Editors' ChoiceMetabolism

A Pregnant Pause in Pancreatic Function

See allHide authors and affiliations

Science Translational Medicine  23 Apr 2014:
Vol. 6, Issue 233, pp. 233ec70
DOI: 10.1126/scitranslmed.3009251

Gestational diabetes (GDM) is a condition in which women with no prior history of glucose intolerance transiently develop diabetes during late pregnancy. GDM affects 3 to 14% of pregnant women and is associated with a spectrum of adverse sequelae for both mother and child, including a high rate of progression to type 2 diabetes (T2D) later in life. Although decline in pancreatic islet β cell function is a major contributor to GDM pathogenesis, its molecular underpinnings remain poorly understood. The discovery of molecular effectors of β cell dysfunction may inform new therapies for GDM and T2D.

Prentice et al. asked whether circulating metabolites could cause β cell abnormalities in GDM. They screened a panel of 342 metabolites in pregnant patients with or without GDM that were matched for age, race, family history of diabetes, and prepregnancy body mass index. Their team discovered that the furan fatty acid metabolite CMPF (3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid) was significantly elevated in patients with GDM as well as in an independent cohort of nonpregnant adults with T2D. Mice injected with doses of CMPF that raised plasma concentrations to the level seen in GDM patients revealed that this metabolite could impair glucose tolerance in mice through a mechanism that involved reduced glucose-stimulated insulin secretion by β cells. Studies in isolated pancreatic islets and cultured β cells revealed that the concentrations of CMPF seen in GDM patients directly impaired insulin biosynthesis via a mechanism involving CMPF import into the β cell by the organic anion transporter OAT3 followed by excess production of reactive-oxygen species. Importantly, CMPF-mediated β cell dysfunction could be rescued in vitro by either pharmacologic inhibition of OAT3 or administering the antioxidant N-acetyl-cysteine.

This study implicates CMPF as a metabolite that might drive pathogenesis of GDM and T2D in humans. Now, researchers can continue to dissect more detailed mechanisms governing CMPF production and toxicity, knowledge that may lead to therapies for GDM, T2D, and other metabolic diseases.

K. J. Prentice et al., The furan fatty acid metabolite CMPF is elevated in diabetes and induces β cell dysfunction. Cell. Metab. 19, 653–656 (2014). [PubMed]

Stay Connected to Science Translational Medicine

Navigate This Article