Causal relationship between chronic obstructive pulmonary disease and heart failure: A Mendelian randomization study.

BACKGROUND: Causal association between chronic obstructive pulmonary disease (COPD) and heart failure (HF) has been controversial. This study used Mendelian Randomization (MR) analysis to clarify the potential causal connection between these two conditions. OBJECTIVES: The purpose of the study was to investigate the causal relationship between COPD and HF based on the hypothesis that the genetic predisposition to COPD could lead to an increased risk of developing HF METHODS: A two-sample MR analysis of genetic data was performed for COPD and HF. This study was based on genome-wide association study (GWAS) data, including 6,915 patients with confirmed COPD and 186,723 controls. The odds ratios (ORs) and their 95 % confidence intervals (95 %CIs) were estimated using a fixed effects inverse variance weighting (IVW) method. Several supplementary statistical methods, including MR-Egger, weighted median, maximum likelihood, penalized weighted median, and random effects IVW, were applied to enhance the robustness of findings. Moreover, MR-PRESSO was employed as an alternative method for statistical detection. RESULTS: Pooled data for HF were obtained from different GWASs, including 4,7309 confirmed HF patients and 930,014 controls. The MR analysis, based on the IVW model, revealed that COPD was significantly associated with an increased risk of HF. Specifically, the obtained findings showed that COPD patients had a higher risk of developing HF (Model 1: OR = 1.068, 95 %CI: 1.006-1.134, p = 0.031; Model 2: OR = 1.038, 95 %CI: 1.006-1.071, p = 0.020), indicating a causal relationship between COPD and HF. No evidence was found to suggest a reverse causal effect of HF on COPD incidence. CONCLUSION: The MR analysis substantiates a causal link between COPD and HF, with no evidence supporting a reverse causation from HF to COPD. These findings underscore the importance of proactive COPD management as a potential strategy to prevent the development of HF, highlighting the need for targeted interventions in patients with COPD to mitigate their risk of HF.

The Influence of Hyperglycemia on Liver Triglyceride Deposition in Partially Pancreatectomized Rats.

Nonalcoholic fatty liver disease and diabetes always coexist. The relationship of fatty liver and hyperglycemia is not clear. We studied the influence of hyperglycemia on triglyceride (TG) accumulation in the liver and explored its possible mechanisms. SD rats were divided into three groups: Group A (sham operation control), Group B (partially pancreatectomized rats), and Group C (partially pancreatectomized rats treated with insulin). At 4 weeks after surgery, pancreatic weights and liver TG contents were measured. Serum biochemical parameters were determined, and oral glucose tolerance tests (OGTT) were performed. The gene expression of sterol regulatory element-binding protein1c (SREBP-1c), carbohydrate regulatory element-binding protein (ChREBP), fatty acid synthase(FAS), carnitine palmitoyltransferase 1 (CPT-1), and fibroblast growth factor 21 (FGF21) was determined by real-time PCR. Compared with Group A, postprandial glucose increased significantly; the concentrations of insulin and C-peptides, pancreatic weights and serum FGF21 levels were decreased, liver TG was increased significantly in Group B, and insulin treatment improved these changes. Compared with Group A, the gene expressions of FGF21, CPT-1 and FAS in the liver were decreased in Group B (all p<0.05). Compared with Group B, the gene expressions of FGF21, FAS, ChREBP, SREBP-1c and CPT-1 in the liver in Group C were all increased significantly (p<0.05, respectively). Hyperglycemia induced by partial pancreatectomy could lead to increased liver TG. Insulin treatment could decrease glucose levels and improve fatty liver, and genes related to lipid metabolism may play a role in this process.

Influence of ursodeoxycholic acid on blood glucose, insulin and GLP-1 in rats with liver fibrosis induced by bile duct ligation.

BACKGROUND: The prevalence of impaired glucose tolerance and diabetes is much higher in people with cirrhosis than that in the general population. However, there are inadequate concrete guidelines for the management of diabetes in these patients, particularly in the early stage. Bile aids (BAs) have been found to exert hormone-like functions in the control of lipid and glucose metabolism. We studied the effect of ursodeoxycholic acid (UDCA) on glucose levels in rats with cirrhosis induced by bile duct ligation (BDL). METHODS: SD rats were divided into three groups: sham operation (Group A); BDL (Group B), and UDCA plus BDL (Group C). After 4 weeks, oral glucose tolerance tests were performed. Serum biochemical parameters and the levels of glucose, insulin, and glucagon-like peptide 1 (GLP-1) were measured. Histopathology of the liver and islet was observed. The gene expression of cholesterol 7α-hydroylase (CYP7A1), microsomal oxysterol 7a-hydroxylase (CYP7B1) in the liver, and Takeda G-protein-coupled receptor-5 (TGR5) in the intestine was determined by real-time PCR. RESULTS: Compared with Group A, fasting glucose and 1-h and 2-h postprandial glucose levels increased slightly (all P > 0.05), 2-h postprandial insulin levels increased significantly (P < 0.05), 15 min postprandial GLP-1 levels decreased (P < 0.05) in Group B. Compared with Group B, fasting glucose and 1-h postprandial glucose levels decreased (all P < 0.05), 2-h postprandial insulin levels decreased (P < 0.01), and 15 min postprandial GLP-1 levels increased (P < 0.05) in Group C. After UDCA intervention, liver fibrosis induced by BDL was alleviated, and the islet areas were increased (P < 0.05). Compared with Group A, the mRNA expression of CYP7A1 and CYP7B1 in the liver increased, and the mRNA expression of TGR5 in the intestine decreased in Group B (all P < 0.05). Compared with Group B, the mRNA expression of CYP7A1 and CYP7B1 in the liver decreased, and TGR5 in the intestine increased in Group C (P < 0.05). CONCLUSIONS: After 4 weeks of BDL, the rats developed liver fibrosis and abnormal glucose metabolism. UDCA administration improved liver fibrosis, increased islet area, decreased glucose levels, inhibited genes in BA synthesis, enhanced TGR5 gene expression in the intestine, and further improved islet function.

Influence of Liver Cirrhosis on Blood Glucose, Insulin Sensitivity and Islet Function in Mice.

BACKGROUND: The relationship between cirrhosis and diabetes is controversial. We studied the influence of cirrhosis on glucose levels and islet function and explored its possible mechanisms. MATERIALS AND METHODS: Cirrhosis was induced in male C57BL/6 mice by bile duct ligation (BDL). Serum biochemical parameters were determined, and oral glucose tolerance tests (OGTT) were performed at 4 and 8 weeks after BDL. Histopathology and phospho-NF-κB-p65/I-kappa B α immunohistochemical staining of the liver and islet were observed. The protein levels of the insulin signaling system and the gene expression of insulin-degrading enzyme (IDE) in the liver and muscle were determined. The activity of glucokinase (GCK) and glucose 6-phosphatase (G6P) and glycogen levels in liver homogenates were measured. RESULTS: After BDL, the mice developed cirrhosis, and fasting glucose decreased significantly, but 2 h postprandial glucose increased, and the insulin areas under the curves increased. At 4 weeks of BDL, the ratios of phospho-NF-κB-p65/I-kappa B α accumulation in the liver and islet increased, the activity of G6P and the glycogen content in liver homogenates decreased, the insulin signaling system and the gene expression of IDE in the liver was downregulated, and the islet areas were decreased. After 8 weeks, these changes were more severe. CONCLUSIONS: In different periods of cirrhosis, the levels of fasting glucose and 2 h postprandial glucose changed in different amplitudes. Glycogen concentrations and the activity of G6P in the liver were decreased. The mice developed insulin resistance and the islet areas were decreased. The NF-κB pathway may play a role in the process.

Ginsenoside Rg3 protects heart against isoproterenol-induced myocardial infarction by activating AMPK mediated autophagy.

BACKGROUND: Panax ginseng is a well-known medicinal herb that is widely used in traditional Chinese medicine for treating various diseases. Ginsenoside Rg3 (Rg3) is thought to be one of the most important active ingredients of Panax ginseng. However, the molecular mechanism underlying the beneficial effects of Rg3 has been elusive. METHODS: In the mouse heart injury model induced by isoproterenol (ISO), we used brain natriuretic peptide (BNP), lactate dehydrogenase (LDH) and caspase-3 ELISA kits to test myocardium injury. To test whether Rg3 protects myocardial injury through AMPK mediated autophagy, we used specific AMPK inhibitor in combination with Rg3. NLRP3 inflammasome related molecules such as NLRP3, ASC and caspase-1 were measured by western-blot following Rg3 treatment. RESULTS: We found that Rg3 significantly reduced ISO induced myocardial injury indicated by the downregulation of serum BNP and LDH. In addition, we showed that the improvement of myocardial injury by Rg3 was associated with enhanced expression of autophagy related protein and activation of AMPK downstream signaling pathway. CONCLUSIONS: We observed that inhibition of AMPK significantly reversed the myocardial protective effect of Rg3, which is associated with a decrease of Rg3 induced autophagy. These together suggested that Rg3 may improve myocardial injury during MI through AMPK mediated autophagy. Our study also provides important translational evidence for using Rg3 in treating myocardial infarction (MI).

Cardioprotective effect of taurine and ß-alanine against cardiac disease in myocardial ischemia and reperfusion-induced rats

BACKGROUND: The present study analyzed the synergistic protective effect of ß-alanine and taurine against myocardial ischemia/reperfusion. Myocardial infarct size, lipid peroxidation, and levels of glutathione peroxidase (Gpx), superoxide dismutase (SOD), reduced glutathione (GSH), catalase, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), reactive oxygen species (ROS), apoptosis, and the mRNA and protein expression of Janus kinase 2 (JAK2) and signal transducer and activator 3 of transcription (STAT3) were determined. The molecular docking was carried out by using AutoDock 4.2.1. RESULTS: Combined treatment with ß-alanine and taurine reduced myocardial infarct size, lipid peroxidation, inflammatory marker, ROS levels, and apoptosis and increased Gpx, SOD activity, GSH, and catalase activity. Furthermore, combined treatment significantly reduced JAK2 and STAT3 mRNA and protein expression compared with the control. The small molecule was docked over the SH2 domain of a STAT3, and binding mode was determined to investigate the inhibitory potential of ß-alanine and taurine. ß-Alanine bound to SH2 domain with ΔG of -7.34 kcal/mol and KI of 1.91 µM. Taurine bound to SH2 domain with ΔG of -7.38 kcal/mol and KI of 1.95 µM. CONCLUSION: Taken together, these results suggest that the combined supplementation of ß-alanine and taurine should be further investigated as an effective therapeutic approach in achieving cardioprotection in myocardial ischemia/reperfusion.

Influences of sterol regulatory element binding protein-1c silencing on glucose production in HepG2 cells treated with free fatty acid.

BACKGROUND: Elevation of exogenous free fatty acid (FFA) level leads to insulin resistance (IR) in liver, IR is manifested by elevated hepatic glucose production. We aim to study whether inhibition of endogenous fatty acid synthesis could decrease hepatic glucose production. METHODS: Low-passage HepG2 cells derived from human liver tissue were cultured in medium supplemented with FFA to induce IR, the influences of sterol regulatory element binding protein-1c (SREBP-1c) silencing on glucose production of HepG2 cells were investigated, and genes responsible for fatty acid and glucose metabolism were detected by real-time PCR. RESULTS: Compared with HepG2 cells cultured in normal growth medium, glucose production of HepG2 cells treated by FFA was significantly increased {[(0.28 ± 0.01) vs (0.83 ± 0.02)] umol.ug- 1 protein, n = 6 wells, P < 0.01}; the mRNA expression of phosphoenolpyruvate carboxylase kinase (PEPCK) and glucose-6-phosphatase (G6PC) in HepG2 cells increased by more than 5-fold and 3-fold, respectively; the mRNA expression of fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD1) increased by approximately 4-fold and 1.1-fold, respectively; the mRNA expression of carnitine palmitoyltransferase-1 (CPT-1) changed slightly. Compared with the scrambled siRNA control, glucose production of HepG2 cells treated by FFA significantly increased after SREBP-1c silencing {[(0.018 ± 0.001) vs (0.028 ± 0.002)] umol.ug- 1 protein, n = 6 wells, P < 0.01}; the mRNA expression of PEPCK and G6PC increased by approximately 1.5-fold and 5-fold, respectively, but the mRNA expression of FAS, SCD1 and CPT-1 changed slightly. CONCLUSIONS: SREBP-1c silencing further augmented glucose production of HepG2 cells treated by FFA significantly, genes responsible for fatty acid synthesis and gluconeogenesis played an important role in this process. SREBP-1c functions not only as a lipid regulator but also plays an important role in regulation of glucose metabolism.

miR-181c-3p and -5p promotes high-glucose-induced dysfunction in human umbilical vein endothelial cells by regulating leukemia inhibitory factor.

Diabetes mellitus is a chronic metabolic disease with high blood glucose level and closely related to endothelial dysfunction, an important factor in the pathogenesis of vascular changes. Several miRNAs have been reported to be altered in a diabetic environment including miR-181c. In the article, we found that the expression of miR-181c-3p and miR-181c-5p was significantly downregulated under glucose treatment in a dose-dependent manner and in peripheral blood from diabetic patients compared with healthy participants. We explored the role of miR-181c-3p and miR-181c-5p in high glucose (HG)-induced dysfunction in human umbilical vein endothelial cells (HUVECs) by regulating leukemia inhibitory factor (LIF), their potential target with binding sites in 3-UTR region, that is also closely related to glucose metabolism. In addition, miR-181c-3p and miR-181c-5p significantly enhanced HG-induced oxidative stress injury by increasing malondialdehyde (MDA) and reactive oxygen species (ROS) production and promoted HG-induced HUVECs apoptosis, confirmed by TUNEL staining. LIF partially reduced those effects by decreasing oxidative stress and inhibiting cell apoptosis. Therefore, knocking down of LIF in HUVECs by LIF siRNA transfection, significantly increased HG-induced MDA and ROS production and induced more intense HUVECs apoptosis. Our results indicate that miR-181c-3p and miR-181c-5p promote HG-induced HUVECs injury through their target LIF.

Coronary Flow Reserve in Non-Infarcted Myocardium Predicts Long-Term Clinical Outcomes in Patients Undergoing Percutaneous Coronary Intervention.

PURPOSE: Coronary flow reserve (CFR) is recognized as an indicator of myocardial perfusion. The aim of this study was to assess the relationship between CFR in the non-infarcted myocardium and the incidence of major adverse cardiac events (MACEs). MATERIALS AND METHODS: 100 consecutive patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) were enrolled in the present study, and divided into MACE and non-MACE groups according to the incidence of 12-month MACEs. Left ventricular function and CFR were analyzed using two-dimensional echocardiography and myocardial contrast echocardiography at one week after PCI. Cardiac troponin I levels were assayed to estimate peak concentrations thereof. RESULTS: The MACE group was associated with lower CFR, compared to the non-MACE group (2.41 vs. 2.77, p<0.001). In the multivariable model, CFR in the non-infarcted myocardium was an independent predictor of 12-month MACE (hazard ratio: 0.093, 95% confidence interval: 0.020-0.426, p=0.002) after adjustment for baseline demographic and clinical characteristics. CONCLUSION: CFR in the non-infarcted myocardium is a useful marker for predicting 12-month MACEs in patients with AMI undergoing primary PCI.

A 3-year observation of testosterone deficiency in Chinese patients with chronic heart failure.

Testosterone deficiency is present in a certain proportion men with chronic heart failure (CHF). Low testosterone levels in American and European patients with CHF lead to the high mortality and readmission rates. Interestingly, this relationship has not been studied in Chinese patients. To this end, 167 Chinese men with CHF underwent clinical and laboratory evaluations associated with determinations of testosterone levels. Total testosterone (TT) levels and sex hormone-binding globulin were measured by chemiluminescence or immunoassays assays and free testosterone (FT) levels were calculated, Based upon results from these assays, patients were divided into either a low testosterone (LT; n = 93) or normal testosterone (NT; n = 74) group. Subsequently, records from each patient were reviewed over a follow-up duration of at least 3 years. Patients in the LT group experienced worse cardiac function and a higher prevalence of etiology (ischemic vs. no ischemic) and comorbidity (both P < 0.05). In addition, readmission rates of patients in the LT group were higher than that of patients in the NT group (3.32 ± 1.66 VS 1.57 ± 0.89). Overall, deficiencies in FT levels were accompanied with increased mortalities (HR = 6.301, 95% CI 3.187-12.459, P < .0001).

The plasma levels of CST and BCKDK in patients with sepsis.

OBJECTIVES: CST has been recently identified as a mediator of various beneficial effects in animal models of sepsis. At present, no data are available concerning the levels of CST in sepsis patients. In sepsis the plasma amino acid pattern is characterized by decreased branced chain amino acids (BCAAs). We investigated the levels of plasma CST or branched-chain α-ketoacid dehydrogenase kinase (BCKDK) and their relationship to component traits in patients with sepsis. DESIGN AND METHODS: We studied 228 patients and divided them into two groups based on severity of infection. Blood samples were taken at study entry, and CST, BCKDK were measured. RESULTS: CST and BCKDK levels were significantly higher in patients with sepsis than in controls: the median plasma CST concentration was 103.1ng/ml (range, <83.13-189.7ng/ml) in patients with sepsis and 49.69ng/ml (range, <19.38-100.8ng/ml) in controls (p=0.0022); the median plasma BCKDK concentration was 801.7ng/ml in sepsis group and 745ng/ml in controls (p=0.0292). Additionally, there was correlation between the plasma concentrations of CST and BCKDK in sepsis patients (r2=0.6357, p<0.01). CONCLUSIONS: We conclude that the plasma levels of CST in sepsis patients were higher than in controls, and there is a relationship between CST and BCKDK in sepsis patients. Future experimental and clinical studies are needed to evaluate CST as a novel prognostic tool in sepsis patients and its potential therapeutic use in sepsis.

Genetic Variant rs10757278 on Chromosome 9p21 Contributes to Myocardial Infarction Susceptibility.

Large-scale genome-wide association studies (GWAS) have revealed that rs10757278 polymorphism (or its proxy rs1333049) on chromosome 9p21 is associated with myocardial infarction (MI) susceptibility in individuals of Caucasian ancestry. Following studies in other populations investigated this association. However, some of these studies reported weak or no significant association. Here, we reevaluated this association using large-scale samples by searching PubMed and Google Scholar databases. Our results showed significant association between rs10757278 polymorphism and MI with p = 6.09 × 10-22, odds ratio (OR) = 1.29, 95% confidence interval (CI) 1.22-1.36 in pooled population. We further performed a subgroup analysis, and found significant association between rs10757278 polymorphism and MI in Asian and Caucasian populations. We identified that the association between rs10757278 polymorphism and MI did not vary substantially by excluding any one study. However, the heterogeneity among the selected studies varies substantially by excluding the study from the Pakistan population. We found even more significant association between rs10757278 polymorphism and MI in pooled population, p = 3.55 × 10-53, after excluding the study from the Pakistan population. In summary, previous studies reported weak or no significant association between rs10757278 polymorphism and MI. Interestingly, our analysis suggests that rs10757278 polymorphism is significantly associated with MI susceptibility by analyzing large-scale samples.

Coronary flow reserve in the remote myocardium predicts left ventricular remodeling following acute myocardial infarction.

PURPOSE: Coronary flow reserve (CFR) in the non-infarcted myocardium is often impaired following acute myocardial infarction (AMI). However, the clinical significance of CFR in the non-infarcted myocardium is not fully understood. The objective of the present study was to assess whether a relationship exists between CFR and left ventricular remodeling following AMI. MATERIALS AND METHODS: We enrolled 18 consecutive patients undergoing coronary intervention. Heart function was analyzed using real-time myocardial contrast echocardiography at one week and six months after coronary angioplasty. Ten subjects were enrolled as the control group and were examined using the same method at the same time to assess CFR. Cardiac troponin I (cTnI) levels were routinely analyzed to estimate peak concentration. RESULTS: CFR was 1.55±0.11 in the infarcted zone and 2.05±0.31 in the remote zone (p<0.01) at one week following AMI. According to CFR values in the remote zone, all patients were divided into two groups: Group I (CFR <2.05) and Group II (CFR >2.05). The levels of cTnI were higher in Group I compared to Group II on admission (36.40 vs. 21.38, p<0.05). Furthermore, left ventricular end diastolic volume was higher in Group I compared to Group II at six months following coronary angioplasty. CONCLUSION: Microvascular dysfunction is commonly observed in the remote myocardium. The CFR value accurately predicts adverse ventricular remodeling following AMI.

LINE-1 hypomethylation is associated with the risk of coronary heart disease in Chinese population.

BACKGROUND: Global methylation level in blood leukocyte DNA has been associated with the risk of coronary heart disease (CHD), with inconsistent results in various populations. Similar data are lacking in Chinese population where different genetic, lifestyle and environmental factors may affect DNA methylation and its risk relationship with CHD. OBJECTIVES: To examine whether global methylation is associated with the risk of CHD in Chinese population. METHODS: A total of 334 cases with CHD and 788 healthy controls were included. Global methylation in blood leukocyte DNA was estimated by analyzing LINE-1 repeats using bisulfite pyrosequencing. RESULTS: In an initial analysis restricted to control subjects, LINE-1 level reduced significantly with aging, elevated total cholesterol, and diagnosis of diabetes. In the case-control analysis, reduced LINE-1 methylation was associated with increased risk of CHD; analysis by quartile revealed odds ratios (95%CI) of 0.9 (0.6-1.4), 1.9 (1.3-2.9) and 2.3 (1.6-3.5) for the third, second and first (lowest) quartile (Ptrend < 0.001), respectively, compared to the fourth (highest) quartile. Lower (

Hipometilação do LINE-1 está Associada ao Risco de Doença Cardíaca Coronariana na População Chinesa / LINE-1 Hypomethylation is Associated with the Risk of Coronary Heart Disease in Chinese Population

Fundamentos: O nível de metilação global do ADN de leucócitos no sangue tem sido associado ao risco de doença arterial coronariana (DAC), com resultados inconsistentes em diferentes populações. Faltam dados semelhantes da população chinesa, onde diferentes fatores genéticos, de estilo de vida e ambientais podem afetar a metilação do ADN e sua relação com o risco de DCC. Objetivos: Analisar se a metilação global está associada ao risco de doença coronariana na população chinesa. Métodos: Foram incluídos um total de 334 casos de DCC e 788 controles saudáveis. A metilação global do ADN de leucócitos de sangue foi estimada por meio da análise das repetições do LINE-1 usando pirosequenciamento de bissulfito. Resultados: Em uma análise inicial restrita aos controles o nível do LINE-1 diminui significativamente com a idade avançada, colesterol total elevado, e diagnóstico de diabetes. Na análise de caso-controle, a redução da metilação do LINE-1 foi associada ao aumento do risco de DCC, tendo a análise por quartil revelado uma odds ratio (IC 95%) de 0,9 (0,6-1,4), 1,9 (1,3-2,9) e 2,3 (1,6 3.5) para o terceiro, segundo e primeiro (o mais baixo) quartil (P da tendência < 0,001), respectivamente, em comparação com o quarto (o mais alto) quartil. A metilação inferior (< mediana) do LINE-1 esteve associada a 2,2 vezes (IC 95% = 1,7-3,0) o aumento de risco de doença coronariana. As estimativas de risco de DCC menores relacionadas com o LINE-1 tenderam a ser mais fortes entre os indivíduos com maior tercil de homocisteína (P interação = 0,042) e naqueles com diagnóstico de hipertensão arterial (P interação = 0,012). Conclusão: A hipometilação do LINE-1 está ...

Background: Global methylation level in blood leukocyte DNA has been associated with the risk of coronary heart disease (CHD), with inconsistent results in various populations. Similar data are lacking in Chinese population where different genetic, lifestyle and environmental factors may affect DNA methylation and its risk relationship with CHD. Objectives: To examine whether global methylation is associated with the risk of CHD in Chinese population. Methods: A total of 334 cases with CHD and 788 healthy controls were included. Global methylation in blood leukocyte DNA was estimated by analyzing LINE-1 repeats using bisulfite pyrosequencing. Results: In an initial analysis restricted to control subjects, LINE-1 level reduced significantly with aging, elevated total cholesterol, and diagnosis of diabetes. In the case-control analysis, reduced LINE-1 methylation was associated with increased risk of CHD; analysis by quartile revealed odds ratios (95%CI) of 0.9 (0.6-1.4), 1.9 (1.3-2.9) and 2.3 (1.6-3.5) for the third, second and first (lowest) quartile (Ptrend < 0.001), respectively, compared to the fourth (highest) quartile. Lower (<median) LINE-1 methylation was associated with a 2.2-fold (95%CI = 1.7-3.0) increased risk of CHD. The lower LINE-1-related CHD risk estimates tended to be stronger among subjects with the highest tertile of homocysteine (Pinteraction = 0.042) and those with diagnosis of hypertension (Pinteraction = 0.012). Conclusion: LINE-1 hypomethylation is associated with the risk of CHD in Chinese population. Potential CHD risk factors such as older age, elevated total cholesterol, and diagnosis of diabetes may have impact on global DNA methylation, whereby exerting their effect on CHD risk. .

[Effects of fenofibrate on the expression of peroxisome proliferator-activated-gamma coactivator-1α in skeletal muscle of rats infused with intralipid].

OBJECTIVE: To observe the effects of fenofibrate on the expression of peroxisome proliferator-activated (PPAR)-gamma coactivator-1α (PGC-1α) in skeletal muscle of rats with insulin resistance (IR) induced by elevated plasma free fatty acid (FFA) levels. METHODS: Male Sprague-Dawley (SD) rats were randomly divided into three groups: control group (Con, infused with saline), lipid infusion group (FFA) and fenofibrate treatment plus lipid infusion group (F-FFA). Plasma glucose, insulin and FFA were measured. Glucose infusion rate (GIR) was used to evaluate the insulin sensitivity by euglycemic-hyperinsulinemic clamp. The gene expression of PGC-1α in skeletal muscle was determined by real-time polymerase chain reaction (PCR). RESULTS: Compared with the control group, the levels of plasma FFA and insulin were elevated significantly in rats infused with lipid, but they decreased significantly in rats pretreated with fenofibrate then infused with lipid [FFA, Con: 0.46 (0.08 - 0.72) mmol/L, FFA: 1.45(0.87-1.70) mmol/L, F-FFA: 0.54 (0.06 - 0.84) mmol/L, all P < 0.01; Insulin, Con: (6.56 ± 0.78) µIU/ml, FFA: (10.54 ± 0.86) µIU/ml, F-FFA: (6.69 ± 0.84) µIU/ml, all P < 0.01]. In addition, the plasma glucose levels did not change markedly after lipid infusion; GIR was significantly reduced by 55.6% in lipid infusion group, but fenofibrate-pretreatment increased glucose infusion rate (GIR) [Con: (25.13 ± 2.10) mg×kg(-1)×min(-1), FFA: (10.16 ± 0.75) mg×kg(-1)×min(-1), F-FFA: (21.72 ± 2.89) mg×kg(-1)×min(-1), all P < 0.01]; the mRNA expression of PGC-1α decreased by about 71% in lipid infusion group but fenofibrate increased the gene expression by about 150% as compared with FFA group (all P < 0.01). CONCLUSION: The elevation of plasma FFA levels may induce IR, and it also decreases the mRNA expression of PGC-1α in skeletal muscle. And fenofibrate pretreatment reverses these changes.

Sequence of fat partitioning and its relationship with whole body insulin resistance.

BACKGROUND: Currently it is unclear whether lipid accumulation occurs in a particular sequence and its relationship with whole body insulin resistance (IR). This study aimed to answer this question. METHODS: Male Sprague-Dawley (SD) rats were fed on a normal or a high-fat diet for 20 weeks. Serum triglycerides (TG), serum free fatty acids (FFA), fasting plasma glucose (FPG), and liver and skeletal muscle TG were measured. The glucose infusion rate (GIR) and mRNA levels of acetyl-CoA carboxylase (ACC) and carnitine palmitoyltransferase-1 (CPT-1) in the liver and skeletal muscle were determined at different stages. RESULTS: Compared with rats fed on the normal diet, serum FFA was not significantly increased in rats fed on the high-fat diet until 20 weeks. In contrast, liver TG was significantly increased by the high-fat diet by four weeks (20-fold; P < 0.01), and remained elevated until the end of the study. However, skeletal muscle TG was not significantly increased by the high-fat diet until 20 weeks (10.6-fold; P < 0.01), and neither was the FPG. The GIR was significantly reduced (1.6-fold; P < 0.01) by the high-fat diet after 8 weeks. The mRNA levels of ACC gradually increased over time and CPT-1 decreased over time, in both the liver and skeletal muscle in rats fed the high-fat diet. CONCLUSIONS: Lipid accumulation in the liver occurs earlier than lipid accumulation in the skeletal muscle. Fatty liver may be one of the early markers of whole body IR. Changes in the gene expression levels of ACC and CPT-1 may have important roles in the process of IR development.

[Relationship between oxidative stress and beta cell lipoapoptosis in rats].

OBJECTIVE: To investigate the effect of beta cell lipoapoptosis after long term high-fat feeding in rats, and to investigate the relationship between oxidative stress, gene expression and beta cell lipoapoptosis. METHODS: Forty-one SD male rats were randomly divided into 2 groups: high-fat diet group (HF group) and control group (NC group). At the end of 28 weeks, the levels of malondialdehyde (MDA) and glutamylcysteinylglycine (GSH) in plasma and pancreatic tissue,the early-phase insulin secretion in beta cells, the beta cell apoptosis (TUNEL technology) and the uncoupling protein 2 (UCP2) gene expression in islets were measured. RESULT: The concentrations of MDA both in plasma and pancreatic tissue were higher in HF group than those in NC group.In contrast, The contents of GSH both in plasma and pancreatic tissue were lower in HF group. Insulin secretion response to glucose load was significantly decreased in HF group (3.0 fold Compared with 5.7 fold, P<0.01). Blood glucose levels at 3 min, 5 min and 10 min during IVGTT were significantly higher in HF group than those in NC group (P<0.05). The frequency of beta cell apoptosis was increased by 40.0% in HF group (P<0.01). The gene expression of UCP2 in islets was increased by 22.4% in HF group (P<0.01). CONCLUSION: The frequency of beta cell apoptosis in high-fat feeding rats is affected by oxidative stress, which results in increasing UCP2 gene expression.

[Relationship between islet beta cell dysfunction and gene expression of uncoupling protein-2 and possible mechanism thereof].

OBJECTIVE: To study the effects of high fat diet on the functions of islet beta cells and the role of uncoupling protein-2 (UCP2) therein and possible mechanism. METHODS: Forty SD rats were randomly divided into two equal groups: high-fat-(HF) diet group, fed with HF diet for 20 weeks, and normal diet control (NC) group, fed with normal diet. At the end of the twentieth week blood samples were collected from the heart to determine the serum fasting blood glucose (FBG) and fasting insulin (FINS), and plasma nitrotyrosine, malondialdehyde (MDA), and glutamylcysteinylglycine (GSH), indicators of oxidative stress. Glucose infusion rate (GIR) was measured using euglycemic hyperinsulinemic clamp test to evaluate the peripheral insulin resistance. Pancreatic islets were isolated and collected. Islet perfusion was conducted to evaluate the insulin secretion in the islet beta cells. Real-time PCR was used to detect the expression of insulin receptor substrate-1 (IRS-1), IRS-2, and uncoupling protein 2 (UCP2) genes in the islet. Immunohistochemistry was used to detect the protein expression of IRS-1 and IRS-2. RESULTS: (1) The concentrations of plasma nitrotyrosine and MDA of the HF group were both significantly higher than those of the NC group (both P < 0.05). However, the plasma GSH of the HF group was significantly lower than that of the NC group (P < 0.01). (2) The blood glucose of both groups became stable since 60 min after the experiment and the GIR of the HF group was (5.25 +/- 1.2) mg x min(-1) x kg(-1), significantly lower r than that of the NC group [(13.6 +/- 1l.7) mg x min(-1) x kg(-1), P < 0.01). (3) The peak of glucose-stimulated insulin secretion (GSIS) of the HF group was significantly lower than that of the NC group; and the GSIS peak increase In comparison with the NC group. (4) In comparison with the NC group, the mRNA expression levels of IRS-1 and IRS-2 genes of the HF group were significantly lower, by 42.3% and 28.1% respectively (both P < 0.05), and the expression of UCP2 was significantly higher, by 32.5% (P < 0.05). (5) Compared with the NC group, the protein expression levels of IRS-1 and IRS-2 in the islets of the HF group were lower, by 26.3% and 11.2% respectively, however not significantly (both P > 0.05). (6) There was a significantly negative correlation between the UCP2 and IRS-1/IRS-2 gene expression in islet beta cells in the HF group (r = -0.621 and r = -0.436, both P < 0.05). CONCLUSION: High-fat-diet impairs the expression of insulin signal transduction molecules and the function of islet beta cells that may be correlated with overexpression of UCP2. The basic insulin secretion of HF group was significantly higher than that of the NC group; but the glucose-stimulated insulin secretion (GSIS) peak decreased in comparison with the NC group. Compared with the NC group, the protein expression levels of IRS-1 and IRS-2 in the islets of the HF group were lower, by 26.3% (P < 0.05) and 11.2% (P > 0.05) respectively.