Introduction: Diabetic Bladder Dysfunction (DBD) is a common complication of diabetes that may present with urinary frequency and urgency (i.e. overactive bladder (OAB)), detrusor underactivity and bladder decompensation (underactive bladder (UAB)), or some combination thereof. In an effort to define the etiology of this complication and develop models of its development, we have characterized the appearance of DBD in Akita Type 1 diabetic mice. Beginning with the female, which develop less severe diabetes, we demonstrated a transition from OAB at 15 weeks to UAB at 30. The purpose of this study is to explore the progression of DBD in the male mice of this diabetic model. We also explore a role for inflammation in this progression.
Methods: Four groups of mice (non-diab/NLRP3+/+, non-diab/ NLRP3-/-, diab/NLRP3+/+, and diab/NLRP3-/-) were evaluated at four different ages, 7, 10, 15 and 30 weeks. Awake, restrained cystometry was performed 7 to 9 days after suprapubic tubes (SPT) were implanted in the bladder. Blood glucose levels were measured prior to SPT placement. The extravasation of Evans blue dye assessed inflammation in the bladder. All parameters were assessed by ANOVA followed by Student-Newman-Keul’s post-hoc using GraphPad InStat software (La Jolla, CA). Statistical significance was defined as p<0.05.
Results: Male mice at 7 weeks showed dramatically increased blood sugar at levels >500 mg/dL which were sustained through 30 weeks of age. In contrast, blood glucose in female diabetic mice are ˜280 mg/dL during this time. At 7 weeks we found there was no difference in void volume or urinary frequency between diabetic and non-diabetic mice (n=8,9). Beginning at 10 weeks the diabetic mice develop signs of UAB with a 55% decrease in urinary frequency and a 240% increase in void volume (n=9/11). At 15 (n=7/6) and 30 weeks (n=10/4) the decrease in frequency was similar (62% and 67%) as was the increase in void volume (305% and 312%). Surprisingly, unlike the females, deletion of the NLRP3 gene did not significantly affect any cystometric parameters. Using Evans blue we confirmed that inflammation was triggered in the bladder by diabetes and was blocked by deletion of NLRP3. In summary, DBD in male Akita mice presents initially as UAB and this pathophysiology does not change over time. While direct development of UAB is correlated with severity of hyperglycemia, NLRP3-dependent inflammation does not seem to play a dominant role.
Conclusions: Development of DBD in male Akita takes a significantly different trajectory from the female suggesting, besides NLRP3-mediated inflammation, alternative pathways can mediate the development of DBD.
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