# Unacylated Ghrelin to Improve FuncTioning in PAD: the GIFT Trial

> **NIH NIH R21** · NORTHWESTERN UNIVERSITY · 2020 · $202,189

## Abstract

Unacylated Ghrelin to Improve FuncTioning in PAD: the GIFT Trial
 Our work and that of others shows that patients with lower extremity peripheral artery disease (PAD)
have greater functional impairment, faster functional decline, and higher rates of mobility loss compared to
people without PAD. In patients with PAD, ischemia results in calf muscle injury that includes myofiber loss
and calf muscle mitochondrial dysfunction. Therapies to regenerate calf skeletal muscle cells, improve
mitochondrial function, and increase calf muscle capillary density may improve functioning and prevent mobility
loss in people with PAD. Yet few effective therapies currently exist for patients with PAD.
 This pilot study will investigate the therapeutic potential of unacylated ghrelin to promote capillary
growth, increase calf muscle perfusion, and reverse PAD-related skeletal muscle abnormalities, thereby
improving PAD-related functional impairment. Ghrelin is a peptide and hormone that circulates in acylated and
unacylated forms. Unacylated ghrelin promotes skeletal muscle cell regeneration, improves mitochondrial
function, and increases muscle capillary density. Unlike acylated ghrelin, unacylated ghrelin does not increase
appetite, or cause insulin resistance.
 The proposed GIFT Trial will provide preliminary data to test our hypothesis that unacylated ghrelin
improves walking performance and prevents mobility loss in older patients with PAD. We further hypothesize
that the favorable effect of unacylated ghrelin will be mediated by increased myofiber regeneration, increased
muscle capillary density, and improved muscle mitochondria function. If our preliminary data support our
hypotheses, results will be used to design a large randomized trial of unacylated ghrelin therapy, in subsequent
study, to improve functioning and prevent mobility loss in older people with PAD.
 We will conduct a pilot randomized trial in 30 participants age 60 and older with PAD, to gather
preliminary evidence about whether daily subcutaneously administered unacylated improves the six-minute
walk distance (primary outcome), maximal treadmill walking distance (secondary outcome), and calf muscle
perfusion (secondary outcome), compared to placebo. We will also perform calf muscle biopsies at baseline
and follow up to determine whether unacylated ghrelin increases Type 1 skeletal muscle myofibers, satellite
cell number, capillary density, and succinate dehydrogenase (SDH) mitochondrial activity in calf skeletal
muscle, compared to placebo. If our hypotheses are correct, results will be used to design a large, definitive
randomized trial of unacylated ghrelin to improve lower extremity functioning and prevent mobility loss in the
large and growing number of older people who are disabled by PAD.

## Key facts

- **NIH application ID:** 9927974
- **Project number:** 5R21AG063076-02
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Mary McGrae McDermott
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $202,189
- **Award type:** 5
- **Project period:** 2019-05-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9927974

## Citation

> US National Institutes of Health, RePORTER application 9927974, Unacylated Ghrelin to Improve FuncTioning in PAD: the GIFT Trial (5R21AG063076-02). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/9927974. Licensed CC0.

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