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

Molecular Metabolism
Nicolai M DolibaFranz M Matschinsky

Abstract

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. Insulin secretion, respiration, ATP generation, fatty acid (FA) metabolite profiles and gene expression were determined in isolated islets treated under glucolipotoxic culture conditions. 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. As long chain 3-hydroxy...Continue Reading

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Citations

Jan 25, 2018·International Journal of Molecular Sciences·Sathish Kumar Natarajan, Jamal A Ibdah
Apr 3, 2019·Annals of the New York Academy of Sciences·Yumi ImaiJoseph A Promes
Jul 26, 2016·Experimental and Therapeutic Medicine·Shaoling ZhouHongli Shi
Mar 22, 2020·Scientific Reports·Nozomi HanzawaYoshihiro Ogawa
Feb 7, 2021·International Journal of Molecular Sciences·Natsuki EguchiHirohito Ichii

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Methods Mentioned

BETA
ATP
PCR

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