While it is generally known that metabolic disorders and circadian dysfunction are intertwined, how the two systems affect each other is not well understood, nor are the genetic factors that might exacerbate this pathological interaction. Blood chemistry is profoundly changed in metabolic disorders, and we have previously shown that serum factors change cellular clock properties. To investigate if circulating factors altered in metabolic disorders have circadian modifying effects, and whether these effects are of genetic origin, we measured circadian rhythms in U2OS cell in the presence of serum collected from diabetic, obese, or control subjects. We observed that circadian period lengthening in U2OS cells was associated with serum chemistry that is characteristic of insulin resistance. Characterizing the genetic variants that altered circadian period length by genome-wide association analysis, we found that one of the top variants mapped to the E3 ubiquitin ligase MARCH1 involved in insulin sensitivity. Confirming our data, the serum circadian modifying variants were also enriched in type 2 diabetes and chronotype variants identified in the UK Biobank cohort. Finally, to identify serum factors that might be involved in period lengthening, we performed detailed metabolomics, and found that the circadian modifying variants are particularly associated with branched chain amino acids, whose levels are known to correlate with diabetes and insulin resistance. Overall, our multi-omics data showed comprehensively that systemic factors serve as a path through which metabolic disorders influence circadian system, and these can be examined in human populations directly by simple cellular assays in common cultured cells.

Objective: To evaluate the efficacy of an exercise intervention, in addition to usual care, to prevent or delay insulin prescription in women with gestational diabetes mellitus (GDM). Design: Randomised controlled trial Setting: University hospital Population: Women at 25-35 weeks pregnancy upon diagnosis of GDM. Methods: In the intervention arm, women had weekly, supervised, 30-45 min long exercise sessions and were encouraged to accumulate more than 5000 steps per day, monitored by a pedometer, in addition to usual care. Women in the control group had usual care only. Main outcome measure: Insulin prescription. Results: From February 2008 through April 2013, 109 women were randomized into intervention (n=57) or usual care (n=52). Two women, both in the intervention group, were excluded from the analysis (one randomised in error and one lost to follow-up). Six women never attended the exercise sessions and two women participated to less than two sessions, while two-third of women were considered as compliant to the intervention. Incidence of insulin prescription was not significantly different between groups: 31 (56%) in the intervention and 24 (46%) in the control group (RR 1.22, 95% CI 0.84 to 1.78); the median time between randomization and insulin prescription was not different between groups (14 and 13 days, respectively). Conclusion: We were unable to show that an exercise program reduces or delays insulin prescription. Low compliance with the intervention, small sample size and the short duration of the program may explain the apparent lack of benefit.