The effect of testosterone, a sex steroid, on endothelial cells is controversial as it is uncertain if it has a protective effect on them. Whether physiological testosterone can inhibit the deleterious effects of advanced glycation end products (AGEs) on endothelial cells remains to be elucidated. The present study focused on elucidating the effect of testosterone on the injury of endothelial cells induced by AGEs. Human umbilical vein endothelial cells (HUVECs) were cultured in vitro and treated with AGEs in the presence or absence of various concentrations of testosterone. The cell viability in each group was measured using an MTS assay. Early-stage apoptosis was detected using flow cytometry with Annexin V-fluorescein isothiocyanate/propidium iodide double staining, and the expression levels of apoptosis-associated proteins, B cell lymphoma-2 (Bcl-2), Bcl-2-associated X protein (Bax) and caspase-3, were determined using western blot analysis. Oxidative stress and pro-inflammatory parameters in the medium were evaluated using an enzyme-linked immunosorbent assay. The MTS results showed that AGEs significantly decreased the proliferation of HUVECs, whereas a physiological concentration of testosterone alleviated this damage. Physiological concentrations of testosterone protected the HUVECs from AGE-induced apoptosis, mediated by caspase-3 and Bax/Bcl-2. In addition, treatment of the HUVECs with AGEs caused a significant decrease in anti-oxidative parameters, but increased the concentrations of malondialdehyde and tumor necrosis factor-α. The activation of Janus kinase 2 and signal transducer and activator of transcription 3 was significantly increased by incubation with AGEs. However, pre-incubation with a physiological concentration of testosterone attenuated these changes. Therefore, the data obtained in the present study established the potential role of physiological testosterone in ameliorating AGE-induced damage in HUVECs.

The incidence of diabetes is increasing globally. We investigated the relationship between diabetes prevalence and patient socioeconomic status across multiple countries. We searched PubMed to identify population-based surveys reporting diabetes prevalence between 1990 and May 2016. Search results were filtered, and Human Development Index (HDI) values from the United Nations Development Programme were used to assess socioeconomic status for a given nation. Our analysis included 45 national surveys from 32 countries. Diabetes prevalence was positively correlated with national HDI (r = 0.421 P = 0.041) in developing countries, and negatively correlated with HDI (r = -0.442 P = 0.045) in developed countries. Diabetes prevalence trends were the same in women and men, although men were associated with increased diabetes risk in developed countries (r = 0.459 P = 0.048). Thus, diabetes prevalence rises with increasing HDI in developing countries, and this is reversed in developed countries. Ours is the first study to investigate the relationship between diabetes and socioeconomic status at global level using HDI values. These results will aid in evaluating global diabetes prevalence and risk with respect to patient socioeconomic status, and will be useful in the development of policies that help reduce disease incidence.

Oxidative stress is considered to be an important factor in producing lethal hepatocyte injury associated with nonalcoholic fatty liver disease (NAFLD). Glucose fluctuation, more pronounced in patients with diabetes, has been recognized as an even stronger oxidative stress inducer than the sustained hyperglycemia. Here, we investigated the role of glucose variability in the development of the NAFLD based on hepatocyte apoptosis and possible mechanisms. To achieve this goal we studied C57BL/6J mice that were maintained on a high fat diet (HFD) and injected with glucose (3 g/kg) twice daily to induce intermittent high glucose (IHG). We also studied hepatic L02 cells incubated with palmitic acid (PA) to induce steatosis. The following experimental groups were compared: normal glucose (NG), sustained high glucose (SHG) and IHG with or without PA. We found that, although hepatic enzyme levels and liver lipid deposition were comparable between HFD mice injected with glucose or saline, the glucose injected mice displayed marked hepatocyte apoptosis and inflammation, accompanied by increased lipid peroxide in liver. In vitro, in the presence of PA, IHG increased L02 cell apoptosis and oxidative stress and produced pronounced mitochondrial dysfunction relative to the NG and SHG groups. Furthermore, treatment with the mitochondrial permeability transition (MPT) inhibitor, cyclosporin A (1.5 μmol/l), prevented mitochondrial dysfunction, oxidative stress and hepatocyte apoptosis. Our data suggests that IHG under lipotoxicity might contribute to the development of NAFLD by increasing oxidative stress and hepatocyte apoptosis via MPT and its related mitochondrial dysfunction.

Metabolic syndrome (MetS) has been identified to be associated with a state of chronic, low-grade inflammation in adipose tissue. Lipoxins are endogenously generated from arachidonic acid, and exhibit anti-inflammatory actions. Currently, there is no available cohort study identifying the association between serum lipoxins level and MetS. Here we investigate the relationship between serum lipoxin A4 (LXA4) level and the risk of incident MetS in a middle-aged Chinese population. A total 624 participants aged 40-65 years were enrolled at baseline, with 417 (including 333 MetS absence) of them were followed up at 2.5 years. Abdominal visceral fat area (VFA) and abdominal subcutaneous fat area (SFA) were determined using MRI. Serum lipoxin A4 levels were measured by ELISA. At baseline, serum LXA4 levels were significantly correlated with a cluster of traditional MetS risk factors related to obesity (P ≤ 0.05). A higher incidence of new Mets was found in the participants of the lowest tertile of LXA4 levels as compared with that in participants of the highest tertile (P = 0.025). Low serum LXA4 levels [OR 2.607(1.151-5.909), P = 0.022] and high VFA [OR 2.571(1.176-5.620), P = 0.018] were associated with an increased incident Mets, respectively, which remained statistically significant after adjustment for age, gender, current smoking, and alcohol drinking status. Logistic regression analysis suggested a combination of low serum LXA4 levels and high WC/VFA might optimize the prediction of incident Mets in middle-aged Chinese population [OR 4.897/4.967, P = 0.009/0.003]. Decrease in serum LXA4 level and increase in VFA are independent predictors of incident Mets in a population-based cohort, and a combination of them enhances the prognostic value of incident Mets. Taken together, our data suggest that serum LXA4 levels might be useful for early detection and prevention of Mets.

Liver X receptors (LXRs) have been recognized as a promising therapeutic target for atherosclerosis; however, their role in insulin sensitivity is controversial. Adiponectin plays a unique role in maintaining insulin sensitivity. Currently, no systematic experiments elucidating the role of LXR activation in insulin function based on adiponectin signaling have been reported. Here, we investigated the role of LXR activation in insulin resistance based on adiponectin signaling, and possible mechanisms. C57BL/6 mice maintained on a regular chow received the LXR agonist, T0901317 (30 mg/kg.d) for 3 weeks by intraperitoneal injection, and differentiated 3T3-L1 adipocytes were treated with T0901317 or GW3965. T0901317 treatment induced significant insulin resistance in C57BL/6 mice. It decreased adiponectin gene transcription in epididymal fat, as well as serum adiponectin levels. Activity of AMPK, a key mediator of adiponectin signaling, was also decreased, resulting in decreased Glut-4 membrane translocation in epididymal fat. In contrast, adiponectin activity was not changed in the liver of T0901317 treated mice. In vitro, both T0901317 and GW3965 decreased adiponectin expression in adipocytes in a dose-dependent manner, an effect which was diminished by LXRα silencing. ChIP-qPCR studies demonstrated that T0901317 decreased the binding of PPARγ to the PPAR-responsive element (PPRE) of the adiponectin promoter in a dose-dependent manner. Furthermore, T0901317 exerted an antagonistic effect on the expression of adiponectin in adipocytes co-treated with 3 µM Pioglitazone. In luciferase reporter gene assays, T0901317 dose-dependently inhibited PPRE-Luc activity in HEK293 cells co-transfected with LXRα and PPARγ. These results suggest that LXR activation induces insulin resistance with decreased adiponectin signaling in epididymal fat, probably due to negative regulation of PPARγ signaling. These findings indicate that the potential of LXR activation as a therapeutic target for atherosclerosis may be limited by the possibility of exacerbating insulin resistance-related disease.

OBJECTIVE:Central obesity is considered to be a central component of metabolic syndrome. Waist circumference (WC) has been widely used as a simple indicator of central obesity. This study is aimed to evaluate the sensitivity of WC cut-off values for predicting metabolic risk factors in middle-aged Chinese. METHODS:The study involved 923 subjects aged 40-65 years. The metabolic risk factors were defined according to the Chinese Joint Committee for Developing Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults. WC cut-off 85-90 cm and ⋝90 cm were used as cut-off values of central pre-obesity and central obesity in males, respectively, while WC 80-85 cm and ⋝85 cm were used as cut-off values of central pre-obesity and central obesity in females. RESULTS:First, WC values corresponding to body mass index (BMI) 24 kg/m2 and visceral fat area (VFA) 80 cm2 were 88.55 cm and 88.51 cm in males, and 81.46 cm and 82.51 cm in females respectively. Second, receiver operating characteristic curves showed that the optimal WC cut-off of value was 88.75 cm in males, higher than that in females (81.75 cm). Third, the subjects with higher WC values were more likely to have accumulating metabolic risk factors. The prevalence of metabolic risk factors increased linearly and significantly in relation to WC levels. CONCLUSION:WC cut-off values of central pre-/central obesity are optimal to predict multiple metabolic risk factors.

The fractalkine/CX3CR1 axis plays an important role in regulating glucose and lipid metabolism. However, the role of fractalkine in metabolic disorders remains to be fully elucidated. We selected 887 Chinese (40–65 years old) at baseline, with a subgroup of 459 participants examined again 2 years later. The relationship of serum fractalkine levels with the metabolic syndrome (MetS) and its components was investigated. At baseline, participants with MetS had higher fractalkine concentrations than their counterparts without MetS (P<0.001). At the 2-year follow-up, participants in the highest quartile of baseline fractalkine exhibited higher values for body mass index, waist circumference, waist-to-hip ratio, body fat percentage, glucose, insulin, total cholesterol, triglycerides (TG), and homeostasis model assessment of insulin resistance (HOMA-IR) and lower value for high density lipoprotein-cholesterol (HDL-c) (allP<0.05). Among 390 participants without MetS at baseline, 45 developed it at year 2. Even after multiple adjustments for visceral adipose tissue area, HOMA-IR, C-reactive protein (CRP), or TG and HDL-c, baseline fractalkine predicted the development of MetS (OR = 7.18, 95%CI: 2.28–18.59). In conclusion, circulating fractalkine predicts the development of the MetS independently of central obesity, CRP, insulin resistance, and dyslipidemia.

OBJECTIVE:To investigate the relationship between serum uric acid (UA) level and abdominal obesity or metabolic syndrome (MS).METHODS:A total of 875 subjects, with 350 males and 525 females, aged 40-65 years old, were enrolled in this study. The clinical and biochemical data were collected and MRI was used to assess the visceral and subcutaneous adipose tissues. The relationships between UA level and abdominal obesity or MS were analyzed, and the cut-off values of UA for abdominal obesity and MS were determined.RESULTS:Raised risks of abdominal obesity(OR = 4.35, 95%CI 1.91-9.90 in males; OR = 5.44, 95%CI 2.41-12.31 in females) and MS(OR = 4.47, 95%CI 2.08-9.62 in males; OR = 11.62, 95%CI 3.43-39.37 in females) were observed with the increase of UA level. The multiple logistic regression analysis showed that UA was an independent risk factor for hypertriglyceridemia(OR = 2.23, 95%CI 1.02-4.87 in males; OR = 3.04, 95%CI 1.49-6.23 in females) in all subjects and for abdominal obesity(OR = 3.23, 95%CI 1.32-7.91) and hypertension (OR = 2.35, 95%CI 1.37-4.05) in the females. Among the females, the regression line analyzed by simple correlation indicated that the UA level of 244.0 µmol/L was corresponded to the visceral adipose tissue area of 80 cm(2). The optimal cut-off point of UA for the diagnosis of MS was 258.8 µmol/L determined by the receiver operating characteristic curve.CONCLUSIONS:The level of UA is closely correlated with abdominal obesity and MS in the middle-aged Chinese. The elevated UA level is an independent risk factor for abdominal obesity and MS in the female.