# Ectopic Lipid in Skeletal Muscle is Associated with Glucose Intolerance in Veterans with HIV

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

The Department of Veterans Affairs is the largest provider of medical care to people with HIV in the United
States; in 2016 ~30,000 Veterans received treatment for HIV from the Veterans Health Administration (VHA).
Over the last several decades, the success of antiretroviral therapy (ART) treatment for HIV infection has
changed the demographics and phenotype of Veterans living with HIV. Although HIV+ Veterans are living longer,
78% of them are overweight or obese, and they have a two-fold greater risk of developing type 2 diabetes
compared to Veterans without HIV. While much of the research on HIV and metabolic disease has focused on
the interaction between obesity and the accumulation of ectopic fat in the liver, several recent studies highlight
the central role of ectopic fat in skeletal muscle in the pathogenesis of insulin resistance and diabetes. However,
this important phenomenon has received little attention in the context of HIV infection and the role of skeletal
muscle ectopic fat in the complex interaction between HIV and obesity remains unclear.
Defects in adipose tissue lipid storage and regulation are hallmark of both HIV infection and obesity, which leads
to a high degree of ectopic fat accumulation in tissues such as the liver and skeletal muscle. While several
studies have investigated ectopic liver fat as a risk factor for diabetes in HIV, our novel hypothesis is that impaired
glucose tolerance in Veterans with treated HIV and obesity is driven by disproportionately greater ectopic lipid
infiltration of skeletal muscle (the primary site of glucose uptake) promoting impaired myocyte bioenergetics and
glucose homeostasis (Fig.1). This is supported by our preliminary CT imaging, MRS imaging, and glucose
metabolism data that implicate skeletal muscle pathology in HIV associated glucose intolerance: 1) Our CT data
show ectopic fat infiltration in muscle is greater in HIV+ diabetics vs nondiabetics; 2) Our MRS data show higher
muscle triglyceride content is associated with a slower rate of ATP synthesis; 3) Our metabolic data show lower
plasma acylcarnitines (indicating impaired mitochondrial oxidation) correlates with insulin resistance in HIV.
In the proposed study, we aim to determine: a) whether the deposition of excess lipid in skeletal muscle in HIV+
Veterans is a phenomenon separate from hepatic fat deposition and a hallmark for T2DM in this population (Aim
1); b) whether skeletal muscle fat accumulates over time in nondiabetic overweight/obese Veterans and is
accompanied by reductions in muscle mitochondrial oxidative capacity, ATP production, and muscle force (Aim
2); and c) whether changes in skeletal muscle ectopic fat and mitochondrial oxidative capacity over time are
accompanied by reductions in insulin sensitivity and glucose tolerance (Aim 3).
To accomplish these aims, we will recruit two cohorts of HIV+ Veterans on long-term ART that will be matched
by sex, age, race, BMI and CD4/CD8 ratio. Group 1: 45 Veterans with HIV...

## Key facts

- **NIH application ID:** 10417013
- **Project number:** 5I01CX001930-03
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** John Koethe
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10417013

## Citation

> US National Institutes of Health, RePORTER application 10417013, Ectopic Lipid in Skeletal Muscle is Associated with Glucose Intolerance in Veterans with HIV (5I01CX001930-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10417013. Licensed CC0.

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