on behalf of the EGIR-RISC Study Group* OBJECTIVE-Physical activity is a modifiable risk factor for type 2 diabetes, partly through its action on insulin sensitivity. We report the relation between insulin sensitivity and physical activity measured by accelerometry.RESEARCH DESIGN AND METHODS-This is a cross-sectional study of 346 men and 455 women, aged 30 -60 years, without cardiovascular disease and not treated by drugs for diabetes, hypertension, dyslipidemia, or obesity. Participants were recruited in 18 clinical centers from 13 European countries. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Physical activity was recorded by accelerometry for a median of 6 days. We studied the relationship of insulin sensitivity with total activity (in counts per minute), percent of time spent sedentary, percent of time in light activity, and activity intensity (whether the participant recorded some vigorous or some moderate activity).RESULTS-In both men and women, total activity was associated with insulin sensitivity (P Ͻ 0.0001). Time spent sedentary, in light activity, and activity intensity was also associated with insulin sensitivity (P Ͻ 0.0004/0.01, 0.002/0.03, and 0.02/0.004, respectively, for men/women) but lost significance once adjusted for total activity. Adjustment for confounders such as adiposity attenuated the relationship with total activity; there were no interactions with confounders. Even in the 25% most sedentary individuals, total activity was significantly associated with better insulin sensitivity (P Ͻ 0.0001).CONCLUSIONS-Accumulated daily physical activity is a major determinant of insulin sensitivity. Time spent sedentary, time spent in light-activity, and bouts of moderate or vigorous activity did not impact insulin sensitivity independently of total activity.

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We previously synthesized dendrogenin A and hypothesized that it could be a natural metabolite occurring in mammals. Here we explore this hypothesis and report the discovery of dendrogenin A in mammalian tissues and normal cells as an enzymatic product of the conjugation of 5,6α-epoxy-cholesterol and histamine. Dendrogenin A was not detected in cancer cell lines and was fivefold lower in human breast tumours compared with normal tissues, suggesting a deregulation of dendrogenin A metabolism during carcinogenesis. We established that dendrogenin A is a selective inhibitor of cholesterol epoxide hydrolase and it triggered tumour re-differentiation and growth control in mice and improved animal survival. The properties of dendrogenin A and its decreased level in tumours suggest a physiological function in maintaining cell integrity and differentiation. The discovery of dendrogenin A reveals a new metabolic pathway at the crossroads of cholesterol and histamine metabolism and the existence of steroidal alkaloids in mammals.

The ability of probiotics to improve bowel habits or transit time has been shown in healthy populations. Additional data are required to support the use of specific probiotics to improve gastrointestinal (GI) well-being. The present study was designed to investigate the effect of consuming fermented milk (FM) on GI well-being, digestive symptoms and health-related quality of life (HRQoL) amongst women without diagnosed GI disorders. In this double-blind, controlled, parallel-design study, subjects were randomised to ingest daily either 2 £ 125 g FM containing Bifidobacterium lactis DN-173 010 and yoghurt strains or a control non-fermented dairy product for 4 weeks followed by a 4-week wash-out period. GI well-being and digestive symptoms were assessed weekly. HRQoL was measured every 4 weeks. Data were analysed using analysis of covariance and logistic regression, correcting for baseline values on the full analysis set population of 197 women (aged 18 -60 years). The percentage of women reporting an improvement in their GI well-being was significantly (P,0·01) higher in the FM group v. the control group (OR 1·69; 95 % CI 1·17, 2·45). A significantly (P, 0·05) more pronounced decrease in the composite score of digestive symptoms was observed in the FM group when comparing with the control group (least squares mean 2 0·57; 95 % CI 21·12, 20·02). Among HRQoL dimensions, the digestive comfort score was significantly (P, 0·05) improved in the FM group compared with the control group. The present study showed that the daily consumption of a specific FM is able to improve GI well-being and digestive symptoms in adult women without GI disorders. Probiotics: Gastrointestinal tract: Adults: Randomised controlled trialsClinical evidence of the efficacy of some probiotics in the improvement of symptoms in irritable bowel syndrome (IBS) has recently emerged (1 -3) . The variability of the effects reported has highlighted the product and strain specificity, which is supported by the high variability in their properties (anti-inflammatory activity, effect on motility or visceral sensation) (1,2) . However, due to the complexity of the pathophysiology of IBS which remains poorly understood to date, specific research is required to demonstrate these benefits in a more general population with minor digestive complaints. Only a few studies have been focused on the effects of probiotics on gastrointestinal (GI) well-being in a general population. Most of these studies have investigated the effect of probiotics on bowel habits and were conducted in small sample sizes (from thirty to eighty subjects). Improvement of stool frequency and/or volume or weight, and stool consistency has been shown (4 -8) . Unfortunately, only one study (4) has investigated the impact on a specific digestive symptom (i.e. flatulence), showing a positive effect on this parameter; therefore, the real end-benefits of such functional changes for the consumers are open to question. Studies in human subjects have been designed to investigate the effect of a fe...

Breast cancer (BC) remains the primary cause of death from cancer among women worldwide. Cholesterol-5,6-epoxide (5,6-EC) metabolism is deregulated in BC but the molecular origin of this is unknown. Here, we have identified an oncometabolism downstream of 5,6-EC that promotes BC progression independently of estrogen receptor α expression. We show that cholesterol epoxide hydrolase (ChEH) metabolizes 5,6-EC into cholestane-3β,5α,6β-triol, which is transformed into the oncometabolite 6-oxo-cholestan-3β,5α-diol (OCDO) by 11β-hydroxysteroid-dehydrogenase-type-2 (11βHSD2). 11βHSD2 is known to regulate glucocorticoid metabolism by converting active cortisol into inactive cortisone. ChEH inhibition and 11βHSD2 silencing inhibited OCDO production and tumor growth. Patient BC samples showed significant increased OCDO levels and greater ChEH and 11βHSD2 protein expression compared with normal tissues. The analysis of several human BC mRNA databases indicated that 11βHSD2 and ChEH overexpression correlated with a higher risk of patient death, highlighting that the biosynthetic pathway producing OCDO is of major importance to BC pathology. OCDO stimulates BC cell growth by binding to the glucocorticoid receptor (GR), the nuclear receptor of endogenous cortisol. Interestingly, high GR expression or activation correlates with poor therapeutic response or prognosis in many solid tumors, including BC. Targeting the enzymes involved in cholesterol epoxide and glucocorticoid metabolism or GR may be novel strategies to prevent and treat BC.