The furan fatty acid metabolite CMPF is elevated in diabetes and induces β cell dysfunction.
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.
Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Kacey J
KJ
Prentice
Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Lemieux
L
Luu
Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Emma M
EM
Allister
Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Ying
Y
Liu
Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Lucy S
LS
Jun
Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Kyle W
KW
Sloop
Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Alexandre B
AB
Hardy
Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Li
L
Wei
Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China.
Weiping
W
Jia
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.
I George
IG
Fantus
Department of Pharmaceutics, Virginia Commonwealth University, Richmond, VA 23298, USA.
Douglas H
DH
Sweet
Department of Biology, York University, Toronto, ON M3J 1P3, Canada.
Gary
G
Sweeney
Department of Medicine, Mount Sinai Hospital, University of Toronto, Toronto, ON M5T 3L9, Canada.
Ravi
R
Retnakaran
Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada.
Feihan F
FF
Dai
Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: michael.wheeler@utoronto.ca.
Michael B
MB
Wheeler
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D005663:Furans / Q000009:adverse effects / Q000097:blood*; D006801:Humans; D007328:Insulin / Q000096:biosynthesis; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000473:pathology*; D055432:Metabolomics; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology*; D008954:Models, Biological; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D011422:Propionates / Q000009:adverse effects / Q000097:blood*; D014157:Transcription Factors / Q000378:metabolism
C468134:3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid; D005663:Furans; D007328:Insulin; D029362:Organic Anion Transporters, Sodium-Independent; D011422:Propionates; D014157:Transcription Factors; C114338:organic anion transport protein 3; D000255:Adenosine Triphosphate