Timing of physical exercise to prevent and treat type 2 diabetes: The role of circadian rhythms in metabolic tissues in humans

Daily fluctuations in metabolism are driven by 24-h circadian molecular clocks across all tissues.

Accordingly, the risk of metabolic diseases, such as type 2 diabetes mellitus (T2DM), is increased by sleep loss and circadian misalignment (e.g. in shift work).

Our work points that this occurs via disrupted circadian regulation of tissue metabolism, and that physical activity (PA) alters molecular clock-driven tissue responses. Even though PA can impact sleep and is a critical lifestyle intervention for improving metabolic health – in e.g.

T2DM – we do not understand its molecular impact on metabolic circadian rhythms in humans, nor how the daily timing of PA modulates circadian molecular responses involved in metabolic diseases such as T2DM.Here I outline a translational approach to dissect the mechanistic pathways through which PA exerts circadian metabolic regulation.

Through interventions in healthy and T2DM patients, with high-resolution circadian adipose and skeletal muscle sampling, I will examine a) PA vs. inactivity (yr 1-3), b) the timing of PA, and c) how genetic disruption in mice alters how the timing of PA impacts circadian metabolism (yr 2-5).

The focus will be on how systemic and tissue-specific transcriptional and epigenetic circadian rhythms regulate glucose and lipid metabolism.

My project will delineate biomarkers and key circadian mechanisms for how exercise and its timing can be utilized to counteract adverse metabolic effects of T2DM and shift work.