# Mechanisms of Prediabetic States in Obstructive Sleep Apnea > **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2022 · $771,557 ## Abstract PROJECT SUMMARY/ABSTRACT Substantial clinical and experimental evidence indicates that obstructive sleep apnea (OSA) is associated with impaired glucose metabolism. Our laboratory has demonstrated that treatment of OSA by all-night continuous positive airway pressure (CPAP) improves insulin sensitivity and glucose tolerance in prediabetes. To date, the mechanisms by which OSA impairs glucose metabolism remain unclear. It is widely recognized that OSA patients have increased sympathetic activity, which is a potent stimulator of adipose tissue lipolysis leading to increased release of free fatty acids (FFA) into the systemic circulation. FFAs are a major source of energy for the skeletal muscle, which is the tissue that accounts for the majority of insulin-stimulated glucose uptake. Extensive research has demonstrated that ectopic lipid accumulation in the skeletal muscle is one of the key determinants of insulin resistance. We therefore hypothesized is that increased adipose tissue lipolysis (i.e. excess FFA delivery) induced by OSA impairs metabolism in the skeletal muscle, leading to insulin resistance and glucose intolerance. We hypothesize that these impairments occur in part through mitochondrial dysfunction, as mitochondria are important in glucose and fatty acid oxidation, and are highly abundant in the skeletal muscle. Specifically, we will determine whether OSA leads to insulin resistance and glucose intolerance through impairments of cellular metabolism resulting in incomplete substrate utilization and ectopic lipid accumulation in the skeletal muscle (Aim 1) and determine to what extent the metabolic impairments in OSA are explained by increased adipose tissue lipolysis and excess FFA release (Aim 2). To address these aims, we propose to study OSA patients with prediabetes under three in-laboratory conditions in a randomized cross-over design: untreated condition (OSA), treated condition (CPAP), untreated but pharmacologically suppressed lipolysis condition (FFA-suppressed). We will perform whole body and cellular assessments under each study condition. Glucose metabolism will be assessed during both fasting and postprandial states using stable isotope tracers. In muscle tissue, we will assess mitochondrial oxygen consumption, reactive oxygen species, glucose and fat oxidation, fatty acid transport to mitochondria, ectopic accumulation of lipid metabolites, and insulin signaling. The proposed work will be the first to assess cellular bioenergetics (i.e. mitochondrial function) in OSA patients and seeks to determine whether cellular metabolic impairments in the skeletal muscle contribute to insulin resistance and glucose intolerance in OSA, and whether these impairments are occurring in the presence of excess FFA delivery (i.e. by overwhelming mitochondrial capacity) and/or are primary (occurring without excess FFA presence). The mechanistic insights that are expected to be gained from the proposed work will help identify novel targets f... ## Key facts - **NIH application ID:** 10439458 - **Project number:** 5R01HL146127-04 - **Recipient organization:** UNIVERSITY OF CHICAGO - **Principal Investigator:** Esra Tasali - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2022 - **Award amount:** $771,557 - **Award type:** 5 - **Project period:** 2019-07-15 → 2024-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10439458 ## Citation > US National Institutes of Health, RePORTER application 10439458, Mechanisms of Prediabetic States in Obstructive Sleep Apnea (5R01HL146127-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10439458. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*