# Tissue-Specific Insulin Resistance in Obstructive Sleep Apnea:  Role of Hypoxia

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $803,867

## Abstract

PROJECT SUMMARY
Obstructive sleep apnea (OSA) is a common condition associated with significant adverse health outcomes.
An estimated 25% of men and 10% of women will have OSA during their lifetime. OSA is associated with an
increased prevalence of insulin resistance and type 2 diabetes and, with severe degrees of OSA, non-alcoholic
fatty liver disease (NAFLD) as well. The mechanisms accounting for the association between insulin resistance
and OSA are not fully understood. We have previously demonstrated that experimentally-induced sleep
restriction in healthy volunteers led to a reduction in whole-body insulin sensitivity and increased rates of
lipolysis and gluconeogenesis, accompanied by an increase in stress hormone levels. Studies by others
suggest that, in animal models studied under hypoxic conditions, hepatic carbohydrate and lipid homeostasis
are perturbed leading to hepatic steatosis and inflammation. Taken together, these observations form the
basis of our overarching hypothesis that patients with OSA and hypoxia (H-OSA) have greater degrees of
insulin resistance in both liver and adipose tissue when compared to those without hypoxia (NH-OSA) thus
leading to increased risk for the development of diabetes in the former group.
In Aim 1 we will test the hypothesis that, although individuals with OSA have been shown to have insulin
resistance in multiple target tissues (adipose, muscle, liver, beta cell), these abnormalities will be significantly
greater in patients with OSA that is accompanied by hypoxia (H-OSA), in comparison to those without hypoxia
(NH-OSA). We will compare tissue-specific insulin sensitivity in 30 subjects with H-OSA and 30 with NH-OSA
matched for sex, ethnicity, age, BMI, and apnea-hypopnea index. Hepatic and extra-hepatic insulin sensitivity
will be measured using hyperinsulinemic-euglycemic clamps and stable isotope tracer studies of endogenous
glucose production, gluconeogenesis, de novo lipogenesis (DNL), and lipolysis. Beta cell function and insulin
kinetics will be assessed from insulin and C-peptide concentrations during an oral glucose tolerance test. Liver
fat will be measured by magnetic resonance and total lean and fat mass by dual-energy X-ray absorptiometry.
In Aim 2 we will test the hypothesis that treatment with continuous positive airway pressure (CPAP) will
improve insulin sensitivity in all of the target tissues and that these improvements will be greater in those with
hypoxia at baseline. After stabilization on CPAP therapy and maintenance for six weeks, each of the
individuals studied in Aim 1 will undergo a repeat sleep study and metabolic assessments identical to those
described above in Aim 1. We speculate that in NH-OSA insulin resistance is primarily triggered by increased
levels of stress hormones due to fragmented sleep and this is manifested largely in extra-hepatic tissues
(muscle and adipose), whereas in H-OSA there is additional stimulation of hepatic DNL, leading to liver fat
accumula...

## Key facts

- **NIH application ID:** 10693797
- **Project number:** 5R01DK117953-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** ANDREW D KRYSTAL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $803,867
- **Award type:** 5
- **Project period:** 2018-09-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10693797

## Citation

> US National Institutes of Health, RePORTER application 10693797, Tissue-Specific Insulin Resistance in Obstructive Sleep Apnea:  Role of Hypoxia (5R01DK117953-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10693797. Licensed CC0.

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