Diverse symptoms of diabetic bladder dysfunction (DBD), ranging from overactive bladder (OAB) to underactive bladder (UAB), manifest in half of all patients with diabetes. While the cause of such symptom variation is unknown, clinical evidence suggests sex hormones influence the presentation of DBD symptoms. Preclinical models like the type 1 diabetic Akita mouse support this notion as Akita females develop OAB while, for unknown reasons, Akita males develop UAB. It has been proposed the more severe hyperglycemia in males is responsible for UAB development rather than the OAB observed in females; however, the same mutation of the insulin 2 gene is responsible for inducing diabetes in both sexes and the only critical variable responsible for differences in the severity of hyperglycemia and DBD phenotype appears to be endogenous levels of sex hormones. Therefore, we hypothesize sex hormone levels are critical to the differential development of diabetic OAB vs. UAB. Here, we aim to test this hypothesis by determining how the absence of primary sex hormones via gonadectomy impacts blood glucose and the development of DBD in a type 1 diabetic mouse model.

Both male and female type 1 diabetic Akita mice on a C57BL/6J background and non-diabetic C57BL/6J mice were either gonadectomized at 8 weeks of age or remained gonadally intact. Blood glucose was measured weekly from 8-15 weeks of age in all groups (n= 9-15 per group). At 15 weeks of age, awake-restrained cystometry was performed in all groups (n= 9-11 per group) to determine void volume and void frequency. Statistical significance defined as p<0.05 was calculated using a two-way analysis of variance with Tukey post hoc for all groups of blood glucose data and a one-way analysis of variance with Tukey post hoc was used for all groups of either male or female cystometry parameter data.

In gonadally intact mice, blood glucose is significantly higher in male diabetics than female diabetics, and blood glucose of male and female diabetics is significantly higher than non-diabetics of both respective sexes. Compared to respective non-diabetics of each sex, male diabetics develop a significant increase in void volume and decrease in voiding frequency consistent with signs of UAB, while female diabetics develop a significant decrease in void volume and increase in voiding frequency consistent with signs of OAB. Within 7 weeks following a gonadectomy, blood glucose of gonadectomized male diabetics significantly decreases to levels comparable to female diabetics, while blood glucose of gonadectomized female diabetics significantly increases to levels comparable to male diabetics. Surprisingly, despite this significant inverse trend the severity of hyperglycemia, both groups of gonadectomized male and female diabetics fail to develop any discernable signs of DBD as their void volumes and frequencies significantly differ from their gonadally intact counterparts but are not significantly different than non-diabetics of each respective sex. Gonadectomies do not significantly alter the blood glucose and voiding parameters of non-diabetic males and females.

Sex hormones are critical regulators of blood glucose in type 1 diabetic mice as endogenous androgens facilitate severe hyperglycemia while endogenous estrogens limit the severity of hyperglycemia to more moderate levels. Regardless of the severity of hyperglycemia, androgen and estrogen deprivation prevents the early development of respective UAB and OAB associated with diabetes.

This is the first study to demonstrate sex hormone levels have a profound impact on the development of DBD regardless of the severity of hyperglycemia. Sex hormone-dependent mechanisms responsible for the development of DBD may serve as novel therapeutic targets to delay or prevent DBD development and potentially treat existing DBD.

Continence 12S (2024) 101494
DOI: 10.1016/j.cont.2024.101494