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

The furan fatty acid metabolite CMPF is elevated in diabetes and induces β cell dysfunction.

Author information

1
Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
2
Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
3
Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
4
Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, ON M5T 3L9, Canada.
5
Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA 23298, USA.
6
Department of Biology, York University, Toronto, ON M3J 1P3, Canada.
7
Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, ON M5T 3L9, Canada.
8
Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: michael.wheeler@utoronto.ca.

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.

PMID:
24703697
DOI:
10.1016/j.cmet.2014.03.008
[Indexed for MEDLINE]
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