The 15-hydroxyprostaglandin dehydrogenase inhibitor SW033291 ameliorates abnormal hepatic glucose metabolism through PGE2-EP4 receptor-AKT signaling in a type 2 diabetes mellitus mouse model

Cell Signal. 2023 Aug:108:110707. doi: 10.1016/j.cellsig.2023.110707. Epub 2023 May 8.


Type 2 diabetes mellitus (T2DM) is associated with high rates of morbidity and mortality worldwide. Prostaglandin E2 (PGE2) is a lipid signaling molecule that can ameliorate the symptoms of some metabolic diseases, including T2DM, and improve tissue repair and regeneration. Although SW033291 can increase PGE2 levels through its action as a small molecule inhibitor of the PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase, its effects on T2DM remain unclear. In the present study, we evaluated whether SW033291 treatment exerts a protective effect against T2DM and explored the underlying mechanisms. A T2DM mouse model was established using a high-fat diet combined with streptozotocin treatment. Palmitic acid-treated LO2 cells were used as an insulin-resistant cell model. SW033291 treatment reduced body weight and fasting blood glucose levels as well as serum triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels in vivo. In addition to ameliorating glucose and insulin tolerance, SW033291 treatment reversed the T2DM-induced decrease in glycogen synthesis and increase in gluconeogenesis in the liver. Furthermore, SW033291 administration increased hepatic glycogen synthase kinase 3 beta (GSK3β) phosphorylation levels to promote glycogen synthesis. SW033291 treatment also inhibited gluconeogenesis by upregulating AKT serine/threonine kinase (AKT) and forkhead box O1 (FOXO1) phosphorylation and reducing glucose-6-phosphatase and phosphoenolpyruvate carboxykinase 1 expression in the livers of T2DM model mice. Additionally, SW033291 treatment improved abnormal hepatic glucose metabolism through the PGE2-EP4 receptor-AKT-GSK3β/FOXO1 signaling pathway in vitro. These results suggest a novel role of SW033291 in improving T2DM and support its potential as a novel therapeutic agent.

Keywords: EP4 receptor; Gluconeogenesis; Glycogen synthesis; Prostaglandin E(2); SW033291; Type 2 diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholesterol / metabolism
  • Diabetes Mellitus, Type 2* / metabolism
  • Dinoprostone / metabolism
  • Disease Models, Animal
  • Glucose / metabolism
  • Glycogen / metabolism
  • Glycogen Synthase Kinase 3 beta / metabolism
  • Insulin / metabolism
  • Insulin Resistance*
  • Liver / metabolism
  • Mice
  • Proto-Oncogene Proteins c-akt / metabolism
  • Signal Transduction


  • 15-hydroxyprostaglandin dehydrogenase
  • Cholesterol
  • Dinoprostone
  • Glucose
  • Glycogen
  • Glycogen Synthase Kinase 3 beta
  • Proto-Oncogene Proteins c-akt
  • SW033291
  • Insulin