Underactive bladder (UAB) or detrusor underactivity (DU) is common in elderly people, and causes distressing storage and voiding symptoms. Treatment options for UAB are extremely limited and generally have poor efficacy. Diabetes mellitus (DM) is well known to cause UAB, however, the underlying molecular mechanism on how DM leads to UAB is not understood. Insulin signaling plays a crucial role in metabolism, and insulin resistance is a key feature in DM. In addition to maintaining metabolic homeostasis, recent progress indicates that insulin signaling is also important for gene transcription, cell proliferation/differentiation, and cell survival, as well. Insulin resistance in different tissues was found to be responsible for hepatic hyperglycemia, cardiac failure, skeletal muscle atrophy, and hyperlipidemia. These activities occur by regulating multiple signaling pathways, including FOXO signaling. However, the role of insulin signaling in bladder tissue is not well studied, and bladder insulin resistance in the pathogenesis of UAB is unknown. Here we are the first to propose that insulin resistance, or disruption of insulin signaling in bladder tissue itself, directly underlies the pathogenesis of diabetic bladder dysfunction (DBD), leading to UAB. To test this hypothesis, we have generated a constitutive heterozygous smooth muscle specific insulin receptor (SMIR+/-) deficient mouse model to mimic the insulin resistance in bladder smooth muscle (BSM). Our preliminary data indicate that SMIR+/- mouse bladder phenocopies DBD/UAB, suggesting a crucial role of insulin resistance in DBD/UAB pathogenesis. In this proposal, we will generate a conditional knockout mouse to specifically delete IR gene in smooth muscle under tamoxifen induction. This model will generate IR signaling deficiency in adult BSM and therefore more closely mimics the human diabetic bladder. We will use this animal model to study its role in the temporal development of DBD/UAB. We will determine: (1) whether IR deletion in BSM contributes significantly to the overall metabolic disorders of the animal by measuring glucose/lipid metabolism, and serum insulin level; (2) whether deficiency of IR mediated signaling in BSM underlies the pathogenesis of DBD/UAB by phenotyping bladder morphology, bladder function, and BSM contractility in these mice. We will further define the potential underlying mechanism in these IR signaling deficiency mice, by studying (1) FoxO family members, (2) FoxO regulated molecules crucial for apoptosis, and (3) molecules critical for smooth muscle structure and function. This study will determine how insulin signaling in BSM impacts its growth, survival, contractility, and the overall bladder function, and provide us with new insights into how insulin resistance leads to DBD/UAB. This knowledge will be important for developing potential novel therapeutic strategies to treat bladder symptoms.!
Underactive bladder or detrusor underactivity is common in diabetic patients, which affects the quality of life significantly with huge economic burden. This project seeks to investigate how insulin receptor mediated signaling controls the bladder muscle function and bladder activity. Understanding of this mechanism is important for us to design logical therapeutic strategies to alleviate, control and prevent these debilitating symptoms.