Despite the well-documented association between insulin resistance and cardiovascular disease, the key targets of insulin relevant to the development of cardiovascular disease are not known. Here, using non-biased profiling methods, we identify the enzyme flavin-containing monooxygenase 3 (Fmo3) to be a target of insulin. FMO3 produces trimethylamine N-oxide (TMAO), which has recently been suggested to promote atherosclerosis in mice and humans. We show that FMO3 is suppressed by insulin in vitro, increased in obese/insulin resistant male mice and increased in obese/insulin-resistant humans. Knockdown of FMO3 in insulin-resistant mice suppresses FoxO1, a central node for metabolic control, and entirely prevents the development of hyperglycaemia, hyperlipidemia and atherosclerosis. Taken together, these data indicate that FMO3 is required for FoxO1 expression and the development of metabolic dysfunction.

We reported that a Mediterranean Diet (MedDiet), supplemented with extra-virgin olive oil (EVOO) and pistachios, reduces GDM incidence and several other adverse outcomes. In order to assess its translational effects in the real world we evaluated the effect of MedDiet from 1st gestational visit in GDM rate compared with control (CG) and intervention (IG) groups from the previously referred trial. As secondary objective we also compared adverse perinatal outcomes between normoglycemic and diabetic women. This trial is a prospective, clinic-based, interventional study with a single group. 1066 eligible normoglycaemic women before 12 gestational weeks were assessed. 932 women (32.4 ± 5.2 years old, pre-gestational BMI 22.5 ± 3.5 kg/m²) received a motivational lifestyle interview with emphasis on daily consumption of EVOO and nuts, were followed-up and analysed. Binary regression analyses were used to examine the risk for each pregnancy outcome, pregnancy-induced hypertension, preeclampsia, gestational weight gain (GWG), caesarean-section, perineal trauma, preterm delivery, small (SGA) and large for gestational age (LGA), and Neonatal Intensive Care Unit admissions. GDM was diagnosed in 13.9%. This rate was significantly lower than the CG: RR 0.81 (0.73–0.93), p < 0.001 and no different from the IG: RR 0.96 (0.85–1.07), p = 0.468. GWG was lower in diabetic women (10.88 ± 6.46 vs. 12.30 ± 5.42 Kg; p = 0.013). Excessive weight gain (EWG) was also lower in GDM [RR 0.91 (0.86–0.96); p < 0.001] without a significant increase of insufficient weight gain. LGA were also lower (1 (0.8%) vs. 31 (3.9%); p < 0.05)), and SGA were similar (5 (3.8%) vs. 30 (3.7%)). LGA were associated to EWG (RR 1.61 (1.35–1.91), p < 0.001). Differences in other maternal-foetal outcomes were not found. In conclusions an early MedDiet nutritional intervention reduces GDM incidence and maternal-foetal adverse outcomes and should be universally applied as 1st line therapy. GDM might not be consider as a high risk pregnancy any longer.