# Role of Insulin Receptor-mediated Signaling In Underactive Bladder

> **NIH NIH R21** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $218,750

## Abstract

Abstract:
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.!

## Key facts

- **NIH application ID:** 9987455
- **Project number:** 5R21AG064633-02
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** weiqun yu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $218,750
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9987455

## Citation

> US National Institutes of Health, RePORTER application 9987455, Role of Insulin Receptor-mediated Signaling In Underactive Bladder (5R21AG064633-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9987455. Licensed CC0.

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