Behavioral Circadian Rhythms, Epigenetics, and Cardiometabolic Risk

Nearly half of US adults have type 2 diabetes (T2D) or prediabetes, which significantly increase risk of CVD morbidity and mortality. In fact, fasting hyperglycemia is identified as 1 of 7 key modifiable CVD risk factors in the AHA's Life's Simple 7. Further, blood glucose displays a diurnal pattern and elevated 24-h glucose and glycemic variability have also been linked to greater CVD risk. Intervention studies that misalign behavioral and endogenous rhythms indicate that circadian disruption leads to impaired glucose tolerance resembling that of prediabetes, suggesting that the circadian rhythmicity of lifestyle behaviors may serve as a novel T2D prevention target. However, intervention studies do not reflect habitual patterns of behavior in a real life setting, do not capture long-term effects of milder circadian misalignment that is highly prevalent in the population, and have yet to elucidate underlying mechanisms. The research goal of this award is to evaluate associations of circadian rest-activity rhythms (CRAR), an innovative behavioral measure of circadian rhythmicity in the free-living setting from objective sleep and activity data, with T2D and prediabetes risk, and to investigate epigenetic pathways as an underlying mechanism. In Aim 1, we will evaluate associations of CRAR with T2D and prediabetes risk and diabetes-related phenotypes in the Multi-Ethnic Study of Atherosclerosis (MESA), and elucidate sex and racial/ethnic differences. In Aim 2, we will conduct a community-based study to examine the influence of CRAR on 24-h glucose measures and glycemic variability from continuous glucose monitoring in real-time. In Aim 3, we will examine the relations between CRAR, epigenetic age (a DNA methylation-based measure of biological aging), and diabetes-related phenotypes in MESA, and determine whether epigenetic aging mediates associations of CRAR with T2D risk. The training component will promote further acquisition of transdisciplinary competencies in circadian concepts and methods, epigenetics, and cardiometabolic disease etiology through didactic instruction, seminars, workshops, and mentored career development activities, including grant writing. The training and research activities will propel me towards my career goal: to be an interdisciplinary independent scientist who specializes in the intersection of behavioral factors, circadian rhythms, and epigenetics in CVD risk, and will prepare me to successfully compete for R01 funding.