Diabetic bladder dysfunction progresses from an overactive to an underactive phenotype in a type-1 diabetic mouse model (Akita female mouse) and is dependent on NLRP3

Aims: Diabetic bladder dysfunction (DBD) is a prevalent diabetic complication thought to progress from overactive (OAB) to underactive (UAB) bladder. Previously we found OAB at 15 weeks in the Akita mouse, a genetic model of Type 1 diabetes. The first aim of this study assesses bladder function at 30 weeks to assess progression. In addition, inflammation triggered by the NLRP3 inflammasome is implicated in DBD. In a second aim we assessed a role for NLRP3 by crossing Akita mice with NLRP3^-/- mice.

Main methods: Akita mice were bred with NLRP3^-/- mice. The effect of diabetes was assessed by comparing nondiabetic to diabetic mice (all NLRP3^+/+). The effect of diabetes in the absence of the NLRP3 inflammasome was assessed by comparing nondiabetic/NLRP3^-/- to diabetic/NLRP3^-/- mice. Mice were assessed at 30 weeks for blood glucose (glucometer), inflammation (Evans blue), bladder morphology (histology) and bladder function (urodynamics).

Key findings: At 30 weeks blood glucose of nondiabetics and diabetics was not affected by the presence of absence of NLRP3. Diabetic/NLRP3^+/+ mice showed bladder inflammation and detrusor hypertrophy which was blocked in the diabetic/NLRP3^-/- mice, clearly showing a role for NLRP3. When bladder function was examined, diabetic/NLRP3^+/+ showed an increase in voiding volume and a decrease in frequency, two signs of underactive bladder. However, in the NLRP3^-/- mice, diabetes was unable to effectuate these changes, demonstrating that NLRP3-induced inflammation is responsible for UAB symptoms in these mice.

Significance: Akita diabetic mice progress from OAB to UAB. NLRP3 is a possible target to treat DBD.