# Role of Microvascular insulin resistance and cardiorespiratory fitness in diabetes

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $683,451

## Abstract

Project Summary
The goal of this two-site proposal is to determine whether and by what means insulin resistance, in the form of
impaired insulin regulation of microvascular perfusion, leads to decreased functional exercise capacity (FEC) in
type 2 diabetes (T2D). Data from our two research teams suggest that the cardiac and skeletal muscle
microvascular dysfunction present in people with T2D contributes to limitations in cardiac and skeletal muscle
oxygenation and function associated with impaired function exercise capacity (a major predictor of CV and all-
cause mortality). Insulin action is a potent predictor of the FEC impairment in T2D. The exact relationship
between insulin action, cardiac and muscle dysfunction, cardiac and skeletal muscle perfusion and decreased
FEC in T2D remains unclear. Here we propose to address this gap in knowledge by defining the roles of impaired
insulin-mediated cardiac and skeletal muscle perfusion and exercise performance in people with T2D.
Hypothesis: Decreased insulin-mediated muscle perfusion found in T2D contributes to the development
of cardiac and skeletal muscle dysfunction and subsequent impairment in exercise capacity. We further
hypothesize that exercise training attenuates insulin resistance and restores insulin-mediated perfusion
to the skeletal and cardiac muscle, leading to improved exercise performance. Specific Aim 1: To test
the hypothesis that impairment in insulin-mediated cardiac perfusion limits exercise performance
through its effect on cardiac function in people with T2D. We will examine the relationship between insulin-
mediated cardiac perfusion, other measures of cardiac function, and VO2 peak at rest and with exercise in
subjects with and without T2D. Given that there is a sex disparity in diabetes outcomes and exercise impairment
with a lack of mechanistic insights on sex differences, we will analyze all parameters for differences by sex on
an exploratory basis in the three aims. Specific Aim 2: To test the hypothesis that impaired insulin-mediated
skeletal muscle perfusion limits exercise performance through its effect on oxidative capacity in people
with T2D. We will examine the relationship between insulin-mediated skeletal muscle perfusion; muscle
oxygenation, skeletal muscle mitochondrial function and in vivo skeletal muscle oxidative flux; and VO2 peak in
subjects with and without T2D. Specific Aim 3: To test the hypothesis that the improvement in FEC
subsequent to exercise training operates via action on cardiac and muscle function in T2D. These
experiments will test whether the improvements in VO2peak observed with exercise training correlate with
improvements in insulin-mediated perfusion, cardiac and skeletal muscle function and the impact of T2D on
these changes. Understanding the role of microvascular disease in the diabetes-mediated exercise impairment
may offer novel targets for intervention to improve exercise capacity, functional status and longevity in people
with di...

## Key facts

- **NIH application ID:** 10816371
- **Project number:** 5R01DK124344-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** ZHENQI LIU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $683,451
- **Award type:** 5
- **Project period:** 2021-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10816371

## Citation

> US National Institutes of Health, RePORTER application 10816371, Role of Microvascular insulin resistance and cardiorespiratory fitness in diabetes (5R01DK124344-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10816371. Licensed CC0.

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