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Accumulation of 3-hydroxytetradecenoic acid: Cause or corollary of glucolipotoxic impairment of pancreatic β-cell bioenergetics?

OBJECTIVES: Hyperglycemia and elevated blood lipids are the presumed precipitating causes of β-cell damage in T2DM as the result of a process termed “glucolipotoxicity”. Here, we tested whether glucolipotoxic pathophysiology is caused by defective bioenergetics using islets in culture. METHODS: Insu...

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Autores principales: Doliba, Nicolai M., Liu, Qing, Li, Changhong, Chen, Jie, Chen, Pan, Liu, Chengyang, Frederick, David W., Baur, Joseph A., Bennett, Michael J., Naji, Ali, Matschinsky, Franz M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731732/
https://www.ncbi.nlm.nih.gov/pubmed/26909309
http://dx.doi.org/10.1016/j.molmet.2015.09.010
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author Doliba, Nicolai M.
Liu, Qing
Li, Changhong
Chen, Jie
Chen, Pan
Liu, Chengyang
Frederick, David W.
Baur, Joseph A.
Bennett, Michael J.
Naji, Ali
Matschinsky, Franz M.
author_facet Doliba, Nicolai M.
Liu, Qing
Li, Changhong
Chen, Jie
Chen, Pan
Liu, Chengyang
Frederick, David W.
Baur, Joseph A.
Bennett, Michael J.
Naji, Ali
Matschinsky, Franz M.
author_sort Doliba, Nicolai M.
collection PubMed
description OBJECTIVES: Hyperglycemia and elevated blood lipids are the presumed precipitating causes of β-cell damage in T2DM as the result of a process termed “glucolipotoxicity”. Here, we tested whether glucolipotoxic pathophysiology is caused by defective bioenergetics using islets in culture. METHODS: Insulin secretion, respiration, ATP generation, fatty acid (FA) metabolite profiles and gene expression were determined in isolated islets treated under glucolipotoxic culture conditions. RESULTS: Over time, chronic exposure of mouse islets to FAs with glucose leads to bioenergetic failure and reduced insulin secretion upon stimulation with glucose or amino acids. Islets exposed to glucolipotoxic conditions displayed biphasic changes of the oxygen consumption rate (OCR): an initial increase in baseline and Vmax of OCR after 3 days, followed by decreased baseline and glucose stimulated OCR after 5 days. These changes were associated with lower islet ATP levels, impaired glucose-induced ATP generation, a trend for reduced mitochondrial DNA content and reduced expression of mitochondrial transcription factor A (Tfam). We discovered the accumulation of carnitine esters of hydroxylated long chain FAs, in particular 3-hydroxytetradecenoyl-carnitine. CONCLUSIONS: As long chain 3-hydroxylated FA metabolites are known to uncouple heart and brain mitochondria [53], [54], [55], we propose that under glucolipotoxic condition, unsaturated hydroxylated long-chain FAs accumulate, uncouple and ultimately inhibit β-cell respiration. This leads to the slow deterioration of mitochondrial function progressing to bioenergetics β-cell failure.
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spelling pubmed-47317322016-02-23 Accumulation of 3-hydroxytetradecenoic acid: Cause or corollary of glucolipotoxic impairment of pancreatic β-cell bioenergetics? Doliba, Nicolai M. Liu, Qing Li, Changhong Chen, Jie Chen, Pan Liu, Chengyang Frederick, David W. Baur, Joseph A. Bennett, Michael J. Naji, Ali Matschinsky, Franz M. Mol Metab Original Article OBJECTIVES: Hyperglycemia and elevated blood lipids are the presumed precipitating causes of β-cell damage in T2DM as the result of a process termed “glucolipotoxicity”. Here, we tested whether glucolipotoxic pathophysiology is caused by defective bioenergetics using islets in culture. METHODS: Insulin secretion, respiration, ATP generation, fatty acid (FA) metabolite profiles and gene expression were determined in isolated islets treated under glucolipotoxic culture conditions. RESULTS: Over time, chronic exposure of mouse islets to FAs with glucose leads to bioenergetic failure and reduced insulin secretion upon stimulation with glucose or amino acids. Islets exposed to glucolipotoxic conditions displayed biphasic changes of the oxygen consumption rate (OCR): an initial increase in baseline and Vmax of OCR after 3 days, followed by decreased baseline and glucose stimulated OCR after 5 days. These changes were associated with lower islet ATP levels, impaired glucose-induced ATP generation, a trend for reduced mitochondrial DNA content and reduced expression of mitochondrial transcription factor A (Tfam). We discovered the accumulation of carnitine esters of hydroxylated long chain FAs, in particular 3-hydroxytetradecenoyl-carnitine. CONCLUSIONS: As long chain 3-hydroxylated FA metabolites are known to uncouple heart and brain mitochondria [53], [54], [55], we propose that under glucolipotoxic condition, unsaturated hydroxylated long-chain FAs accumulate, uncouple and ultimately inhibit β-cell respiration. This leads to the slow deterioration of mitochondrial function progressing to bioenergetics β-cell failure. Elsevier 2015-10-08 /pmc/articles/PMC4731732/ /pubmed/26909309 http://dx.doi.org/10.1016/j.molmet.2015.09.010 Text en © 2015 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Doliba, Nicolai M.
Liu, Qing
Li, Changhong
Chen, Jie
Chen, Pan
Liu, Chengyang
Frederick, David W.
Baur, Joseph A.
Bennett, Michael J.
Naji, Ali
Matschinsky, Franz M.
Accumulation of 3-hydroxytetradecenoic acid: Cause or corollary of glucolipotoxic impairment of pancreatic β-cell bioenergetics?
title Accumulation of 3-hydroxytetradecenoic acid: Cause or corollary of glucolipotoxic impairment of pancreatic β-cell bioenergetics?
title_full Accumulation of 3-hydroxytetradecenoic acid: Cause or corollary of glucolipotoxic impairment of pancreatic β-cell bioenergetics?
title_fullStr Accumulation of 3-hydroxytetradecenoic acid: Cause or corollary of glucolipotoxic impairment of pancreatic β-cell bioenergetics?
title_full_unstemmed Accumulation of 3-hydroxytetradecenoic acid: Cause or corollary of glucolipotoxic impairment of pancreatic β-cell bioenergetics?
title_short Accumulation of 3-hydroxytetradecenoic acid: Cause or corollary of glucolipotoxic impairment of pancreatic β-cell bioenergetics?
title_sort accumulation of 3-hydroxytetradecenoic acid: cause or corollary of glucolipotoxic impairment of pancreatic β-cell bioenergetics?
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731732/
https://www.ncbi.nlm.nih.gov/pubmed/26909309
http://dx.doi.org/10.1016/j.molmet.2015.09.010
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