Resveratrol intervention attenuates chylomicron secretion via repressing intestinal FXR-induced expression of scavenger receptor SR-B1.

Two common features of dietary polyphenols have hampered our mechanistic understanding of their beneficial effects for decades: targeting multiple organs and extremely low bioavailability. We show here that resveratrol intervention (REV-I) in high-fat diet (HFD)-challenged male mice inhibits chylomicron secretion, associated with reduced expression of jejunal but not hepatic scavenger receptor class B type 1 (SR-B1). Intestinal mucosa-specific SR-B1-/- mice on HFD-challenge exhibit improved lipid homeostasis but show virtually no further response to REV-I. SR-B1 expression in Caco-2 cells cannot be repressed by pure resveratrol compound while fecal-microbiota transplantation from mice on REV-I suppresses jejunal SR-B1 in recipient mice. REV-I reduces fecal levels of bile acids and activity of fecal bile-salt hydrolase. In Caco-2 cells, chenodeoxycholic acid treatment stimulates both FXR and SR-B1. We conclude that gut microbiome is the primary target of REV-I, and REV-I improves lipid homeostasis at least partially via attenuating FXR-stimulated gut SR-B1 elevation.

Comparison of Beneficial Metabolic Effects of Liraglutide and Semaglutide in Male C57BL/6J Mice.

OBJECTIVES: Semaglutide and liraglutide are glucagon-like peptide-1 (GLP-1)-based diabetes drugs. Semaglutide possesses a longer half-life. Utilizing relatively lower doses, we compared the beneficial metabolic effects of these 2 drugs in mice fed a high-fat diet (HFD), aiming to deepen our mechanistic understanding on their energy homeostatic functions. METHODS: Male C57BL/6J mice were fed an HFD for 10 weeks, followed by daily phosphate-buffered saline (PBS, as control); liraglutide (150 µg/kg body weight); or semaglutide (12 µg/kg body weight, low dose [LD]; or 60 µg/kg body weight, high dose [HD]) injection for 4 weeks. Metabolic tolerance and other tests were conducted within the 4-week period. Expression of metabolism-related genes, including Fgf21 in the liver and adipose tissues, was assessed after mice were euthanized. RESULTS: HFD-induced body weight gain, increasing inguinal fat tissue mass, glucose defects and insulin intolerance were effectively and comparably attenuated in the 3 experimental groups. HD semaglutide showed an even better effect on attenuating hyperleptinemia. Liraglutide but not semaglutide treatment enhanced hepatic fibroblast growth factor 21 (FGF21) protein level. All 3 experimental groups showed elevated expression of genes that encode pyruvate dehydrogenase kinase 4 and enoyl-CoA hydratase and 3-hydroxyacyl-coenzyme A dehydrogenase, associated with reduced plasma triglyceride levels. Finally, the plasma "GLP-1" level in HD semaglutide-treated mice was 14-fold higher than in HFD-fed control mice. CONCLUSIONS: Liraglutide, but not semaglutide, increased hepatic FGF21 protein level, whereas semaglutide had a greater effect on attenuating hyperleptinemia. Thus, these 2 GLP-1-based diabetes drugs may target metabolic organs, including liver and adipose tissue, with differing levels of efficacy.

Liraglutide stimulates the ß-catenin signaling cascade in mouse epididymal fat tissue.

Although canonical Wnt signaling pathway activation was shown to negatively regulate adipogenesis, recent investigations suggest that Wnt pathway effectors TCF7L2 and ß-catenin (ß-cat) in adipose tissues are also involved in energy homeostasis during adulthood. In assessing the metabolic beneficial effect of GLP-1-based diabetes drugs in high-fat diet (HFD)-challenged mice, we observed that liraglutide treatment affected the expression of a battery of adipose tissue-specific genes, including those that encode adiponectin and leptin, mainly in epididymal white adipose tissue (eWAT). Fourteen-week HFD challenge repressed TCF7L2 and ß-cat S675 phosphorylation in eWAT, while such repression was reversed by liraglutide treatment (150 µg/kg body weight daily) during weeks 10-14. In Glp1r-/-mice, liraglutide failed in stimulating TCF7L2 or ß-cat in eWAT. We detected Glp1r expression in mouse eWAT and its level is enriched in its stromal vascular fraction (SVF). Mouse eWAT-SVF showed reduced expression of Tcf7l2 and its Tcf7l2 level could not be stimulated by liraglutide treatment; while following adipogenic differentiation, rat eWAT-SVF showed elevated Tcf7l2 expression. Direct in vitro liraglutide treatment in eWAT-SVF stimulated CREB S133, ß-cat S675 phosphorylation, and cellular cAMP level. Thus, cAMP/ß-cat signaling cascade can be stimulated by liraglutide in eWAT via GLP-1R expressed in eWAT-SVF.

Estrogen-Wnt signaling cascade regulates expression of hepatic fibroblast growth factor 21.

We have generated the transgenic mouse line LTCFDN in which dominant negative TCF7L2 (TCF7L2DN) is specifically expressed in the liver during adulthood. Male but not female LTCFDN mice showed elevated hepatic and plasma triglyceride (TG) levels, indicating the existence of estrogen-ß-cat/TCF signaling cascade that regulates hepatic lipid homeostasis. We show here that hepatic fibroblast growth factor 21 (FGF21) expression was reduced in male but not in female LTCFDN mice. The reduction was not associated with altered hepatic expression of peroxisome proliferator-activated receptor α (PPARα). In mouse primary hepatocytes (MPH), Wnt-3a treatment increased FGF21 expression in the presence of PPARα inhibitor. Results from our luciferase-reporter assay and chromatin immunoprecipitation suggest that evolutionarily conserved TCF binding motifs (TCFBs) on Fgf21 promoter mediate Wnt-3a-induced Fgf21 transactivation. Female mice showed reduced hepatic FGF21 production and circulating FGF21 level following ovariectomy (OVX), associated with reduced hepatic TCF expression and ß-catenin S675 phosphorylation. Finally, in MPH, estradiol (E2) treatment enhanced FGF21 expression, as well as binding of TCF7L2 and ribonucleic acid (RNA) polymerase II to the Fgf21 promoter; and the enhancement can be attenuated by the G-protein-coupled estrogen receptor 1 (GPER) antagonist G15. Our observations hence indicate that hepatic FGF21 is among the effectors of the newly recognized E2-ß-cat/TCF signaling cascade.NEW & NOTEWORTHY FGF21 is mainly produced in the liver. Therapeutic effect of FGF21 analogues has been demonstrated in clinical trials on reducing hyperlipidemia. We show here that Fgf21 transcription is positively regulated by Wnt pathway effector ß-cat/TCF. Importantly, hepatic ß-cat/TCF activity can be regulated by the female hormone estradiol, involving GPER. The investigation enriched our understanding on hepatic FGF21 hormone production, and expanded our view on metabolic functions of the Wnt pathway in the liver.

Hepatic Fibroblast Growth Factor 21 Is Involved in Mediating Functions of Liraglutide in Mice With Dietary Challenge.

BACKGROUND AND AIMS: Several studies have shown that expression of hepatic fibroblast growth factor 21 (FGF21) can be stimulated by glucagon-like peptide 1 (GLP-1)-based diabetes drugs. As GLP-1 receptor (GLP-1R) is unlikely to be expressed in hepatocytes, we aimed to compare such stimulation in mice and in mouse hepatocytes, determine the involvement of GLP-1R, and clarify whether FGF21 mediates certain functions of the GLP-1R agonist liraglutide. APPROACH AND RESULTS: Liver FGF21 expression was assessed in mice receiving a daily liraglutide injection for 3 days or in mouse primary hepatocytes (MPHs) undergoing direct liraglutide treatment. The effects of liraglutide on metabolic improvement and FGF21 expression were then assessed in high-fat diet (HFD)-fed mice and compared with the effects of the dipeptidyl-peptidase 4 inhibitor sitagliptin. Animal studies were also performed in Glp1r-/- mice and liver-specific FGF21-knockout (lFgf21-KO) mice. In wild-type mouse liver that underwent RNA sequencing and quantitative reverse-transcription PCR, we observed liraglutide-stimulated hepatic Fgf21 expression and a lack of Glp1r expression. In MPHs, liraglutide did not stimulate Fgf21. In mice with HFD-induced obesity, liraglutide or sitagliptin treatment reduced plasma triglyceride levels, whereas their effect on reducing body-weight gain was different. Importantly, increased hepatic FGF21 expression was observed in liraglutide-treated mice but was not observed in sitagliptin-treated mice. In HFD-fed Glp1r-/- mice, liraglutide showed no beneficial effects and could not stimulate Fgf21 expression. In lFgf21-KO mice undergoing dietary challenge, the body-weight-gain attenuation and lipid homeostatic effects of liraglutide were lost or significantly reduced. CONCLUSIONS: We suggest that liraglutide-stimulated hepatic Fgf21 expression may require GLP-1R to be expressed in extrahepatic organs. Importantly, we revealed that hepatic FGF21 is required for liraglutide to lower body weight and improve hepatic lipid homeostasis. These observations advanced our mechanistic understanding of the function of GLP-1-based drugs in NAFLD.

Oleic acid-induced perilipin 5 expression and lipid droplets formation are regulated by the PI3K/PPARα pathway in HepG2 cells.

Perilipin 5 (Plin5), a member of the PAT (Perilipin, ADRP, and Tip47) protein family, has been implicated in the regulation of cellular neutral lipid accumulation in nonalcoholic fatty liver diseases. However, the underlying regulatory mechanisms of Plin5 are not clear. The goal of the present study was to explore the mechanism of oleic acid (OA)-induced Plin5 expression in HepG2 cells. We found that the expression of Plin5 was increased during OA-induced lipid droplets formation in a dose- and time-dependent manner. During this process of OA-stimulated lipid droplets formation, peroxisome proliferator-activated receptor alpha (PPARα) was also upregulated. When PPARα activation was blocked by GW6471, OA-induced Plin5 expression and lipid droplets formation were effectively ablated. We further found that the phosphoinositide 3-kinase (PI3K) inhibitor LY294002 was able to downregulate both PPARα and Plin5 expression and lipid droplets formation. Thus, we concluded that PI3K may, at least in part, act upstream of PPARα to regulate Plin5 expression and lipid droplets formation in HepG2 cells.

Effects of sodium-glucose cotransporter 2 inhibitors in addition to insulin therapy on cardiovascular risk factors in type 2 diabetes patients: A meta-analysis of randomized controlled trials.

AIMS/INTRODUCTION: In the present meta-analysis, we aimed to determine the effects of sodium-glucose cotransporter 2 inhibitor (SGLT-2i) in addition to insulin therapy on cardiovascular risk factors in type 2 diabetes patients. MATERIALS AND METHODS: Randomized controlled trials were identified by searching the PubMed, Embase and Cochrane Library databases published before September 2017. The intervention group received SGLT-2i as add-on treatment to insulin therapy, and the control group received placebos in addition to insulin. We assessed pooled data, including weighted mean differences and 95% confidence intervals (CIs) using a random-effects model. RESULTS: A total of 10 randomized controlled trials (n = 5,159) were eligible. The weighted mean differences for systolic blood pressure and diastolic blood pressure were -3.17 mmHg (95% CI -4.53, -1.80, I2 = 0%) and -1.60 mmHg (95% CI -2.52, -0.69, I2 = 0%) in the intervention groups. Glycosylated hemoglobin, fasting plasma glucose, postprandial glucose and daily insulin were also lower in the intervention groups, with relative weighted mean differences of -0.49% (95% CI -0.71, -0.28%, I2 = 92%), -1.10 mmol/L (95% CI -1.69, -0.51 mmol/L, I2 = 84%), -3.63 mmol/L (95% CI -4.36, -2.89, I2 = 0%) and -5.42 IU/day (95% CI -8.12, -2.72, I2 = 93%). The transformations of uric acid and bodyweight were -26.16 µmol/L (95% CI -42.14, -10.17, I2 = 80%) and -2.13 kg (95% CI -2.66, -1.60, I2 = 83%). The relative risk of hypoglycemia was 1.09 (95% CI 1.02, 1.17, P < 0.01). The relative risks of urinary tract and genital infection were 1.29 (95% CI 1.03, 1.62, P = 0.03) and 5.25 (95% CI 3.55, 7.74, P < 0.01). CONCLUSIONS: The results showed that in the intervention group, greater reductions were achieved for blood pressure, glucose control, uric acid and bodyweight. This treatment regimen might therefore provide beneficial effects on the occurrence and development of cardiovascular events.

Pycnogenol® Induces Browning of White Adipose Tissue through the PKA Signaling Pathway in Apolipoprotein E-Deficient Mice.

Beige adipocytes in white adipose tissue (WAT) have received considerable recognition because of their potential protective effect against obesity. Pycnogenol (PYC), extracted from French maritime pine bark, has anti-inflammatory and antioxidant properties and can improve lipid profiles. However, the effect of PYC on obesity has never been explored. In this study, we investigated the effects of PYC on obesity and WAT browning in apolipoprotein E- (ApoE-) deficient mice. The results showed that PYC treatment clearly reversed body weight and the mass of eWAT gain resulting from a high-cholesterol and high-fat diet (HCD), but no difference in food intake. The morphology results showed that the size of the adipocytes in the PYC-treated mice was obviously smaller than that in the HCD-fed mice. Next, we found that PYC upregulated the expression of genes related to lipolysis (ATGL and HSL), while it decreased the mRNA level of PLIN1. PYC significantly increased the expression of UCP1 and other genes related to beige adipogenesis. Additionally, PYC increased the expression of proteins related to the protein kinase A (PKA) signaling pathway. The findings suggested that PYC decreased obesity by promoting lipolysis and WAT browning. Thus, PYC may be a novel therapeutic target for obesity.

Pycnogenol protects against diet-induced hepatic steatosis in apolipoprotein-E-deficient mice.

PycnogenolR (PYC), a combination of active flavonoids derived from French maritime pine bark, is a natural antioxidant that has various pharmacological activities. Here, we investigated the beneficial effect of PYC on diet-induced hepatic steatosis. Apolipoprotein E (ApoE)-deficient male mice were administered PYC at oral doses of 30 or 100 mg·kg-1·day-1 for 2 wk in advance and were then fed a high-cholesterol and -fat diet (HCD) for 8 wk. Biochemical, immunohistochemical, and gene expression analyses were conducted to explore the effect of PYC on lipid metabolism in ApoE-deficient mice on a HCD. Short-term treatment with HCD in ApoE-deficient mice induced hepatic injuries, such as lipid metabolism disorder and hepatic histopathological changes. We found that PYC reduced body weight and the increase of serum lipids that had been caused by HCD. Supplementation of PYC significantly reduced lipid deposition in the liver, as shown by the lowered hepatic lipid content and histopathological lesions. We subsequently detected genes related to lipid metabolism and inflammatory cytokines. The study showed that PYC markedly suppressed the expression of genes related to hepatic lipogenesis, fatty acid uptake, and lipid storage while increasing the lipolytic gene, which thus reduced hepatic lipid content. Furthermore, PYC mainly reduced the expression of inflammatory cytokines and the infiltration of inflammatory cells, which were resistant to the development of hepatic steatosis. These results demonstrate that PYC protects against the occurrence and development of hepatic steatosis and may provide a new prophylactic approach for nonalcoholic fatty liver disease (NAFLD).

Exendin-4 Promotes Survival of Mouse Pancreatic ß-Cell Line in Lipotoxic Conditions, through the Extracellular Signal-Related Kinase 1/2 Pathway.

Type 2 diabetes is a heterogeneous disorder that develops as a result of relatively inappropriate insulin secretion and insulin resistance. Increased levels of free fatty acids (FFAs) are one of the important factors for the pathogenesis of type 2 diabetes and contribute to defective ß-cell proliferation and increased ß-cell apoptosis. Recently, glucagon-like peptide-1 (GLP-1) receptor agonists have been shown to possess an antiapoptotic effect, by increasing ß-cell mass and improving ß-cell function. However, their effects on ß-cells in vitro against lipotoxicity have not been elucidated completely. In this study, we investigated whether the GLP-1 receptor agonist exendin-4 displays prosurvival effects in pancreatic ß-cells exposed to chronic elevated FFAs. Results showed that exendin-4 inhibited apoptosis induced by palmitate in MIN6 cells. After 24 h of incubation, exendin-4 caused rapid activation of extracellular signal-related kinase 1/2 (ERK1/2) under lipotoxic conditions. The ERK1/2 inhibitor PD98059 blocked the antilipotoxic effect of exendin-4 on MIN6 cells. Exendin-4 also inhibited the mitochondrial pathway of apoptosis. This inhibition is associated with upregulation of BCL-2. Our findings suggested that exendin-4 may exert cytoprotective effects through activation of ERK1/2 and inhibition of the mitochondrial apoptosis pathway.

The efficacy and safety of liraglutide added to metformin in patients with diabetes: a meta-analysis of randomized controlled trials.

Liraglutide, a glucagon-like peptide (GLP-1) receptor agonist, has showed favorable effects in the glycaemic control and weight reduction in patients with type 2 diabetes mellitus (T2DM). The meta-analysis was to compare the efficacy and safety of liraglutide added to metformin with other treatments in patients with T2DM. A systematic literature search on PubMed, Embase, Web of Science and the Cochrane library databases were performed. Eligible studies were randomized controlled trials (RCTs) of patients with T2DM who received the combination treatment of liraglutide and metformin. Pooled estimates were performed using a fixed-effects model or random-effects model. A total of nine RCTs met the inclusion criteria. Compared with control (placebo, sitagliptin, glimepiride, dulaglutide, insulin glargine, and NPH), liraglutide in combination with metformin resulted in significant reductions in HbA1c, bodyweight, FPG, and PPG, and similar reductions in SBP, and DBP. Moreover, liraglutide combined with metformin did not increase the risk of hypoglycemia, but induced a higher incidence of gastrointestinal disorders. In conclusion, this meta-analysis confirmed the use of liraglutide as add-on to metformin appeared to be effective and safe for patients with T2DM. However, considering the potential limitations in this study, more large-scale, well-conducted RCTs are needed to identify our findings.

Pycnogenol Reduces Toll-Like Receptor 4 Signaling Pathway-Mediated Atherosclerosis Formation in Apolipoprotein E-Deficient Mice.

Pycnogenol (PYC) is an extract from French maritime pine bark. Its antioxidative and anti-inflammatory effects have been shown to be beneficial for atherosclerosis. Here, we tested whether PYC could suppress high cholesterol and fat diet (HCD)-induced atherosclerosis formation in apolipoprotein E (apoE)-deficient mice. In our study, PYC suppressed oxidized low-density lipoprotein (ox-LDL)-induced lipid accumulation in peritoneal macrophages. Apolipoprotein E-deficient mice were orally administered PYC or a control solvent for ten weeks, and these mice were fed a standard diet or high cholesterol and fat diet during the latter eight weeks. Pycnogenol markedly decreased the size of atherosclerotic lesions induced by high cholesterol and fat diet compared with the nontreated controls. In addition, TLR4 expression in aortic sinus was stimulated by high cholesterol and fat diet feeding and was significantly reduced by PYC. A mechanistic analysis indicated that lipopolysaccharide (LPS) significantly increased expression of fatty acid binding protein (aP2) and macrophage scavenger receptor class A (SR-A), which were blocked by a JNK inhibitor. Furthermore, PYC inhibited the lipopolysaccharide-induced upregulation of aP2 and scavenger receptor class A via the JNK pathway. In conclusion, PYC administration effectively attenuates atherosclerosis through the TLR4-JNK pathway. Our results suggest that PYC could be a potential prophylaxis or treatment for atherosclerosis in humans.

Factors Significantly Associated With the Increased Prevalence of Carotid Atherosclerosis in a Northeast Chinese Middle-aged and Elderly Population: A Cross-sectional Study.

Carotid atherosclerosis is associated with many serious cardiovascular diseases; hence, it is necessary to identify factors related to its occurrence in order to develop preventive and therapeutic strategies. This study was conducted to identify risk factors associated with carotid atherosclerosis among the population residing in Northeast China.This epidemiological survey was conducted in a representative group of relatively healthy community residents. All participants answered questions about their medical histories and underwent physical examination, blood biochemical analysis, and ultrasonography examinations of their necks and abdomens. The prevalence rates of carotid atherosclerosis under different factors and conditions were then analyzed.The results of this study showed that age, gender, and diabetes significantly affected the prevalence of carotid atherosclerosis in this Northeast Chinese population. In addition, gender-based subgroup analysis revealed additional factors correlated with the prevalence of carotid atherosclerosis in men or women, although their correlations were not significant in the overall population. While high serum TC and LDL-C levels were risk factors for carotid atherosclerosis in men, it showed no clear correlation with the prevalence of carotid atherosclerosis in women. In contrast, the prevalence of carotid atherosclerosis in female participants with high serum TG level, hypertension, obesity and nonalcoholic fatty liver disease were higher than that of the control population, a trend not observed in male participants.Older age, male sex, and diabetes were independently associated with increased risk of carotid atherosclerosis in Northeast China. These findings could lead to improved screening for carotid atherosclerosis for better disease management.

Prevalence of Hyperuricemia and Gout in Mainland China from 2000 to 2014: A Systematic Review and Meta-Analysis.

We systematically identified the prevalence of hyperuricemia and gout in mainland China and provided informative data that can be used to create appropriate local public health policies. Relevant articles from 2000 to 2014 were identified by searching 5 electronic databases: PubMed, Google Scholar, Chinese Wanfang, CNKI, and Chongqing VIP. All of the calculations were performed using the Stata 11.0 and SPSS 20.0 software. The eligible articles (n = 36; 3 in English and 33 in Chinese) included 44 studies (38 regarding hyperuricemia and 6 regarding gout). The pooled prevalence of hyperuricemia and gout was 13.3% (95% CI: 11.9%, 14.6%) and 1.1% (95% CI: 0.7%, 1.5%), respectively. Although publication bias was observed, the results did not change after a trim and fill test, indicating that that impact of this bias was likely insignificant. The prevalence of hyperuricemia and gout was high in mainland China. The subgroup analysis suggested that the geographical region, whether the residents dwell in urban or rural and coastal or inland areas, the economic level, and sex may be associated with prevalence.

Pycnogenol Attenuates the Release of Proinflammatory Cytokines and Expression of Perilipin 2 in Lipopolysaccharide-Stimulated Microglia in Part via Inhibition of NF-κB and AP-1 Activation.

Over activation of microglia results in the production of proinflammatory agents that have been implicated in various brain diseases. Pycnogenol is a patented extract from French maritime pine bark (Pinus pinaster Aiton) with strong antioxidant and anti-inflammatory potency. The present study investigated whether pycnogenol may be associated with the production of proinflammatory mediators in lipopolysaccharide-stimulated BV2 (mouse-derived) microglia. It was found that pycnogenol treatment was dose-dependently associated with significantly less release of nitricoxide (NO), TNF-α, IL-6 and IL-1ß, and lower levels of intercellular adhesion molecule1 (ICAM-1) and perilipin 2 (PLIN2). Furthermore, this effect was replicated in primary brain microglia. Levels of inducible NO synthase mRNA and protein were attenuated, whereas there was no change in the production of the anti-inflammatory cytokine IL-10. Further evidence indicated that pycnogenol treatment led to the suppression of NF-κB activation through inhibition of p65 translocation into the nucleus and inhibited DNA binding of AP-1, suggesting that these proinflammatory factors are associated with NF-κB and AP-1. We conclude that pycnogenol exerts anti-inflammatory effects through inhibition of the NF-κB and AP-1pathway, and may be useful as a therapeutic agent in the prevention of diseases caused by over activation of microglia.

Type 1 Diabetic Populations Have an Increased Prevalence of Parietal Cell Antibody: A Systematic Review and Meta-Analysis.

The presence of parietal cell antibody (PCA) in serum is a biomarker of autoimmune gastritis. PCA directly recognizes the H/K ATPase expressed in parietal cells, which is responsible for the active transport of hydrogen ions in exchange for potassium ions to increase the acidity of gastric secretions. Type 1 diabetes mellitus (T1DM) mainly results from pancreatic ß-cell destruction due to cell-type specific autoimmunity. Considering autoimmune factors may be the common characteristics of both PCA positivity and T1DM, it is likely that both disorders may coexist within the same patient. The main objective of this meta-analysis is to provide a reliable evaluation to clarify the association between PCA positivity and T1DM by combining the raw data from all of the relevant studies.Literature databases, including the Medline, Embase, and Web of Science, were systematically queried for studies investigating the association between PCA positivity and T1DM and were published from January 1980 to December 2014. A total of 3,584 T1DM cases and 2,650 non-T1DM controls were included in this meta-analysis, which showed that PCA positivity was more prevalent in patients with T1DM than healthy controls. Publication bias testing found no significant biases and sensitivity analysis demonstrated that our statistics were relatively stable and credible.Our findings suggested that T1DM was associated with an increased risk of PCA positivity compared to control populations.

Systematic investigation into the role of intermittent high glucose in pancreatic beta-cells.

OBJECTIVES: Glucose fluctuation is suggested to be the leading cause of beta-cell damages. To determine how it induces beta-cell dysfunction, we systematically evaluated the effects of intermittent high glucose (IHG) in INS-1 rat pancreatic beta-cells on their proliferation activity, apoptosis, insulin secretion, reactive oxygen species (ROS), intracellular concentration of Ca(2+) ([Ca(2+)]i), and the PTEN expression as well as AKT phosphorylation. METHODS: Prior to the examinations, INS-1 cells were treated with normal glucose (NG, 11.1 mmol/L), sustained high glucose (SHG, 33 mmol/L), IHG (switching per 12 h in 11.1 mmol/l or 33 mmol/L), NG+α-lipoic acid (LA, pretreated with LA 12 h before exposure to NG), SHG+LA (pretreated with LA 12 h before being exposed to 33.3 mmol/L glucose) and IHG+LA (pretreated with LA 12 h before being cultured with IHG). The cells in each group were cultured with indicated concentrations of glucose for 3 days. The evaluations were carried out on the cell viability, apoptosis rate, insulin secretion, [Ca(2+)]i, ROS and the expressions of PTEN and p-AKT. RESULTS: The current study determined that IHG induces more apoptosis and significant increases of [Ca(2+)]i and intracellular ROS levels, compared to SHG and NG treatments to INS-1 cells. Moreover, IHG leads to more than 20% decrease on cell viability and over 50% reduction on insulin secretion (from 5.48±0.79 mIU/L to 2.51±0.58 mIU/L). The negative regulation of IHG on insulin signaling in beta-cells is identified via western blot analysis with results of the elevated expression of PTEN and lowered phosphorylation levels of AKT post IHG treatment. While the pretreatment of the antioxidant LA can significantly suppress the above responses induced by high glucose treatment. CONCLUSIONS: This study demonstrated that IHG plays a detrimental role in the viability, expansion, and function of beta-cells. IHG could be more harmful to the INS-1 cells than the SHG treatment. The rate increase of apoptosis in beta-cells could be caused by the suppressed insulin signaling, which is resulted from the raised ROS level by abnormal glucose treatments. Undergoing oxidative stress induced by high glucose treatments, including SHG and IHG, might be an important player in mediating the injury process to beta-cells, concluded from the beneficial rescue by the antioxidant LA treatment.

Suppression of phosphatase and tensin homolog protects insulin-resistant cells from apoptosis.

In the present study, a glucosamine-induced model of insulin-resistant skeletal muscle cells was established in order to investigate the effect of inhibition of phosphatase and tensin homolog (PTEN)/5'-adenosine monophosphate-activated protein kinase (AMPK) on these cells. The glucosamine-induced insulin-resistant skeletal muscle cells were produced and the rate of glucose uptake was measured using the glucose oxidase-peroxidase method. The expression levels of PTEN and phosphorylated PTEN (p-PTEN) were assessed using western blotting. Glucose transporter 4 (GLUT4) translocation was detected by immunofluorescence. Cell apoptosis was evaluated using flow cytometry. Following insulin stimulation, the rate of glucose uptake was significantly reduced in the cells with glucosamine-induced insulin-resistance in comparison with those in the control group. The expression and translocation of GLUT4 were reduced in the insulin-resistant muscle cells. By contrast, the expression of PTEN and p-PTEN as well as apoptosis were significantly increased. Following treatment with bisperoxopicolinatooxovanadate (BPV) or metformin in the insulin-resistant skeletal muscle cells, there was an increase in the rate of glucose uptake, an increase in GLUT4 expression and its translocation, a reduction in the expression of PTEN and p-PTEN, and a decrease in cell apoptosis compared with untreated insulin-resistant cells. Glucosamine may be used to produce an effective model of insulin-resistant skeletal muscle cells. Cells with glucosamine-induced insulin-resistance exhibited a reduced expression of GLUT4 and dysfunction in GLUT4 translocation, as well as increased activation of PTEN and increased cell apoptosis. Inhibition of PTEN or its upstream regulator, AMPK, protects glucosamine-induced insulin-resistant skeletal muscle cells from apoptosis.

Patients with systemic lupus erythematosus have higher prevalence of thyroid autoantibodies: a systematic review and meta-analysis.

BACKGROUND: Thyroid autoimmunity is considered the most common type of organ-specific autoimmune disorder and can be associated with other autoimmune endocrine disorders or non-endocrine diseases. Systemic lupus erythematosus is a prototypical autoimmune disorder with multifactorial etiology. The pathogenesis and development of the disease may result from a loss of immune tolerance and the resulting synthesis of autoantibodies against nuclear antigens. Autoimmune factors may be common features of both thyroid autoimmunity and systemic lupus erythematosus, making it likely that both conditions may coexist within some patients. METHODS AND FINDINGS: A number of studies have investigated whether an association between thyroid autoimmunity and systemic lupus erythematosus exists. However, the results of these studies have been inconsistent. Furthermore, most of these studies have had relatively small sample sizes, which have rendered them insufficiently powerful to determine whether there is an association between systemic lupus erythematosus and thyroid autoimmunity. The main objective of this meta-analysis is to provide reliable estimates of the extent of any association between thyroid autoimmunity and systemic lupus erythematosus by combining the primary data from all relevant studies. Literature databases were searched, including the Medline, Embase, Web of Science, Chinese Wanfang and CBM databases, from January 1970 to May 2014. A total of 1076 systemic lupus erythematosus cases and 1661 healthy controls were included in this study. From these data, the odds ratio (OR) and the corresponding 95% confidence interval (95% CI) were calculated. The meta-analysis results showed that the prevalence of thyroid autoantibody positivity in patients with systemic lupus erythematosus was higher than in healthy controls (TgAb: OR = 2.99, 95% CI = 1.83-4.89; TPOAb: OR = 2.20, 95% CI = 1.27-3.82, respectively). CONCLUSION: The results of this meta-analysis suggest that thyroid autoimmunity is more prevalent in patients with systemic lupus erythematosus than in a control group.

Increased risk of thyroid autoimmunity in rheumatoid arthritis: a systematic review and meta-analysis.

Thyroid autoimmunity, which is the most common immune-mediated disease, is frequently together with other organ- as well as nonorgan-specific autoimmune disorders. Meanwhile, rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disorder that mainly results in cartilage destruction as well as synovial joint inflammation, and both the adaptive and innate immune responses involve in the progression of this disease. Considering that autoimmune elements may be common characteristics of thyroid autoimmunity and RA, it is likely that both disorders may coexist within some patients. A great number of studies have researched whether an association between thyroid autoimmunity and RA exists; however, the results of these studies have been inconsistent. Most of these studies have included relatively small sample sizes, which have rendered them insufficiently powerful to determine whether there is a relationship between RA and thyroid autoimmunity. The main objective of this meta-analysis was to provide reliable estimates of the extent of any association between thyroid autoimmunity and RA by combining the primary data from all related studies. Literature databases, including the Embase, Medline, Web of Science, Chinese Wanfang, and CBM databases, were searched for studies published from January 1980 to May 2014, with a language restriction of English and Chinese. A total of 1,021 RA cases and 1,500 healthy controls were included in this study. From these data, the odds ratios (OR) and the corresponding 95 % confidence intervals (95 % CI) were calculated. The results of the meta-analysis showed that the prevalence of thyroid autoantibody positivity in patients with RA was higher than that in healthy controls (TgAb: OR 3.17, 95 % CI 2.24-4.49; TPOAb: OR 2.33, 95 % CI 1.24-4.39). The results of this meta-analysis suggest that thyroid autoimmunity is more prevalent in patients with RA than in the control population.