Controlled, Randomized Chronotherapeutic Lifestyle Intervention Studies in First degree relatives of Type 2 Diabetes Patients

Implementation of chronotherapeutic lifestyle interventions (melatonin and light exposure) in newly designed, intensely phenotyped high risk non-diabetic first degree relatives of subjects with type 2 diabetes in U.K., Germany, and Italy to analyze changes in diurnal variation in clock regulatory mRNA and changes in insulin resistance by lifestyle intervention (primary endpoint).

Shift workers who are known to have a high probability of developing disturbances of circadian rhythm and sleep disorders will be included in WP2, and their glucose metabolism assessed before and after chronotherapeutic lifestyle intervention. In WP3 we shall include first degree relatives with a metabolic syndrome in order to study a high-risk group to develop diabetes, irrespectively of any potential pre-existing disturbances of circadian rhythms or existing sleep disorders. Essentially, the main reason why first-degree relatives of patients with type 2 diabetes have been selected as a target population for WP3 is because they are a clear source of a prediabetic state which would be otherwise very difficult to recruit.

Murine studies indicate that disturbances of the clock lead to the metabolic syndrome. First degree relatives are a group who display features of the metabolic syndrome, and having the metabolic syndrome conveys a 9-fold risk of developing diabetes and a 2-3- fold increased risk of cardiovascular disease. The questions we pose are 1) In this group at high risk of developing diabetes can we identify biomarkers of clock disturbance?, and 2) Can we modify diabetes and cardiovascular risk by light therapy/melatonin.

With the aim in WP3 to assess the disruption of clock gene expression and circadian rhythm in these subjects, pre-selecting for such dysregulation would bias our results