Prentice, K J, et al. The furan fatty acid metabolite CMPF is elevated in diabetes and induces beta cell dysfunction. Cell Metab, 2014. 19(4):653-66.
Gestational diabetes (GDM) results from failure of the beta 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 beta 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 beta cell dysfunction. Thus, CMPF provides a link between beta cell dysfunction and GDM/T2D that could be targeted therapeutically.
Metabolon Results Lead To:
- A new translatable biomarker for gestational diabetes
- Mechanistic insight into metabolite-driven decline in beta-cell function