Urological complications of obesity and diabetes in males and females of three mouse models: temporal manifestations.

Diabetic bladder dysfunction is a frequent complication of diabetes. Although many mouse models of diabetes now exist, there has been little systematic effort to characterize them for the timing of onset and severity of bladder dysfunction. We monitored metabolic status and tested bladder function by void spot assay and limited anesthetized cystometry in both male and female mice of three models of obesity and diabetes: a type 1 diabetes model (the Akita mouse) and two type 2 diabetes models [the diet-induced obese (DIO) model and the ob/ob mouse]. Akita mice had insulin pellets implanted subcutaneously every 3 mo to mimic poorly controlled type 1 diabetes in humans. Mice were hyperglycemic by 48 days after implants. Female mice exhibited no bladder dysfunction at any age up to 20 mo and gained weight normally. In contrast, by 7 mo, male Akita mice developed a profound polyuria and failed to show normal weight gain. There were no observable signs of bladder dysfunction in either sex. DIO mice on high/low-fat diets for 16 mo exhibited mild hyperglycemia in female mice (not in male mice), mild weight gain, and no evidence of bladder dysfunction. Ob/ob mice were followed for 8 mo and became extremely obese. Male and female mice were glucose intolerant, insulin intolerant, and hyperinsulinemic at 4 mo. By 8 mo, their metabolic status had improved but was still abnormal. Urine volume increased in male mice but not in female mice. Bladder dysfunction was observed in the spotting patterns of female mice at 4 and 6 mo of age, resolving by 8 mo. We conclude there are dramatic sex-related differences in lower urinary tract function in these models. Male Akita mice may be a good model for polyuria-related bladder remodeling, whereas female ob/ob mice may better mimic storage problems related to loss of outlet control in a setting of type 2 diabetes complicated by obesity.

Effect of filling rate on cystometric parameters in young and middle aged mice.

OBJECTIVES: To investigate the effect of changing the bladder filling rate during cystometry in younger (2-3 months) and older (13-14 months) C57BL/6J male mice. METHODS: Cystometry was performed on mice under anesthesia. Voiding cycles were established in each mouse at a pump delivery rate of 17 µl/min. After 30 min, the rate was increased sequentially to 25, 33, 41 and 49 µl/min. Each rate was maintained for 30 min. The following cystometric parameters were quantified: peak pressure amplitude, intercontractile interval (ICI), compliance, micturition pressure threshold and voiding efficiency. RESULTS: Bladder weights were significantly greater in older mice (42 mg vs. 27 mg, P < 0.01), but functional capacities were not different. The pressure amplitudes did not change as filling rate increased, nor did they differ between the 4-month and 13-month-old males. ICIs were not significantly different between young and mature mice. However, both groups exhibited a non-linear reduction in ICI with increasing filling rate, best described by a power curve (R2 > 0.93). Compliance was higher in the older mice at low filling rates (17 and 25 µl/min) but this difference diminished at higher rates. Compliance decreased with increasing flow rate in a non-linear manner, again with greater effects at low filling rates. Micturition pressure thresholds increased with increasing flow rate in a linear manner and older mice began voiding at higher pressures than younger. Both young and old mice exhibited voiding efficiencies of ~70%. CONCLUSIONS: The rate of volume delivery has complex effects on the timing of voiding and compliance. These findings argue for greater standardization of cystometry protocols and further investigation into afferent signaling to higher centers at different filling rates.