ArticleMolecular metabolism2015
Accumulation of 3-hydroxytetradecenoic acid: Cause or corollary of glucolipotoxic impairment of pancreatic β-cell bioenergetics?
Article in Molecular metabolism, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 11 papers.
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Who cites it
11 citing papers in PubMed, 14 citations in OpenAlex.
- Perilipin 2 downregulation in β cells impairs insulin secretion under nutritional stress and damages mitochondria.JCI insight · 2021Article
- The Role of Oxidative Stress in Pancreatic β Cell Dysfunction in Diabetes.International journal of molecular sciences · 2021Review
- Targeted DNA demethylation of the Fgf21 promoter by CRISPR/dCas9-mediated epigenome editing.Scientific reports · 2020Article
- Article
- Connecting pancreatic islet lipid metabolism with insulin secretion and the development of type 2 diabetes.Annals of the New York Academy of Sciences · 2020Review
- Role of 3-Hydroxy Fatty Acid-Induced Hepatic Lipotoxicity in Acute Fatty Liver of Pregnancy.International journal of molecular sciences · 2018Review
- Inhibition of cholinergic potentiation of insulin secretion from pancreatic islets by chronic elevation of glucose and fatty acids: Protection by casein kinase 2 inhibitor.Molecular metabolism · 2017Article
- Functional and Metabolomic Consequences of KDiabetes · 2017Article
- Deletion of histone deacetylase 3 in adult beta cells improves glucose tolerance via increased insulin secretion.Molecular metabolism · 2017Article
- A 3-year follow-up study of β-cell function in patients with early-onset type 2 diabetes.Experimental and therapeutic medicine · 2016Article
- Article
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
Abstract
objectivesHyperglycemia 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.
methodsInsulin secretion, respiration, ATP generation, fatty acid (FA) metabolite profiles and gene expression were determined in isolated islets treated under glucolipotoxic culture conditions.
resultsOver 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.
conclusionsAs 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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