2. Academic Validation
  3. mPGES-2 blockade antagonizes β-cell senescence to ameliorate diabetes by acting on NR4A1

mPGES-2 blockade antagonizes β-cell senescence to ameliorate diabetes by acting on NR4A1

  • Nat Metab. 2022 Feb;4(2):269-283. doi: 10.1038/s42255-022-00536-6.
Dandan Zhong  # 1,  Zhikang Wan  # 1 2,  Jie Cai  # 1 3,  Lingling Quan 1,  Rumeng Zhang 1 3,  Tian Teng 1,  Hang Gao 1,  Chenyu Fan 1,  Meng Wang 4,  Dong Guo 1,  Hongxing Zhang 5,  Zhanjun Jia 6 7,  Ying Sun 8
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, P. R. China.
  • 2 Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, P. R. China.
  • 3 Public Experimental Research Center of Xuzhou Medical University, Xuzhou Medical University, Xuzhou, P. R. China.
  • 4 Cancer Institute, Xuzhou Medical University, Xuzhou, P. R. China.
  • 5 Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, P. R. China.
  • 6 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, P. R. China. jiazj72@hotmail.com.
  • 7 Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing, P. R. China. jiazj72@hotmail.com.
  • 8 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, P. R. China. sunyingwyo@163.com.
  • # Contributed equally.
PMID: 35228744 DOI: 10.1038/s42255-022-00536-6
Abstract

β-cell dysfunction is a hallmark of type 1 and type 2 diabetes. Type 2 diabetes is strongly associated with ageing-related β-cell abnormalities that arise through unknown mechanisms. Here we show better β-cell identity, less β-cell senescence, enhanced glucose-stimulated Insulin secretion and improved glucose homeostasis in global microsomal prostaglandin E synthase-2 (mPGES-2)-deficient mice challenged with a high-fat diet or bred with a genetic model of type 2 diabetes (db/db mice). Furthermore, the function of mPGES-2 in β-cells is validated using mice with β-cell-specific mPGES-2 deficiency or overexpression. Mechanistically, the protective role of mPGES-2 deletion is induced by antagonizing β-cell senescence via interference of the PGE2-EP3-NR4A1 signalling axis. We also discover an inhibitor of mPGES-2, SZ0232, which protects against β-cell dysfunction and diabetes, similar to mPGES-2 deletion. We conclude that mPGES-2 contributes to ageing-associated β-cell senescence and dysfunction via the PGE2-EP3-NR4A1 signalling axis. Pharmacologic blockade of mPGES-2 might be effective for treating ageing-associated β-cell dysfunction and diabetes.

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