title: Accumulation of 3-hydroxytetradecenoic acid: Cause or corollary of glucolipotoxic impairment of pancreatic β-cell bioenergetics?
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, United States; Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, United States.
authors.forename: Nicolai M
authors.initials: NM
authors.lastname: Doliba
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, United States; Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, United States.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, United States; Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States.
authors.forename: Changhong
authors.initials: C
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States.
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States.
authors.forename: Pan
authors.initials: P
authors.lastname: Chen
authors.affiliation: Department of Surgery, University of Pennsylvania School of Medicine, United States; Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, United States.
authors.forename: Chengyang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Physiology, University of Pennsylvania School of Medicine, United States; Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, United States.
authors.forename: David W
authors.initials: DW
authors.lastname: Frederick
authors.affiliation: Department of Physiology, University of Pennsylvania School of Medicine, United States; Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, United States.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Baur
authors.affiliation: Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, United States; Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bennett
authors.affiliation: Department of Surgery, University of Pennsylvania School of Medicine, United States; Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, United States.
authors.forename: Ali
authors.initials: A
authors.lastname: Naji
authors.affiliation: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, United States; Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, United States.
authors.forename: Franz M
authors.initials: FM
authors.lastname: Matschinsky
keywords: Fatty acids; Insulin secretion; Mitochondrial fatty acid oxidation; Oxygen consumption; Pancreatic islets