Akita (Type I Diabetic) Mice Develop Bladder Dysfunction

Abstract

Although lower urinary tract symptoms (LUTS) occur commonly in diabetics, the symptoms vary widely and the mechanisms involved are poorly understood. We used male Akita mice, a strain which harbors a spontaneous mutation resulting in insulin misfolding and the depletion of β‐cells (C57BL/6‐Ins2Akita/J), to develop a model of LUTS in Type I diabetics (T1D). These mice developed hyperglycemia, which was partially treated with subcutaneous insulin pellets, mimicking poorly controlled T1D in humans. As the animals aged, we performed spontaneous void spot assays and cystometrograms to evaluate urine storage and micturition. At 1 month of age, little difference was observed in the bladder function of the Akitas and the age‐ and sex‐ matched controls. However, by 7 months, Akita mice demonstrated an increase in the total voided volume (P>.05) consistent with diabetic polyuria. By 10 months, void spot assays revealed that spot numbers were significantly elevated (P<0.005), suggesting loss of normal continence, and total voided volumes were larger (506±154 vs 151±63 µl; P<0.005). Cystometry with continuous filling demonstrated multiple pre‐voiding contractions with urine leakage, suggesting overactive bladder and urge incontinence, and longer voiding intervals in Akita mice (905±509 vs 360±160s) consistent with bladder enlargement (P<0.005). Results to date indicate that Akita mice, but not controls develop bladder hypercontractility, myogenic and neurogenic alterations, and compensatory bladder hypertrophy in the initial phase of diabetic disease. Planned measurements at 13 and 16 months will determine the progression of bladder dysfunction in this model of T1D. This model will permit direct investigation of mechanisms underlying bladder dysfunction in diabetes. (Supported by P20 DK097818‐02S2).