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Phosphodiesterase ENPP2, which is co-upregulated in obese and pregnant mice, is essential for islet beta cell

Yiqing Zhou1, Yongchun Zeng2, Yu Chen1

  • 1State Key Laboratory of Ultrasound in Medicine and Engineering, Chongqing Medical University, Chongqing, China.

Diabetologia
|December 26, 2025
PubMed
Abstract

Insights

Ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) promotes beta cell proliferation and survival, aiding compensation during obesity. Modulating ENPP2 offers a potential therapeutic strategy for diabetes by preventing beta cell loss.

Area of Science:

  • Endocrinology and Metabolism
  • Cell Biology
  • Molecular Biology

Background:

  • Obesity leads to beta cell stress and dysfunction, impairing glucose homeostasis.
  • Identifying molecules that enhance beta cell compensatory capacity is crucial for metabolic health.

Purpose of the Study:

  • To identify key molecules that enhance beta cell compensatory capacity during obesity.
  • To investigate the role of ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) in beta cell function.

Main Methods:

  • Single-cell RNA-sequencing of islet cells from diet-induced obese and pregnant mice.
  • Gene and protein expression analysis of ENPP2.
  • Gain-of-function and loss-of-function studies of ENPP2 in vitro and in vivo.

Main Results:

  • Beta cell proliferation is a common compensatory mechanism in obesity and pregnancy, more pronounced in pregnancy.
  • ENPP2 expression is moderately increased in obese mice and significantly in pregnant mice.
  • ENPP2 promotes beta cell proliferation, inhibits apoptosis, and enhances insulin secretion via the LPA-Akt/mTOR pathway.
  • ENPP2 deficiency impairs beta cell compensation in obese mice; its expression is reduced in diabetes models.

Conclusions:

  • ENPP2 is a key regulator of beta cell compensation during obesity.
  • Targeting ENPP2 levels in beta cells represents a potential therapeutic approach for diabetes to prevent beta cell deterioration.
Keywords:
CompensationDiabetes mellitusObesityPancreatic isletSingle-cell RNA sequencing

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