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Metformin modulates the TXNIP-NLRP3-GSDMD pathway to improve diabetic bladder dysfunction.

Bincheng Huang1,2, Jin Zhang1,2, Haifu Tian1

  • 1Urology Department of General Hospital, Ningxia Medical University, Yinchuan, Ningxia, China.

Scientific Reports
|October 12, 2024
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Summary

Metformin effectively treats diabetic bladder dysfunction (DBD) in mice by improving glucose metabolism and reducing inflammation. It targets the TXNIP-NLRP3-GSDMD pathway, restoring bladder function and urothelial cell integrity.

Keywords:
DBDNLRP3Pyroptotic

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Area of Science:

  • Endocrinology
  • Urology
  • Molecular Biology

Background:

  • Diabetic bladder dysfunction (DBD) is a common complication of diabetes.
  • The TXNIP-NLRP3-GSDMD inflammasome pathway is implicated in DBD pathogenesis.
  • Metformin's therapeutic potential for DBD requires further investigation.

Purpose of the Study:

  • To validate metformin's efficacy in treating diabetic bladder dysfunction (DBD).
  • To determine if the TXNIP-NLRP3-GSDMD axis is a therapeutic target for metformin in ameliorating DBD.

Main Methods:

  • A high-fat diet (HFD) induced obesity and diabetes in C57BL/6J mice.
  • Metformin treatment (4 weeks) assessed glucose metabolism, bladder function (urodynamics, urine spot assays), and histology.
  • Western blot analyzed pyroptotic factors (TXNIP, NLRP3, GSDMD) and tight junction proteins.

Main Results:

  • Metformin improved glucose tolerance and insulin sensitivity.
  • It reduced urinary frequency, non-voiding contractions, and peak urinary pressure.
  • Metformin restored urothelial structure, increased muscular layer thickness, and decreased muscle fiber content.
  • Expression of TXNIP, NLRP3, and GSDMD was reduced, while tight junction proteins (Zo-1, Claudin-1, Occludin) were restored.

Conclusions:

  • Metformin effectively ameliorates diabetic bladder dysfunction in mice.
  • It achieves this by inhibiting TXNIP production and reducing NLRP3 and GSDMD expression.
  • The TXNIP-NLRP3-GSDMD axis is a key target for metformin's therapeutic effects in DBD.