Obstructive sleep apnea (OSA) is a common disorder that impairs stable breathing during sleep. OSA is a risk factor for type 2 diabetes, a leading cause of worldwide disability and cardiovascular disease. Furthermore, OSA can induce insulin resistance, vascular dysfunction, and inflammation ? insults that ultimately lead to diabetes and atherosclerotic cardiovascular disease. Currently, the mechanism by which OSA causes cardiometabolic dysfunction is not known. This lack of knowledge makes it impossible to determine which asymptomatic patients require treatment, or to salvage the metabolic health of those unable to tolerate continuous positive airway pressure (CPAP) therapy. Intermittent hypoxia (IH) has been used to simulate a OSA in mice. Chronic IH has been shown to cause dyslipidemia, vascular stiffness, and glucose intolerance. Moreover, acute IH increased plasma free fatty acids (FFA) and hyperglycemia in a dose- dependent manner, and these effects were abolished by pharmacologic or surgical interruption of the sympathetic nervous system. Recently, it has also been shown that OSA increases nocturnal FFA and glucose levels and causes insulin resistance during sleep. These findings demonstrate that OSA is a potent episodic cause of adipose tissue lipolysis and inhibited glucose clearance, with potentially devastating cumulative long-term impacts. The goal of this project is to understand:
(Aim 1) in which OSA patients do FFA and glucose elevations occur, and (Aim 2) by what mechanism? Answers to these questions will identify susceptible patients with OSA, and identify treatment targets for these individuals. It is hypothesized that severity of OSA (as measured by AHI or by increased median heart rate during sleep) correlates with substrate elevations. Additionally, independent and/or interactive effects of gender and AHI on metabolism will be assessed. In a mouse model of IH, beta adrenergic blockade with propranolol prevented metabolic dysfunction. Thus, the second aim of this project is to test the efficacy of propranolol versus placebo in human OSA for preventing nocturnal substrate elevations. This proposal will discover mechanisms by which OSA contributes to metabolic dysfunction, identify patients susceptible to this pathophysiology, and introduce the novel use of beta blockade for therapy.

Public Health Relevance

Obstructive sleep apnea (OSA) impairs breathing during sleep, and increases risks of diabetes and cardiovascular disease. Mechanisms linking OSA to these outcomes are not known, but we have shown that levels of glucose and free fatty acids are dynamically increased in OSA patients during sleep, compared to when they sleep with continuous positive airway pressure (CPAP) therapy. In this pilot clinical study, we examine clinical determinants of these metabolic changes, and whether OSA-induced glucose and fatty acid elevations can be prevented by beta adrenergic blockade with propranolol.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Small Research Grants (R03)
Project #
1R03HL138068-01
Application #
9372432
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Brown, Marishka
Project Start
2017-09-01
Project End
2019-07-31
Budget Start
2017-09-01
Budget End
2018-07-31
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21205
Pham, Luu V; Schwartz, Alan R; Jun, Jonathan C (2018) Oxyhemoglobin Saturation Overshoot Following Obstructive Breathing Events Mitigates Sleep Apnea-Induced Glucose Elevations. Front Endocrinol (Lausanne) 9:477
Gu, Chenjuan; Jun, Jonathan C (2018) Does Hypoxia Decrease the Metabolic Rate? Front Endocrinol (Lausanne) 9:668
Gu, Chenjuan; Younas, Haris; Jun, Jonathan C (2017) Sleep apnea: An overlooked cause of lipotoxicity? Med Hypotheses 108:161-165
Chopra, Swati; Rathore, Aman; Younas, Haris et al. (2017) Obstructive Sleep Apnea Dynamically Increases Nocturnal Plasma Free Fatty Acids, Glucose, and Cortisol During Sleep. J Clin Endocrinol Metab 102:3172-3181