# Cardiovascular Mechanisms of Exercise Intolerance in Diabetes and the Role of Sex

> **NIH VA I01** · VA EASTERN COLORADO HEALTH CARE SYSTEM · 2021 · —

## Abstract

Statement of Problem: Type 2 Diabetes (T2D) affects 24% of Veterans and it is associated with
impaired cardiovascular exercise capacity (CVEC) which is important because of a strong relationship between
CVEC and excess mortality. The goal of this proposal is to understand the contribution of preclinical
cardiac, vascular dysfunction and skeletal muscle perfusion abnormalities to impaired CVEC in men
and women with T2D and, further, to test the adaptive response to intervention using exercise training
to reveal modifiable targets for therapy to improve cardiometabolic health.
 Overall Hypothesis: Impaired CVEC in T2D is the result of preclinical cardiac, vascular dysfunction
and skeletal muscle perfusion abnormalities. Exercise training will improve CVEC and will reveal specific
reversible therapeutic aspects of this pathology.
Specific Aims: SA#1: To test the hypothesis that the integration of cardiac function, macrovascular function,
and microvascular function is impaired in T2D and correlates with CVEC impairment.
Rationale: CVEC is dependent upon a coordinated delivery of substrate (E.g. O2) from the pulmonary circula-
tion to the working tissue (e.g. muscle). We postulate that poor integration of CV function and net blood flow
and/or flow distribution to working muscle results in diminished CVEC. Measurements to examine CV effects
of diabetes to date have focused on cardiac, vascular and skeletal muscle tissues separately but not simulta-
neously. Experiments: Conventional endpoints (peak O2 consumption (VO2peak), resting echocardiography
and insulin clamp) and advanced imaging modalities (4D flow CV magnetic resonance imaging (MRI), 2D PC-
MRI and muscle 1H magnetic resonance spectroscopy (1H MRS) will be employed to construct a systemic
model of pathological changes in CVEC in men and women with and without T2D at rest and during exercise.
Outcomes: The proposed studies will employ a comprehensive view of integrated CV systemic function in
health and T2D using MR-based imaging in men and women with and without T2D.
 SA#2: To test the hypothesis that exercise training will elicit specific adaptive responses in the
integrated CV system, muscle perfusion and metabolism with differences by T2D status.
Rationale: Exercise training impacts cardiac, macrovascular and microvascular function and metabolism
through improving the integrated CV system. New pilot data demonstrate that abnormal muscle oxidative
function in vivo in T2D is acutely normalized with supplemental O2 (consistent with an O2 supply limitation) and
unchanged in obese nondiabetic control subjects. Perfusion heterogeneity has been reported in rodent models
and human subjects with T2D. New modeling algorithms, developed in our lab, indicate that perfusion
heterogeneity can explain impaired O2 extraction in DM models. With our novel systematic approach, we will
be able to discern which aspects of the systemic response to exercise improve with training. Experiments: All
participants wi...

## Key facts

- **NIH application ID:** 10451482
- **Project number:** 5I01CX001532-05
- **Recipient organization:** VA EASTERN COLORADO HEALTH CARE SYSTEM
- **Principal Investigator:** JANE E REUSCH
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10451482

## Citation

> US National Institutes of Health, RePORTER application 10451482, Cardiovascular Mechanisms of Exercise Intolerance in Diabetes and the Role of Sex (5I01CX001532-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10451482. Licensed CC0.

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