Mapping sleep and circadian rhythm disruption impacts on cardiometabolic disease

In the UK more than 4.3 million people live with Type-2 Diabetes (T2D), and 2.4 million more are at increased risk of developing the disease. T2D, obesity, hypertension, and fatty liver disease frequently cluster together in the same individuals, termed cardiometabolic multimorbidity. The risk factors for cardiometabolic disease (CMD) are multiple, but disturbances of sleep and our bodies’ internal clock are emerging as important drivers of disease incidence and severity. Sleep and body clock problems are made worse by shiftwork, light at night, and other aspects of modern living. But importantly, they are often disturbed by CMD; thereby creating a vicious cycle perpetuating poor health and wellbeing. It is this vicious cycle we seek to break – yet the contribution of sleep and circadian rhythms disruption (SCRD) to CMD remains under-researched. We will use large amounts of data available from human studies (millions of people, carefully studied over years, and with genetics, and other health-related measurements). We will use sophisticated genetic techniques and analytical approaches to discover how changes to the body clock, or its alignment to the environment (e.g. shiftwork) and nutrition (e.g. altered patterns of daily eating) contribute to cardiometabolic disease. This can also find the genes and processes that links the body clock and health outcomes. In parallel, we will study animals in which we can manipulated the body clock itself and alter the environment (e.g. light dark cycle) and diet to model the changes that we see in people. We will determine how these changes affect processes involved in cardiometabolic disease. We can also test interventions that may be effective in slowing or reversing progressing to disease, which may ultimately help people already living with cardiometabolic disease. Our pilot work has already identified promising new targets and genes to study. We will test these new discoveries using both our pre-clinical animal models, in which we can delete the gene and see how this affects CMD and the underlying disease mechanisms. We capitalise on a valuable resource of human volunteers who have agreed to be involved in our research. Within this group we have significant numbers who have natural variations in a gene that we have identified as linking SCRD, CMD, and alteration in a specific family of lipids, the sphingomyelins, which include a potentially harmful group of ceramides. We will study these volunteers in detail to see how the variation affects their health. Throughout our work, we involve and communicate with people living with CMD, and those who are living with sleep and body clock issues (including shiftworkers). This communication helps us understand the impact of the problems on people lives, and also what kind of steps people can take to protect themselves, what works, and what does not. We will transform understanding of how sleep and body clock affects cardiometabolic disease, find new ways of measuring this burden, discover new approaches to mitigate the risk, and to treat the consequences. We will also make new discoveries into why cardiometabolic disease is so common and rising in scale with time. Our work will synergise with initiatives to improve the measurement of sleep, and rhythmic human activity using wearable devices, identify novel risk biomarkers, and the moves to prevent the development of T2D using targeted lifestyle interventions.