# Effect of Type II Diabetes on Bladder Function

> **NIH VA I01** · VA BOSTON HEALTH CARE SYSTEM · 2020 · —

## Abstract

Bladder dysfunction is one of the most common complications of diabetes with significant negative
consequences on quality of life and healthcare costs, as well as social and mental well-being. Untreated or
undetected bladder dysfunction can result in diabetic cystopathy, leading to chronic urinary tract infections,
nephrolithiasis, pyelonephritis and vesicoureteric reflux. Given the escalating diabetes epidemic, prevention of
this deleterious end-stage condition becomes imperative, requiring a better understanding of mechanisms
contributing to progressive bladder dysfunction, particularly in relation to type II diabetes mellitus (T2DM).
Defects in Akt signaling, though poorly studied in the bladder, play a prominent role in the pathophysiology of
T2DM in other tissues. We hypothesize that defective Akt signaling in T2DM differentially affects smooth
muscle as well as intrinsic neural components of the bladder to cumulatively cause bladder dysfunction. Our
preliminary data suggests that Akt is enriched in bladder smooth muscle caveolae, membrane microdomains
that provide a platform for cross-talk among different signaling pathways. Therefore the goal of specific aim 1
will be to demonstrate that hyperglycemia alters caveolae-Akt dependent bladder smooth muscle responses.
Functional responses of bladder smooth muscle are enhanced in diabetic patients and in animal models of
diabetes. These augmented responses may reflect impaired caveolin-mediated Akt signaling and interaction
with pathways regulating smooth muscle contraction. Akt has also been shown to directly activate myosin 5a, a
motor protein involved in vesicular transport. Our preliminary data suggests that myosin 5a is localized in
intrinsic bladder nerves and mediates excitatory synaptic neurotransmission. Thus the goal of specific aim 2
will be to determine whether hyperglycemia impairs myosin 5a-Akt dependent neurotransmission, by
measuring the release of purinergic and cholinergic neurotransmitters and identifying the interaction between
myosin 5a and Akt under varied experimental conditions. We propose that altered Akt signaling in T2DM
underpins both smooth muscle and neurotransmission defects, leading to a complex dysfunction of bladder
storage and voiding. Therefore, in specific aim 3, we will demonstrate that a T2DM-induced defect in intrinsic
neurotransmission in the bladder impairs voiding function despite hyperreactive SM. Using in vivo and ex vivo
cystometry, we will show that reduced neurotransmission in early T2DM combined with enhanced smooth
muscle activity results in concomitant organ overactivity during filling and underactivity during voiding. At the
conclusion of this work, we expect to have (1) uncovered the dual differential roles of Akt signaling in bladder
neurotransmission and smooth muscle contraction, (2) determined the contributions of caveolae and caveolin
protein expression to signaling pathways affecting bladder smooth muscle contractility, (3) determined th...

## Key facts

- **NIH application ID:** 9864020
- **Project number:** 5I01BX001790-07
- **Recipient organization:** VA BOSTON HEALTH CARE SYSTEM
- **Principal Investigator:** MARYROSE P SULLIVAN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9864020

## Citation

> US National Institutes of Health, RePORTER application 9864020, Effect of Type II Diabetes on Bladder Function (5I01BX001790-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9864020. Licensed CC0.

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