The Furan Fatty Acid Metabolite CMPF Is Elevated in Diabetes and Induces β Cell Dysfunction

Cell Metab. 2014 Apr 1;19(4):653-66. doi: 10.1016/j.cmet.2014.03.008.

Abstract

Gestational diabetes (GDM) results from failure of the β cells to adapt to increased metabolic demands; however, the cause of GDM and the extremely high rate of progression to type 2 diabetes (T2D) remains unknown. Using metabolomics, we show that the furan fatty acid metabolite 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) is elevated in the plasma of humans with GDM, as well as impaired glucose-tolerant and T2D patients. In mice, diabetic levels of plasma CMPF induced glucose intolerance, impaired glucose-stimulated insulin secretion, and decreased glucose utilization. Mechanistically, we show that CMPF acts directly on the β cell, causing impaired mitochondrial function, decreasing glucose-induced ATP accumulation, and inducing oxidative stress, resulting in dysregulation of key transcription factors and ultimately reduced insulin biosynthesis. Importantly, specifically blocking its transport through OAT3 or antioxidant treatment could prevent CMPF-induced β cell dysfunction. Thus, CMPF provides a link between β cell dysfunction and GDM/T2D that could be targeted therapeutically.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Furans / adverse effects
  • Furans / blood*
  • Humans
  • Insulin / biosynthesis
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / pathology*
  • Metabolomics
  • Mice
  • Mitochondria / drug effects
  • Mitochondria / pathology*
  • Models, Biological*
  • Organic Anion Transporters, Sodium-Independent / metabolism*
  • Oxidative Stress / physiology
  • Propionates / adverse effects
  • Propionates / blood*
  • Transcription Factors / metabolism

Substances

  • 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid
  • Furans
  • Insulin
  • Organic Anion Transporters, Sodium-Independent
  • Propionates
  • Transcription Factors
  • organic anion transport protein 3
  • Adenosine Triphosphate

Associated data

  • GEO/GSE40709
  • GEO/GSE55028