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Insulin directly stimulates mitochondrial glucose oxidation in the heart
BACKGROUND: Glucose oxidation is a major contributor to myocardial energy production and its contribution is orchestrated by insulin. While insulin can increase glucose oxidation indirectly by enhancing glucose uptake and glycolysis, it also directly stimulates mitochondrial glucose oxidation, indep...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722314/ https://www.ncbi.nlm.nih.gov/pubmed/33287820 http://dx.doi.org/10.1186/s12933-020-01177-3 |
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author | Karwi, Qutuba G. Wagg, Cory S. Altamimi, Tariq R. Uddin, Golam M. Ho, Kim L. Darwesh, Ahmed M. Seubert, John M. Lopaschuk, Gary D. |
author_facet | Karwi, Qutuba G. Wagg, Cory S. Altamimi, Tariq R. Uddin, Golam M. Ho, Kim L. Darwesh, Ahmed M. Seubert, John M. Lopaschuk, Gary D. |
author_sort | Karwi, Qutuba G. |
collection | PubMed |
description | BACKGROUND: Glucose oxidation is a major contributor to myocardial energy production and its contribution is orchestrated by insulin. While insulin can increase glucose oxidation indirectly by enhancing glucose uptake and glycolysis, it also directly stimulates mitochondrial glucose oxidation, independent of increasing glucose uptake or glycolysis, through activating mitochondrial pyruvate dehydrogenase (PDH), the rate-limiting enzyme of glucose oxidation. However, how insulin directly stimulates PDH is not known. To determine this, we characterized the impacts of modifying mitochondrial insulin signaling kinases, namely protein kinase B (Akt), protein kinase C-delta (PKC-δ) and glycogen synthase kinase-3 beta (GSK-3β), on the direct insulin stimulation of glucose oxidation. METHODS: We employed an isolated working mouse heart model to measure the effect of insulin on cardiac glycolysis, glucose oxidation and fatty acid oxidation and how that could be affected when mitochondrial Akt, PKC-δ or GSK-3β is disturbed using pharmacological modulators. We also used differential centrifugation to isolate mitochondrial and cytosol fraction to examine the activity of Akt, PKC-δ and GSK-3β between these fractions. Data were analyzed using unpaired t-test and two-way ANOVA. RESULTS: Here we show that insulin-stimulated phosphorylation of mitochondrial Akt is a prerequisite for transducing insulin’s direct stimulation of glucose oxidation. Inhibition of mitochondrial Akt completely abolishes insulin-stimulated glucose oxidation, independent of glucose uptake or glycolysis. We also show a novel role of mitochondrial PKC-δ in modulating mitochondrial glucose oxidation. Inhibition of mitochondrial PKC-δ mimics insulin stimulation of glucose oxidation and mitochondrial Akt. We also demonstrate that inhibition of mitochondrial GSK3β phosphorylation does not influence insulin-stimulated glucose oxidation. CONCLUSION: We identify, for the first time, insulin-stimulated mitochondrial Akt as a prerequisite transmitter of the insulin signal that directly stimulates cardiac glucose oxidation. These novel findings suggest that targeting mitochondrial Akt is a potential therapeutic approach to enhance cardiac insulin sensitivity in condition such as heart failure, diabetes and obesity. |
format | Online Article Text |
id | pubmed-7722314 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-77223142020-12-08 Insulin directly stimulates mitochondrial glucose oxidation in the heart Karwi, Qutuba G. Wagg, Cory S. Altamimi, Tariq R. Uddin, Golam M. Ho, Kim L. Darwesh, Ahmed M. Seubert, John M. Lopaschuk, Gary D. Cardiovasc Diabetol Original Investigation BACKGROUND: Glucose oxidation is a major contributor to myocardial energy production and its contribution is orchestrated by insulin. While insulin can increase glucose oxidation indirectly by enhancing glucose uptake and glycolysis, it also directly stimulates mitochondrial glucose oxidation, independent of increasing glucose uptake or glycolysis, through activating mitochondrial pyruvate dehydrogenase (PDH), the rate-limiting enzyme of glucose oxidation. However, how insulin directly stimulates PDH is not known. To determine this, we characterized the impacts of modifying mitochondrial insulin signaling kinases, namely protein kinase B (Akt), protein kinase C-delta (PKC-δ) and glycogen synthase kinase-3 beta (GSK-3β), on the direct insulin stimulation of glucose oxidation. METHODS: We employed an isolated working mouse heart model to measure the effect of insulin on cardiac glycolysis, glucose oxidation and fatty acid oxidation and how that could be affected when mitochondrial Akt, PKC-δ or GSK-3β is disturbed using pharmacological modulators. We also used differential centrifugation to isolate mitochondrial and cytosol fraction to examine the activity of Akt, PKC-δ and GSK-3β between these fractions. Data were analyzed using unpaired t-test and two-way ANOVA. RESULTS: Here we show that insulin-stimulated phosphorylation of mitochondrial Akt is a prerequisite for transducing insulin’s direct stimulation of glucose oxidation. Inhibition of mitochondrial Akt completely abolishes insulin-stimulated glucose oxidation, independent of glucose uptake or glycolysis. We also show a novel role of mitochondrial PKC-δ in modulating mitochondrial glucose oxidation. Inhibition of mitochondrial PKC-δ mimics insulin stimulation of glucose oxidation and mitochondrial Akt. We also demonstrate that inhibition of mitochondrial GSK3β phosphorylation does not influence insulin-stimulated glucose oxidation. CONCLUSION: We identify, for the first time, insulin-stimulated mitochondrial Akt as a prerequisite transmitter of the insulin signal that directly stimulates cardiac glucose oxidation. These novel findings suggest that targeting mitochondrial Akt is a potential therapeutic approach to enhance cardiac insulin sensitivity in condition such as heart failure, diabetes and obesity. BioMed Central 2020-12-07 /pmc/articles/PMC7722314/ /pubmed/33287820 http://dx.doi.org/10.1186/s12933-020-01177-3 Text en © The Author(s) 2020 Open AccessThis 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/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Original Investigation Karwi, Qutuba G. Wagg, Cory S. Altamimi, Tariq R. Uddin, Golam M. Ho, Kim L. Darwesh, Ahmed M. Seubert, John M. Lopaschuk, Gary D. Insulin directly stimulates mitochondrial glucose oxidation in the heart |
title | Insulin directly stimulates mitochondrial glucose oxidation in the heart |
title_full | Insulin directly stimulates mitochondrial glucose oxidation in the heart |
title_fullStr | Insulin directly stimulates mitochondrial glucose oxidation in the heart |
title_full_unstemmed | Insulin directly stimulates mitochondrial glucose oxidation in the heart |
title_short | Insulin directly stimulates mitochondrial glucose oxidation in the heart |
title_sort | insulin directly stimulates mitochondrial glucose oxidation in the heart |
topic | Original Investigation |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722314/ https://www.ncbi.nlm.nih.gov/pubmed/33287820 http://dx.doi.org/10.1186/s12933-020-01177-3 |
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