Impact of Circulating and Tissue-specific Lipids on Vascular Function and Insulin Sensitivity in Chronic Night Shift Workers

Overview

People who experience repeated bouts of circadian misalignment, such as shift workers, are at higher risk of cardiovascular disease (CVD) and Type 2 diabetes (T2D) compared to daytime workers. However, the mechanism(s) by which shift work and associated circadian misalignment increase CVD and T2D risk are unknown. This project will examine whether elevated plasma lipids are a mechanism by which circadian misalignment impairs vascular function, insulin sensitivity, glucose homeostasis and muscle lipid accumulation, which could be targeted to prevent and treat cardiometabolic disease in people who chronically experience circadian misalignment, which includes more than 20% of the US workforce.

There is growing recognition that timing of behaviors, such as eating, sleeping, and activity, have a significant impact on human health and disease risk. For example, when people are awake at the "wrong" time of the day (i.e. during the biological night), a mismatch occurs between behavior and biology, termed circadian misalignment. Shift workers experience repeated bouts of circadian misalignment and are at higher risk of cardiovascular disease (CVD) and Type 2 diabetes (T2D) compared to people who work days. However, the mechanism(s) by which shift work and associated circadian misalignment increase CVD and T2D risk are unknown. Data from the investigators and others demonstrate impaired vascular endothelial function and insulin sensitivity during circadian misalignment, two important risk factors for future development of CVD and T2D. Furthermore, the investigators published and unpublished data support that circadian misalignment increases circulating bioactive lipids known to associate with impaired endothelial function and insulin resistance. Indeed, shift workers also have elevated circulating lipids, though it is not known which specific lipids are elevated, and whether they are associated with impaired vascular function and/or insulin sensitivity. Using a circadian-based eating intervention (time-restricted eating; TRE), we can consistently reduce lipids in circulation, as well as reduce heart rate and blood pressure and improve glucose homeostasis. Therefore, the overall objective for this project is to examine whether increased plasma lipids are a potential mechanism by which chronic circadian misalignment impairs cardiovascular and metabolic health with the long-term goal of identifying novel therapeutic targets to combat the risks for disease when circadian misalignment is unavoidable. The central hypothesis is that reducing plasma lipids in night shift workers via TRE will improve vascular function, insulin sensitivity and glucose homeostasis, and reduce muscle tissue lipid accumulation. To test the hypothesis, we will conduct a 12-week randomized crossover study in 50 non-rotating night shift workers (25Females/25Males; 18-65years) with existing cardiometabolic risk factors. At the end of each 4-week outpatient condition (TRE vs Control with an intervening 4-week washout period), we will conduct rigorous 3-day inpatient assessment to determine the impact of plasma lipid reduction via TRE in chronic night shift workers on 1) vascular function and blood pressure; and 2) whole body and muscle-specific insulin sensitivity, glucose homeostasis and muscle lipid accumulation. Achievement of these aims will identify a potential mechanism by which circadian misalignment impairs vascular function and insulin sensitivity (elevated plasma lipids), as well as a non-pharmacological tool (TRE) that could be implemented to reduce cardiometabolic disease risk in populations at elevated risk, in 20% of the US workforce who work nonstandard hours including military personnel, police, paramedics, firefighters, pilots, medical doctors and nurses, as well as people with sleep and circadian disorders.