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Strict glucose control and elimination of NLRP3-induced inflammation prevents diabetic bladder dysfunction in the
Francis M Hughes1, Shelby N Harper1, Huixia Jin1
1Department of Urology, Duke University Medical Center, Division of Urology, Durham, North Carolina, USA.
Purpose:
Diabetic bladder dysfunction (DBD) is the most common diabetic complication. Logically, regulation of blood glucose should reverse dysfunction, but the Epidemiology of Diabetes Interventions and Complications study found strict control ineffective. However, it is possible that strict control may prevent DBD if initiated before symptoms appear. We examine the effect of early glucose control on development of DBD in the female diabetic Akita mouse (Type 1) and test the potential of inhibiting/deleting NLRP3 as adjunct therapy to glucose control.
Materials And Methods:
Female Akita mice were bred NLRP3+/+ or NLRP3-/-. At 6 weeks of age, diabetics received either no glucose control or insulin pellets (s.c., Linshin) designed to poorly or strictly control blood glucose. At Week 15, blood glucose (glucometer), the extravasation potential of bladder (an indirect measurement of inflammation) and bladder function (urodynamics) were assessed.
Results:
Blood glucose of diabetics was reduced in poorly controlled and strongly reduced in strictly controlled groups. Levels were not affected by deletion of NLRP3. Evans blue dye extravasation correlated with glucose control and was eliminated in the NLRP3-/- groups. Urodynamics found markers of overactivity in diabetics which was improved in the poorly controlled group and eliminated in the strictly controlled group. In the NLRP3-/- mice, no bladder dysfunction developed, regardless of glucose control.
Conclusions:
Early-initiated strict glycemic control and NLRP3 elimination can effectively prevent DBD, suggesting hyperglycemia acts through NLRP3-induced inflammation to trigger DBD.
Insights
Early strict glucose control and NLRP3 inhibition prevent diabetic bladder dysfunction (DBD) by reducing inflammation. This suggests hyperglycemia triggers DBD via NLRP3-mediated inflammation in type 1 diabetes.
Area of Science:
- Urology
- Endocrinology
- Immunology
Background:
- Diabetic bladder dysfunction (DBD) is a common complication of diabetes.
- Strict glycemic control has shown limited efficacy in reversing established DBD.
- Early intervention may be key to preventing DBD development.
Purpose of the Study:
- To investigate the impact of early strict glucose control on preventing DBD in female diabetic Akita mice (Type 1 diabetes).
- To evaluate the potential of inhibiting or deleting NLRP3 inflammasome as an adjunct therapy to glucose control for DBD prevention.
Main Methods:
- Female Akita mice (NLRP3+/+ and NLRP3-/-) were used.
- Mice received no glucose control, poor glucose control, or strict glucose control via insulin pellets starting at 6 weeks.
- Bladder inflammation (Evans blue extravasation) and function (urodynamics) were assessed at 15 weeks.
Main Results:
- Strict glucose control significantly reduced blood glucose levels.
- NLRP3 deletion eliminated bladder inflammation and dysfunction, irrespective of glucose control.
- Early strict glycemic control and NLRP3 elimination prevented DBD development.
Conclusions:
- Early strict glycemic control and NLRP3 elimination are effective in preventing diabetic bladder dysfunction.
- Hyperglycemia appears to induce DBD through NLRP3-dependent inflammation.
