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Mechanisms Underlying the Onset of Oral Lipid–Induced Skeletal Muscle Insulin Resistance in Humans

Several mechanisms, such as innate immune responses via Toll-like receptor-4, accumulation of diacylglycerols (DAG)/ceramides, and activation of protein kinase C (PKC), are considered to underlie skeletal muscle insulin resistance. In this study, we examined initial events occurring during the onset...

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Autores principales: Nowotny, Bettina, Zahiragic, Lejla, Krog, Dorothea, Nowotny, Peter J., Herder, Christian, Carstensen, Maren, Yoshimura, Toru, Szendroedi, Julia, Phielix, Esther, Schadewaldt, Peter, Schloot, Nanette C., Shulman, Gerald I., Roden, Michael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Diabetes Association 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712035/
https://www.ncbi.nlm.nih.gov/pubmed/23454694
http://dx.doi.org/10.2337/db12-1179
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author Nowotny, Bettina
Zahiragic, Lejla
Krog, Dorothea
Nowotny, Peter J.
Herder, Christian
Carstensen, Maren
Yoshimura, Toru
Szendroedi, Julia
Phielix, Esther
Schadewaldt, Peter
Schloot, Nanette C.
Shulman, Gerald I.
Roden, Michael
author_facet Nowotny, Bettina
Zahiragic, Lejla
Krog, Dorothea
Nowotny, Peter J.
Herder, Christian
Carstensen, Maren
Yoshimura, Toru
Szendroedi, Julia
Phielix, Esther
Schadewaldt, Peter
Schloot, Nanette C.
Shulman, Gerald I.
Roden, Michael
author_sort Nowotny, Bettina
collection PubMed
description Several mechanisms, such as innate immune responses via Toll-like receptor-4, accumulation of diacylglycerols (DAG)/ceramides, and activation of protein kinase C (PKC), are considered to underlie skeletal muscle insulin resistance. In this study, we examined initial events occurring during the onset of insulin resistance upon oral high-fat loading compared with lipid and low-dose endotoxin infusion. Sixteen lean insulin-sensitive volunteers received intravenous fat (iv fat), oral fat (po fat), intravenous endotoxin (lipopolysaccharide [LPS]), and intravenous glycerol as control. After 6 h, whole-body insulin sensitivity was reduced by iv fat, po fat, and LPS to 60, 67, and 48%, respectively (all P < 0.01), which was due to decreased nonoxidative glucose utilization, while hepatic insulin sensitivity was unaffected. Muscle PKCθ activation increased by 50% after iv and po fat, membrane Di-C18:2 DAG species doubled after iv fat and correlated with PKCθ activation after po fat, whereas ceramides were unchanged. Only after LPS, circulating inflammatory markers (tumor necrosis factor-α, interleukin-6, and interleukin-1 receptor antagonist), their mRNA expression in subcutaneous adipose tissue, and circulating cortisol were elevated. Po fat ingestion rapidly induces insulin resistance by reducing nonoxidative glucose disposal, which associates with PKCθ activation and a rise in distinct myocellular membrane DAG, while endotoxin-induced insulin resistance is exclusively associated with stimulation of inflammatory pathways.
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spelling pubmed-37120352014-07-01 Mechanisms Underlying the Onset of Oral Lipid–Induced Skeletal Muscle Insulin Resistance in Humans Nowotny, Bettina Zahiragic, Lejla Krog, Dorothea Nowotny, Peter J. Herder, Christian Carstensen, Maren Yoshimura, Toru Szendroedi, Julia Phielix, Esther Schadewaldt, Peter Schloot, Nanette C. Shulman, Gerald I. Roden, Michael Diabetes Original Research Several mechanisms, such as innate immune responses via Toll-like receptor-4, accumulation of diacylglycerols (DAG)/ceramides, and activation of protein kinase C (PKC), are considered to underlie skeletal muscle insulin resistance. In this study, we examined initial events occurring during the onset of insulin resistance upon oral high-fat loading compared with lipid and low-dose endotoxin infusion. Sixteen lean insulin-sensitive volunteers received intravenous fat (iv fat), oral fat (po fat), intravenous endotoxin (lipopolysaccharide [LPS]), and intravenous glycerol as control. After 6 h, whole-body insulin sensitivity was reduced by iv fat, po fat, and LPS to 60, 67, and 48%, respectively (all P < 0.01), which was due to decreased nonoxidative glucose utilization, while hepatic insulin sensitivity was unaffected. Muscle PKCθ activation increased by 50% after iv and po fat, membrane Di-C18:2 DAG species doubled after iv fat and correlated with PKCθ activation after po fat, whereas ceramides were unchanged. Only after LPS, circulating inflammatory markers (tumor necrosis factor-α, interleukin-6, and interleukin-1 receptor antagonist), their mRNA expression in subcutaneous adipose tissue, and circulating cortisol were elevated. Po fat ingestion rapidly induces insulin resistance by reducing nonoxidative glucose disposal, which associates with PKCθ activation and a rise in distinct myocellular membrane DAG, while endotoxin-induced insulin resistance is exclusively associated with stimulation of inflammatory pathways. American Diabetes Association 2013-07 2013-06-14 /pmc/articles/PMC3712035/ /pubmed/23454694 http://dx.doi.org/10.2337/db12-1179 Text en © 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
spellingShingle Original Research
Nowotny, Bettina
Zahiragic, Lejla
Krog, Dorothea
Nowotny, Peter J.
Herder, Christian
Carstensen, Maren
Yoshimura, Toru
Szendroedi, Julia
Phielix, Esther
Schadewaldt, Peter
Schloot, Nanette C.
Shulman, Gerald I.
Roden, Michael
Mechanisms Underlying the Onset of Oral Lipid–Induced Skeletal Muscle Insulin Resistance in Humans
title Mechanisms Underlying the Onset of Oral Lipid–Induced Skeletal Muscle Insulin Resistance in Humans
title_full Mechanisms Underlying the Onset of Oral Lipid–Induced Skeletal Muscle Insulin Resistance in Humans
title_fullStr Mechanisms Underlying the Onset of Oral Lipid–Induced Skeletal Muscle Insulin Resistance in Humans
title_full_unstemmed Mechanisms Underlying the Onset of Oral Lipid–Induced Skeletal Muscle Insulin Resistance in Humans
title_short Mechanisms Underlying the Onset of Oral Lipid–Induced Skeletal Muscle Insulin Resistance in Humans
title_sort mechanisms underlying the onset of oral lipid–induced skeletal muscle insulin resistance in humans
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712035/
https://www.ncbi.nlm.nih.gov/pubmed/23454694
http://dx.doi.org/10.2337/db12-1179
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