Circadian Mechanisms of Glycemic Control and Cardiovascular Risk in Adults with Type 1 Diabetes

Abstract People with type 1 diabetes (T1D) are disproportionately affected by cardiovascular disease (CVD). CVD is a leading cause of death in T1D, contributing to 40% of mortality. Sleep is recognized by both the American Heart Association and the American Diabetes Association as a critical health behavior to maintain glycemic

control and reduce CVD risk. Short and/or irregular sleep have been associated with reduced glycemic control and non-dipping blood pressure in T1D, both of which are predictors of CV events. Emerging data suggest that behavioral sleep interventions targeting short or irregular sleep led to improved glycemic parameters. However,

little is known about the mechanism by which improving sleep duration and/or regularity improves glycemic control and reduces CV risk in T1D. Our group and others have shown that people with T1D often experience poor sleep health, including inadequate sleep duration, sleep irregularity, and poor sleep quality. In particular,

studies from our lab have demonstrated that objectively measured sleep regularity (irregularity in sleep timing or duration) is a strong predictor of glycemic control and insulin resistance. We have tested a behavioral sleep intervention among adults with T1D and demonstrated improved sleep regularity and time spent in a desirable

glucose range from continuous glucose monitoring (CGM). Furthermore, we also found that poor self-reported sleep quality in young T1D adults was associated with reduced flow mediated dilatation (FMD), a marker of endothelial dysfunction. These observational studies demonstrate that the timing and quality of sleep are

related to key metabolic and CVD risk markers in T1D, but lack the detailed measurements and experimental design needed to determine mechanisms. The goals of this proposal are to examine the mechanisms by which improving sleep regularity through behavioral sleep intervention affects glycemic control and CVD risks in T1D

adults. We propose to extend our previous research by conducting a mechanistic study using a sleep stability manipulation. We hypothesize that sleep stability impacts glycemic control and CV outcomes by improving circadian regulation. We will conduct a 4-week behavioral sleep stability intervention in 80 T1D adults with

irregular sleep, utilizing a sleep pre/post design. Circadian regulation will be assessed by dim-light melatonin onset (DLMO), melatonin metabolite amplitude (overnight urinary 6-sulfatoxymelatonin levels), actigraphy- derived rest-activity rhythm, endothelial cell CLOCK gene mRNA expression, and known zeitgebers of the

central and peripheral circadian clocks (light exposure, meal timing). Main glycemic outcomes will be assessed by CGM, A1C, and assessment of insulin sensitivity. Main CV outcomes will include 24h blood pressure and endothelial FMD and other secondary vascular measures (pulse wave velocity, carotid intima media thickness,

and echocardiographic parameters). Sleep will be objectively recorded. All parameters will be measured at baseline and end of intervention. This proposal will advance the understanding of mechanisms by which improving sleep regularity influences glycemic control and cardiovascular risk in T1D.