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  • Periodic Report Summary 3 - EURHYTHDIA (Chronotherapeutic lifestyle intervention for diabetes and obesity to reset the circadian rhythm and improve cardiometabolic risk in the European working population)

Periodic Report Summary 3 - EURHYTHDIA (Chronotherapeutic lifestyle intervention for diabetes and obesity to reset the circadian rhythm and improve cardiometabolic risk in the European working population)

Project Context and Objectives:
Epidemiological evidence indicates that obesity-related insulin resistance predates the development of frank type 2 diabetes by up to 20 years, but that during this important period, risk of cardiovascular disease begins to merge. Exciting recent data from experimental and clinical Research strongly supports the view that weight gain, for example, disrupts the endogenous circadian clock, and that this disruption puts metabolism out of time with our energy needs, creating a strong determinant of type 2 diabetes risk. In murine studies genetic disruptions in circadian clock genes lead to the development of a phenotype similar to human type 2 diabetes/obesity. Although there are no studies in human subjects yet that causally relate clock genes to the development of type 2 diabetes, members of our consortium have reported that variation in Clock genotype relates to the metabolic syndrome in man, and epidemiological data has shown that shift workers – who are known to experience disrupted circadian rhythms – are at increased risk of developing type 2 Diabetes mellitus. The portions of the population affected by this increased risk related to disrupted circadian rhythms are vast. Modern European lifestyle has dramatically changed the daily, circadian, rhythm of life in almost the entire European population. Physical activity, food intake and light exposure are no longer restricted to daytime hours, and sleep duration has been continuously reduced over the last century. Shift work, late night activities in adolescents and adults, and increasingly popular long-distance
travel have incrementally increased the percentage of the population affected. These lifestyle changes affect psychomental health, sleep and fatigue, and – as more recent studies indicate – cardiometabolic health. Recent experimental and clinical data suggest that lifestyle Intervention might benefit from consideration of the impact of the timing of application during the day. Accordingly, EuRhythDia aims to understand the importance of circadian regulation of metabolism in and the ability of timed lifestyle intervention to modify the development of cardiometabolic risk associated with obesity, type 2 diabetes and cardiovascular disease.
In order to achieve this ambitious goal, the consortium`s research efforts will combine data from existing prospective cohorts with that from new interventional cohorts, supplemented by existing genetically engineered animal models, high throughput screening methods, and state-of-the-art ´omics´ technologies to 1) identify novel biomarkers of circadian disruption and 2) characterize the effects of novel lifestyle interventions on identified biomarkers and established cardiometabolic risk.

Project Results:
EuRhythDia investigators have performed in-depth analyses of metabolite patterns and epigenomic modifications in clock genes to elucidate the molecular links between night shift work and disrupted metabolic homeostasis. Bioinformatics approaches are being undertaken to dissect molecular Tracers that may be useful for early diagnosis and intervention. Intervention studies in night shift workers are about to be completed in which diverse approaches to reset the circadian clock (by light therapy, circadian-timed exercise, and melatonin treatment) have been tested in controlled clinical studies. In addition, circadian intervention with melatonin has been launched in first degree relatives of patients with type 2 diabetes, thus allowing us to carry previous results further to one of the main at-risk groups for type 2 diabetes. Samples from both clinical intervention projects are currently submitted to bioanalytical investigation. In addition, currently ongoing animal experiments have revealed that circadian regulatory target genes a priori selected by the EuRhythDia consortium play a major role in regulating metabolic state. Specifically, our experiments in knock-out mouse models suggest that under conditions of time-restricted feeding and exercise the molecular intervention in clock genes does affect the metabolic phenotype, which supports the view that the circadian clock controls glucose homeostasis. In addition, a zebrafish model of circadian disorder has been validated, which is now being used to study the molecular sequelae of our interventions. Assay development and small molecule screening for circadian- and metabolic-related targets have led to diagnostic tools and compounds that were identified and will now be further developed beyond the scope of this project.

Potential Impact:
EuRhythDia aims to close the existing research gap in our understanding of the molecular links between disturbed circadian rhythms and the incidence of type 2 diabetes/obesity in man. This is the first translational research project that aims to prove causality whether chronotherapeutic lifestyle intervention alters risk of diabetes /obesity to a clinically relevant degree. Combined with efforts for identification of new drug targets in animals, this will allow the characterization of novel diagnostic approaches for early identification of patients at risk, when preventive measures still have a chance to ameliorate and prevent disease, and to address novel molecular targets for chronopharmacotherapy and targeted lifestyle intervention of metabolic disease. The EuRhythDia consortium expects the results of the interventional and translational studies to significantly modify strategies aiming at modifying the risk of type 2 diabetes and the metabolic syndrome in high-risk populations in Europe.

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