Glucose oscillations, more than constant high glucose, induce p53 activation and a metabolic memory in human endothelial cells.

AIMS/HYPOTHESIS: Damage persists in HUVECs exposed to a constant high glucose concentration long after glucose normalisation, a phenomenon termed 'metabolic memory'. Evaluation of the effects of exposure of HUVECs to oscillating high glucose on the induction of markers of oxidative stress and DNA damage (phospho-γ-histone H2AX and PKCδ) and onset of metabolic memory, and the possible role of the tumour suppressor transcriptional factor p53 is of pivotal interest. METHODS: HUVECs were incubated for 3 weeks in 5 or 25 mmol/l glucose or oscillating glucose (24 h in 5 mmol/l glucose followed by 24 h in 25 mmol/l glucose) or for 1 week in constant 5 mmol/l glucose after being exposed for 2 weeks to continuous 25 mmol/l high glucose or oscillating glucose. Transcriptional activity of p53 was also evaluated in the first 24 h after high glucose exposure. RESULTS: High constant glucose upregulated phospho-γ-histone H2AX and protein kinase C (PKC)δ compared with control. Oscillating glucose was even more effective than both normal and constant high glucose. Both constant and oscillating glucose resulted in a memory effect, which was more pronounced in the oscillating condition. Transcriptional activity of p53 peaked 6 h after glucose exposure, showing a predicted oscillatory behaviour. CONCLUSIONS/INTERPRETATION: Exposure to oscillating glucose was more deleterious than constant high glucose and induced a metabolic memory after glucose normalisation. Hyperactivation of p53 during glucose oscillation might be due to the absence of consistent feedback inhibition during each glucose spike and might account for the worse outcome of this condition.

Interleukin-20 circulating levels in obese women: effect of weight loss.

BACKGROUND AND AIMS: Obesity is associated with an increased risk of developing atherosclerosis. Interleukin-20 (IL-20) is a pleiotropic cytokine thought to be involved in the onset and progression of atherosclerosis. The aim of this study was to determine whether circulating levels of IL-20 are elevated in obese women and whether they could be affected by a substantial decrease in body weight. METHODS AND RESULTS: Fifty obese and 50 age-matched, normal weight, premenopausal women participated in the study. Obese women entered into a medically supervised weight loss program aimed at reducing body weight to 90% of baseline. We measured anthropometric, glucose and lipid parameters, and IL-20, C-Reactive Protein (CRP) and interleukin-10 (IL-10) circulating levels. Circulating IL-20 and CRP levels were significantly higher in obese than control women (P=0.01), while IL-10 levels were significantly lower; IL-20 levels were positively associated with body weight (r=0.35; P=0.02) and visceral fat (waist-hip ratio; r=0.32; P=0.025). Caloric restriction-induced weight loss (>10% of original weight) over 6 months reduced IL-20 levels from 152 (112/184) to 134 (125/153)pg/ml (median and 25%/75%; P=0.03), and it was positively associated with changes in body mass index and waist-hip ratio. CONCLUSION: In premenopausal obese women, IL-20 levels are higher than matched normal weight control women, are associated with body weight and waist-hip ratio, and are reduced by weight loss.

Mediterranean diet improves sexual function in women with the metabolic syndrome.

In the present study, we tested the effect of a Mediterranean-style diet on sexual function in women with the metabolic syndrome. Women were identified in our database of subjects participating in controlled trials evaluating the effect of lifestyle changes and were included if they had a diagnosis of female sexual dysfunction (FSD) associated with a diagnosis of metabolic syndrome, a complete follow-up in the study trial and an intervention focused mainly on dietary changes. Fifty-nine women met the inclusion/exclusion criteria; 31 out of them were assigned to the Mediterranean-style diet and 28 to the control diet. After 2 years, women on the Mediterranean diet consumed more fruits, vegetables, nuts, whole grain and olive oil as compared with the women on the control diet. Female sexual function index (FSFI) improved in the intervention group, from a mean basal value of 19.7+/-3.1 to a mean post-treatment value of 26.1+/-4.1 (P=0.01), and remained stable in the control group. C-reactive protein (CRP) levels were significantly reduced in the intervention group (P<0.02). No single sexual domain (desire, arousal, lubrication, orgasm, satisfaction, pain) was significantly ameliorated by the dietary treatment, suggesting that the whole female sexuality may find benefit from lifestyle changes. A Mediterranean-style diet might be effective in ameliorating sexual function in women with metabolic syndrome.

Association of body weight with sexual function in women.

Sexual difficulties in women appear to be widespread in society; the relationship between female sexual function and obesity is unclear. This study aimed to investigate the relationship between body weight, the distribution of body fat and sexual function in women. Fifty-two, otherwise healthy women with abnormal values of female sexual function index (FSFI) score (< or =23) were compared with 66 control women (FSFI >23), matched for age and menopausal status. All women were free from diseases known to affect sexual function. FSFI strongly correlated with body mass index (BMI) (r=-0.72, P=0.0001), but not with waist-to-hip ratio (r=-0.09, P=0.48), in women with sexual dysfunction. Of the six sexual function parameters, desire and pain did not correlate with BMI, while arousal (r=-0.75), lubrication (r=-0.66), orgasm (r=-0.56) and satisfaction (r=-0.56, all P<0.001) did. FSFI score was significantly lower in overweight women as compared with normal weight women, while cholesterol and triglyceride levels were higher. On multivariate analysis, both age and BMI explained about 68% of FSFI variance, with a primacy of BMI over age (ratio 4:1). In conclusion, obesity affects several aspects of sexuality in otherwise healthy women with sexual dysfunction.

Endothelial microparticles correlate with erectile dysfunction in diabetic men.

Cell-derived microparticles are supposed to be involved in endothelial dysfunction and atherogenesis. This study aimed to evaluate circulating microparticles in diabetic subjects with erectile dysfunction (ED) and their relation with endothelial dysfunction. Thirty diabetic men with ED and 20 age-matched control subjects without ED were assessed for circulating microparticles and endothelial dysfunction. Flow cytometry was used to assess microparticles by quantification of circulating endothelial (EMP, CD31(+)/CD42b(-)) and platelet (PMP, CD31(+)/CD42b(+)) microparticles in peripheral blood. Endothelium-dependent flow-mediated dilation (FMD) was evaluated in the right brachial artery after reactive hyperemia. Compared with non-diabetic subjects, diabetic men presented significantly higher numbers of EMP (P=0.001), and reduced FMD (P=0.01), with a significant inverse correlation between the number of circulating EMP and the International Index of Erectile Function (IIEF) score (r=-0.457, P=0.01). Multivariate analysis correcting for age, anthropometric indices, glucose and lipid parameters, FMD and PMP identified EMP as the only independent predictor for IIEF score (P=0.03). EMP are elevated in impotent diabetic subjects and independently involved in the pathogenesis of ED.

Oxidative stress in the metabolic syndrome.

The metabolic syndrome represents a cluster of several risk factors for atherosclerosis that increases the risk of future cardiovascular events. In this study, we evaluated whether oxidative stress is increased in subjects with the metabolic syndrome. We studied 100 subjects (50 men and 50 women) with the metabolic syndrome, as defined by the Adult Treatment Panel III, and 50 (25 men and 25 women) matched subjects without the syndrome. Insulin sensitivity was assessed with the homeostasis model assessment (HOMA) methods; endothelium-dependent flow-mediated vasodilation (FMD) was evaluated in the right brachial artery with a high-resolution ultrasound machine; oxidative stress was assessed by measuring the circulating levels of nitrotyrosine (NT), considered a good marker for the formation of endogenous peroxynitrite. Compared with control subjects, patients with the metabolic syndrome had greater waist circumference, higher HOMA and systolic pressure values, higher triglyceride and lower HDL-cholesterol levels. NT levels were higher (0.44+/-0.12 micromol/l, mean+/-SD) while FMD was lower [7.3 (4.4/9.6), median and interquartile range] in subjects with the metabolic syndrome as compared with control subjects [0.27+/-0.08 and 11.8 (8.6/14.9), respectively, p<0.001]. There was an increase in NT levels and HOMA score as the number of components of the metabolic syndrome increased. NT levels were associated with waist circumference (r=0.38, p=0.01), triglycerides (r=0.32, p<0.02), systolic blood pressure (r=0.21, p<0.05) and fasting glucose (r=0.24, p<0.05). The oxidative stress that accompanies the metabolic syndrome is associated with both insulin resistance and endothelial dysfunction, providing a connection which is highly deleterious for vascular functions.