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

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.