MiR-338 controls BPA-triggered pancreatic islet insulin secretory dysfunction from compensation to decompensation by targeting Pdx-1

FASEB J. 2017 Dec;31(12):5184-5195. doi: 10.1096/fj.201700282R. Epub 2017 Aug 3.


Bisphenol A (BPA) can disrupt glucose homeostasis and impair pancreatic islet function; however, the mechanisms behind these effects are poorly understood. Male mice (4 wk old) were treated with BPA (50 or 500 μg/kg/d) for 8 wk. Whole-body glucose homeostasis, pancreatic islet morphology and function, and miR-338-mediated molecular signal transduction analyses were examined. We showed that BPA treatment led to a disruption of glucose tolerance and a compensatory increase of pancreatic islets insulin secretion and pancreatic and duodenal homeobox 1 (Pdx1) expression in mice. Inhibition of Pdx1 reduced glucose-stimulated insulin secretion and ATP production in the islets of BPA-exposed mice. Based on primary pancreatic islets, we also confirmed that miR-338 regulated Pdx1 and thus contributed to BPA-induced insulin secretory dysfunction from compensation to decompensation. Short-term BPA exposure downregulated miR-338 through activation of G-protein-coupled estrogen receptor 1 (Gpr30), whereas long-term BPA exposure upregulated miR-338 through suppression of glucagon-like peptide 1 receptor (Glp1r). Taken together, our results reveal a molecular mechanism, whereby BPA regulates Gpr30/Glp1r to mediate the expression of miR-338, which acts to control Pdx1-dependent insulin secretion. The Gpr30/Glp1r-miR-338-Pdx1 axis should be represented as a novel mechanism by which BPA induces insulin secretory dysfunction in pancreatic islets.-Wei, J., Ding, D., Wang, T., Liu, Q., Lin, Y. MiR-338 controls BPA-triggered pancreatic islet insulin secretory dysfunction from compensation to decompensation by targeting Pdx-1.

Keywords: Glp1; Gpr30; diabetes; estrogen receptor; glucose homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Benzhydryl Compounds / pharmacology*
  • Blotting, Western
  • Glucose / metabolism
  • HEK293 Cells
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism*
  • Homeostasis / drug effects
  • Humans
  • Insulin / metabolism*
  • Insulin Resistance
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Phenols / pharmacology*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism*


  • Benzhydryl Compounds
  • Homeodomain Proteins
  • Insulin
  • MicroRNAs
  • Mirn338 microRNA, mouse
  • Phenols
  • Trans-Activators
  • pancreatic and duodenal homeobox 1 protein
  • Adenosine Triphosphate
  • Glucose
  • bisphenol A