent glucose uptake and utilization in skeletal muscle and heart in vivo, while preventing glycogen accumulation. Combined glucose uptake and utilization requires an increased metabolic demand and we show that O304 acts as a mitochondrial uncoupler, i.e., generates a metabolic demand. O304 averts gene expression changes associated with metabolic inflexibility in skeletal muscle and heart of diabetic mice and reverts diabetic cardiomyopathy. In Type 2 diabetes, insulin resistance elicits compensatory insulin hypersecretion, provoking β-cell stress and eventually compensatory failure. In db/db mice O304 preserves β-cell function by preventing decline in insulin secretion, β-cell mass, and pancreatic insulin content. Thus, as a dual AMPK activator and mitochondrial uncoupler O304 mitigates two central defects of T2D; impaired glucose uptake/utilization and β-cell failure, which today lack effective treatment. Nature Publishing Group UK 2023-08-25 /pmc/articles/PMC10457357/ /pubmed/37626210 http://dx.doi.org/10.1038/s42003-023-05255-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Norlin, Stefan
Axelsson, Jan
Ericsson, Madelene
Edlund, Helena
O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function
title O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function
title_full O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function
title_fullStr O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function
title_full_unstemmed O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function
title_short O304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function
title_sort o304 ameliorates hyperglycemia in mice by dually promoting muscle glucose effectiveness and preserving β-cell function
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10457357/
https://www.ncbi.nlm.nih.gov/pubmed/37626210
http://dx.doi.org/10.1038/s42003-023-05255-6
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