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Islet ß cell dedifferentiation is one of the most important mechanisms in the occurrence and development of diabetes. We studied the possible effects of chemokine stromal cell-derived factor-1 (SDF-1) in the dedifferentiation of islet ß cells. It was noted that the number of dedifferentiated islet ß cells and the expression of SDF-1 in pancreatic tissues significantly increased with diabetes. In islet ß cell experiments, inhibition of SDF-1 expression resulted in an increase in the number of dedifferentiated cells, while overexpression of SDF-1 resulted in a decrease. This seemed to be contradicted by the effect of diabetes on the expression of SDF-1 in pancreatic tissue, but it was concluded that this may be related to the loss of SDF-1 activity. SDF-1 binds to CXCR4 to form a complex, which activates and phosphorylates AKT, subsequently increases the expression of forkhead box O1 (FOXO1), and inhibits the dedifferentiation of islet ß cells. This suggests that SDF-1 may be a novel target in the treatment of diabetes.
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Hiperglicemia , Células Secretoras de Insulina , Ilhotas Pancreáticas , Quimiocina CXCL12/metabolismo , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Humanos , Hiperglicemia/metabolismo , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Pâncreas/metabolismo , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Transdução de SinaisRESUMO
OBJECTIVE: Obesity and sarcopenia are known to be closely related to nonalcoholic fatty liver disease (NAFLD). We attempted to explore the combined influence of fat and muscle tissue on NAFLD by using visceral fat area to appendicular muscle mass ratio (VAR) as a novel parameter. MATERIAL AND METHODS: In this cross-sectional study, a total of 3255 adults (1399 men and 1856 women) coming for a health examination were enrolled. NAFLD was diagnosed using ultrasound and VAR was measured by bioelectrical impedance analyzer. RESULTS: The prevalence of NAFLD was 46.5% in men and 26.6% in women. VAR differed significantly between subjects with and without NAFLD (4.27 vs. 3.26 in men, 7.89 vs. 5.01 in women, respectively, p < .001). Logistic regression analysis determined VAR as a risk factor for NAFLD, and the multivariable-adjusted odds ratios in the highest VAR quartile was 9.57 (95%CI: 5.98-15.30) for men and 12.37 (95%CI: 6.37-24.05) for women. From the receiver operating characteristic analysis, the area under the curve was 0.767 and 0.834, with the suitable cut-off VAR value of 3.469 and 6.357 for men and women, respectively. To control the influence of obesity, all subjects were stratified according to their BMI. For each BMI group, individuals with VAR above the cut-off value had significant higher prevalence and risk of NAFLD, with odds ratios ranging from 1.76 to 4.75. CONCLUSIONS: Increased VAR is strongly associated with higher risk of NAFLD in both sexes independent of obesity and can serve as a screening reference for NAFLD.
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Hepatopatia Gordurosa não Alcoólica , Adulto , Índice de Massa Corporal , Estudos Transversais , Feminino , Humanos , Gordura Intra-Abdominal/diagnóstico por imagem , Masculino , Músculos , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Fatores de RiscoRESUMO
AIM: Glucagon-like peptide-1 receptor agonists (GLP-1Ras) have been reported to prevent non-alcoholic fatty liver disease (NAFLD), but the potential mechanisms are still debated. MicroRNAs (miRNAs) play a prominent role in the field of metabolic disorders, including NAFLD. Our study was designed to further evaluate the effect of GLP-1Ra liraglutide on NAFLD in terms of miRNAs. METHODS: MicroRNA expression was evaluated by clustering analysis of microRNA arrays in high fat diet-fed mice. The luciferase reporter assay was carried out to validate the cross-talk between adipose triglyceride lipase (ATGL) and miR-124a. MicroRNA-124a mimics and inhibitor plasmids were transfected to study the role of miR-124a in palmitate-treated normal human liver cell line (HL-7702). Liraglutide treatment was used to observe the effect of GLP-1Ra on the miR-124a/ATGL pathway. RESULTS: Expression of ATGL decreased and miR-124a expression increased in hepatosteatosis in vivo and in vitro. Mechanistically, miR-124a interacted with the 3'-untranslated region of ATGL mRNA and induced its degradation. MicroRNA-124a overexpression antagonized the effect of liraglutide on NAFLD by inhibiting ATGL expression, whereas miR-124a knockdown led to elevated ATGL and sirtuin 1 (Sirt1) expression, and subsequently decreased lipid accumulation and inflammation in cells. CONCLUSIONS: MicroRNA-124a overexpression contributes to the progression of NAFLD through reduction of ATGL expression, whereas miR-124a knockdown can reverse this trend, suggesting that miR-124a and its downstream target ATGL can be novel therapeutic targets of NAFLD. We reveal a novel mechanism by which liraglutide attenuates NAFLD by the miR-124a/ATGL/Sirt1 pathway.
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BACKGROUND Protective effects of reduced beta 2 glycoprotein I (Rb2GPI) against vascular injury of diabetes mellitus have been extensively investigated. However, the effects of Rb2GPI on liver injury in diabetic animals have not been reported. MATERIAL AND METHODS A diabetic rat model of was produced by systemic injection of streptozotocin (STZ). Rats were divided into a normal control group, a model group, and an Rb2GPI treatment group (N=6 in each group). After treatments, blood serum and liver tissue were collected to test the protection of Rb2GPI. AMP-activated protein kinase (AMPK) was detected by immunohistochemistry and Western blotting. RESULTS Our results revealed that Rß2GPI reduced blood glucose, serum creatinine, and urea nitrogen levels, as well as serum inflammation cytokines, including interleukin (IL)-6, tumor necrosis factor (TNF)-α and C-reactive protein in the diabetic rats. Importantly, Rß2GPI prevented liver injury in the diabetic rats as confirmed by hematoxylin-eosin (H&E) staining, alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase. Reactive oxygen species (ROS) were promoted by diabetic modeling and were attenuated by Rß2GPI administration. Moreover, Rß2GPI significantly reduced liver catalase, malondialdehyde, and superoxide dismutase levels in the diabetic rats. Rß2GPI reduced liver glycolipid storage in STZ diabetic rats. Both immunohistochemistry and Western blotting demonstrated that Rß2GPI promoted AMPK phosphorylation in the diabetic rats. CONCLUSIONS Our data proved that Rß2GPI prevented liver injury in diabetic rats, likely through activating the AMPK signaling pathway.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , beta 2-Glicoproteína I/metabolismo , beta 2-Glicoproteína I/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Glicemia/análise , Proteína C-Reativa/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Creatinina/análise , Creatinina/sangue , Complicações do Diabetes/tratamento farmacológico , Complicações do Diabetes/metabolismo , Diabetes Mellitus Experimental/metabolismo , Modelos Animais de Doenças , Interleucina-6/metabolismo , Fígado/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estreptozocina/farmacologia , Superóxido Dismutase/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Long noncoding RNA taurine-upregulated gene 1 (lncRNA TUG1) has been reported to play a key role in the progression of diabetic nephropathy (DN). However, the role of lncRNA TUG1 in the regulation of diabetic nephropathy remains largely unknown. The aim of the present study is to identify the regulation of lncRNA TUG1 on extracellular matrix accumulation via mediating microRNA-377 targeting of PPARγ, and investigate the underlying mechanisms in progression of DN. Microarray was performed to screen differentially expressed miRNAs in db/db DN mice. Afterwards, computational prediction programs (TargetScan, miRanda, PicTar and miRGen) was applied to predict the target gene of miRNAs. The complementary binding of miRNA and lncRNA was assessed by luciferase assays. Protein and mRNA expression were detected by western blot and real time quantitate PCR. MiRNA-377 was screened by miRNA microarray and differentially up-regulated in db/db DN mice. PPARγ was predicted to be the target of miR-377 and the prediction was verified by luciferase assays. Expression of miR-377 was up-regulated in mesangial cell treated with high glucose (25 mM), and overexpression of miR-377 inhibited PPARγ expression and promoted PAI-1 and TGF-ß1 expression. The expression of TUG1 antagonized the effect of miR-377 on the downregulation of its target PPARγ and inhibited extracellular matrix accumulation, including PAI-1, TGF-ß1, fibronectin (FN) and collagen IV (Col IV), induced by high glucose. LncRNA TUG1 acts as an endogenous sponge of miR-377 and downregulates miR-377 expression levels, and thereby relieving the inhibition of its target gene PPARγ and alleviates extracellular matrix accumulation of mesangial cells, which provides a novel insight of diabetic nephropathy pathogenesis.
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Nefropatias Diabéticas/metabolismo , Matriz Extracelular/patologia , Células Mesangiais/patologia , MicroRNAs/metabolismo , PPAR gama/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Células Cultivadas , Nefropatias Diabéticas/patologia , Matriz Extracelular/metabolismo , Células Mesangiais/metabolismo , Camundongos , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND/AIMS: Metabolic acidosis is a common consequence of end-stage renal disease (ESRD) which may result in a substantial adverse outcome. The effect of oral bicarbonate on the preservation of residual renal function (RRF) in peritoneal dialysis (PD) patients has been rarely reported. METHODS: We randomly assigned 40 continuous ambulatory peritoneal dialysis (CAPD) patients to the oral bicarbonate group or placebo group at a 1: 1 ratio. All enrollments were followed for a duration of 104 weeks. We took residual creatinine clearance (CCr), a measure of residual renal function (RRF), as the primary outcome. Residual CCr was calculated as the average of urea and creatinine clearance from a 24-hour urine collection. RESULTS: Thirteen patients in the placebo group and 15 patients in the treatment group completed the 104 weeks of follow-up with a comparable dropout rate (placebo group: 35% vs treatment group: 25%). Compared with the placebo group, serum bicarbonate in treatment group was significantly increased at each time point, and oral bicarbonate resulted in a slower declining rate of residual CCr (F=5.113, p=0.031). Baseline residual CCr at enrollment also had a significant effect on residual CCr (F=168.779, P<0.001). Charlson Comorbidity Index which was adopted to calculate a comorbidity score had no significant effect on residual CCr loss (F=0.168, P=0.685). CONCLUSION: Oral bicarbonate may have a RRF preserving effect in CAPD patients, and a normal to high level of serum bicarbonate (≥24mmol/L) may be appropriate for RRF preservation.
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Bicarbonatos/farmacologia , Falência Renal Crônica/tratamento farmacológico , Acidose/tratamento farmacológico , Adulto , Idoso , Bicarbonatos/administração & dosagem , Bicarbonatos/sangue , Creatinina/metabolismo , Creatinina/urina , Feminino , Humanos , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Diálise Peritoneal Ambulatorial ContínuaRESUMO
BACKGROUND Subclinical hypothyroidism (SCH) is typically featured by elevated serum concentration of thyroid-stimulating hormone (TSH). This study aimed to determine the relationship between TSH levels and microvascular complications in type 2 diabetes patients. MATERIAL AND METHODS A total of 860 type 2 diabetes patients were enrolled in this cross-sectional study. Subjects were evaluated for anthropometric measurements, thyroid function, diabetic retinopathy, and diabetic kidney disease. TSH was divided into 3 levels: 0.27-2.49 mU/l, 2.5-4.2 mU/l, and >4.2 mU/l. RESULTS Among the participants, 76 subjects (8.8%) were diagnosed with subclinical hypothyroidism (SCH) (male: 6.6% and female: 11.8%). The prevalence of diabetic retinopathy did not differ among the groups (P=0.259). Of the 860 type 2 diabetic subjects, we further excluded invalid or missing data. Therefore, 800 and 860 subjects were included in our study of diabetic retinopathy (DR) and diabetic kidney disease (DKD), respectively. The frequencies of microalbuminuria and macroalbuminuria differed significantly among the different groups. The frequency of DKD was significantly different among the 3 groups (P=0.001) and was higher in subjects with higher TSH levels. After an adjustment for confounding variables, TSH levels were significantly associated with DKD (P<0.001). When compared with subjects with TSH 0.27-2.49 mU/l, the frequency of DKD was higher in subjects with TSH >4.20 mU/l (OR 1.531, 95% CI 1.174-1.997) and with TSH 2.50-4.20 mU/l (OR 1.579, 95% CI 1.098-2.270). However, TSH levels was not significantly correlated with DR (P=0.126). CONCLUSIONS Type 2 diabetic patients with higher TSH values had a higher prevalence of DKD.
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Complicações do Diabetes/sangue , Diabetes Mellitus Tipo 2/sangue , Microvasos/patologia , Tireotropina/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , PrevalênciaRESUMO
Cigarette smoking damages the extracellular matrix in a variety of locations, leading to atherosclerotic plaque instability and emphysematous lung destruction, but the underlying mechanisms remain poorly understood. Here, we sought to determine whether exposure of human macrophages, a key participant in extracellular matrix damage, to tobacco smoke extract (TSE) induces the release of microvesicles (MVs; or microparticles) with proteolytic activity; the major proteases involved; and the cellular mechanisms that might mediate their generation. We found that MVs released from TSE-exposed macrophages carry substantial gelatinolytic and collagenolytic activities that surprisingly can be predominantly attributed to a single transmembrane protease of the matrix metalloproteinase (MMP) superfamily (namely, MMP14). Flow cytometric counts revealed that exposure of human macrophages to TSE for 20 hours more than quadrupled their production of MMP14-positive MVs (control, 1112 ± 231; TSE-induced, 5823 ± 2192 MMP14-positive MVs/µL of conditioned medium; means ± SEM; n = 6; P < 0.01). Our results indicate that the production of these MVs by human macrophages relies on a series of regulated steps that include activation of two mitogen-activated protein kinases (MAPKs, i.e., the Jun N-terminal kinase and p38 MAPK), and then MAPK-dependent induction and maturation of cellular MMP14, a remarkable accumulation of MMP14 into nascent plasma membrane blebs, and finally caspase- and MAPK-dependent apoptosis and apoptotic microvesicle generation. Proteolytically active MVs induced by tobacco smoke may be novel mediators of clinical important matrix destruction in smokers.
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Micropartículas Derivadas de Células/metabolismo , Macrófagos/metabolismo , Proteólise , Fumar , Apoptose , Linhagem Celular , Membrana Celular/metabolismo , Ativação Enzimática , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Macrófagos/enzimologia , Metaloproteinase 14 da Matriz/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND AND AIMS: Liraglutide treatment can improve glycemic control with a concomitant weight loss, but the underlying mechanism on weight loss is not completely understood. Cardiac natriuretic peptides (NPs) can resist body fat accumulation through increasing adipocytes lypolysis. In this study, we tested the hypothesis that liraglutide-induced weight loss was associated with increased plasma NPs concentrations. METHODS: Thirty-one outpatients with type 2 diabetes (T2D) treated with metformin and other oral antidiabetic drugs except for thiazolidinediones (TZDs) were subcutaneously administered with liraglutide for 12 weeks. Body composition, abdominal visceral adipose tissue areas (VAT) and subcutaneous adipose tissue areas (SAT) were assessed at pre- and post-treatment by dual-energy X-ray absorptiometry (DXA) scanning and abdominal computerized tomography (CT). Plasma atrial natriuretic peptides (ANP) and B-type ventricular natriuretic peptides (BNP) concentrations were tested by commercial ELISA Kit quantitatively. RESULTS: Following 12-week liraglutide treatment, body weight, waist circumference, total fat and lean mass, fat percentage, SAT and VAT areas were significantly reduced from baseline. Concurrently, plasma ANP and BNP levels were significantly increased following 12-week liraglutide treatment. There were significant correlations between the reductions in body compositions and the increases in both plasma ANP and BNP levels. CONCLUSIONS: There were significant correlations between increases in both plasma ANP and BNP levels and changes in liraglutide-induced body composition. Our data implied that increases in plasma NPs may add a novel dimension to explain how liraglutide induces weight loss.
Assuntos
Fator Natriurético Atrial/sangue , Composição Corporal/fisiologia , Diabetes Mellitus Tipo 2/sangue , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo Natriurético Encefálico/sangue , Obesidade/sangue , Adulto , Biomarcadores/sangue , Composição Corporal/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Seguimentos , Peptídeo 1 Semelhante ao Glucagon/farmacologia , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Humanos , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Liraglutida , Masculino , Pessoa de Meia-Idade , Peptídeos Natriuréticos/sangue , Obesidade/tratamento farmacológico , Estudos ProspectivosRESUMO
Objective: To investigate the impact of sarcopenia on the 10-year risk of atherosclerotic cardiovascular disease (ASCVD) among individuals with type 2 diabetes mellitus (T2DM). Methods: This study included the clinical, laboratory, and body composition data of 1491 patients with T2DM who were admitted to the Department of Endocrinology and Metabolism at Tianjin Union Medical Center from July 2018 to July 2023. The China-PAR model was utilized to evaluate cardiovascular disease risk. Associations between ASCVD risk and various clinical parameters were analyzed, and the relationship between body composition parameters and ASCVD risk was assessed using logistic regression. Results: The analysis revealed that T2DM patients with sarcopenia had a higher 10-year ASCVD risk compared to those without sarcopenia, with reduced muscle mass independently predicting an increased risk of cardiovascular disease. This association was significant among female T2DM patients, while male T2DM patients with sarcopenia showed a marginally higher median ASCVD risk compared to their non-sarcopenic counterparts. ASCVD risk inversely correlated with body muscle parameters and positively correlated with fat content parameters. Specifically, height- and weight-adjusted fat mass (FM, FM%, FMI) were identified as risk factors for ASCVD. Conversely, muscle parameters adjusted for weight and fat (ASM%, SMM%, FFM%, ASM/FM, SMM/FM, FMM/FM) were protective against ASCVD risk. These findings highlight the critical role of sarcopenia in influencing cardiovascular disease risk among Chinese patients with T2DM, as predicted by the China-PAR model. Conclusion: This study highlights the importance of sarcopenia in T2DM patients, not only as an indicator of ASCVD risk, but possibly as an independent risk factor in this demographics.
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BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of major depression. Individuals with type 2 diabetes (T2DM) have a high prevalence of major depression and low levels of BDNF. We therefore explored whether the BDNF Val66Met polymorphism is associated with co-morbid depression and whether depression affects the serum levels of BDNF in a Han Chinese subjects with T2DM. METHODS: A Total of 296 T2DM patients and 70 healthy volunteers (Health control, HC group) were recruited in this study. T2DM patients were divided into two subgroups: depressive diabetes group (DDM group, n = 64) and non-depressive diabetes group (NDDM group, n = 232), according to the presence or the absence of depression assessed by Center for Epidemiologic Studies Depression Scale (CES-D) and Patient Health Questionnaire-9 (PHQ-9). Val66Met polymorphism was detected by polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP). Serum BDNF levels were measured by ELISA kit. RESULTS: In this study, 21.6% (64/296) patients with T2DM had depression. The BDNF Val66Met genotype distributions were statistically different among the three groups (χ2 = 7.39, p < 0.05). DDM group carried the highest frequencies of Met allele (53.9%) compared to HC group (39.3%) and NDDM group (38.8%). Subjects with Met/Met had lowest serum BDNF levels (76.59 ± 5.12 pg/ml, F = 7.39, p < 0.05) compared to subjects with Val/Met (79.04 ± 5.19 pg/ml) and Val/Val (83.83 ± 3.97 pg/ml). Within T2DM group, it was also observed that the serum BDNF levels in DDM group were significantly lower than those in NDDM group (76.67 ± 5.35 vs. 79.84 ± 3.97 pg/ml, p < 0.05). In type 2 diabetes subjects, BDNF serum levels were significant correlations with genotypes (r = -0.346, p < 0.01), depression scores (r = -0.486, p < 0.01) and HbA1c (r = -0.168, p < 0.05). After adjustment for gender, HbA1c, BMI and numbers of complications, BDNF Val/Met genotype distributions (OR = 2.105, p < 0.05) and decreased serum BDNF levels (OR = 0.835, p < 0.01) were independently associated with depression in T2DM. CONCLUSIONS: The BDNF Val66Met polymorphism might be implicated in the pathogenesis of depression in T2DM by decreasing serum BDNF levels in Han Chinese Subjects.
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Fator Neurotrófico Derivado do Encéfalo/genética , Transtorno Depressivo/genética , Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleotídeo Único , Alelos , Povo Asiático/genética , Fator Neurotrófico Derivado do Encéfalo/sangue , China , Transtorno Depressivo/sangue , Transtorno Depressivo/complicações , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Reduced beta2-glycoprotein I (beta2-GPI) is a free thiol-containing form of beta2-GPI that displays a powerful effect in protecting endothelial cells from oxidative stress-induced cell death. The present study aims to investigate the effect of beta2-GPI or reduced beta2-GPI on ox-LDL-induced foam cell formation and on cell apoptosis and to determine the possible mechanisms. METHODS: The RAW264.7 macrophage cell line was selected as the experimental material. Oil red O staining and cholesterol measurement were used to detect cholesterol accumulation qualitatively and quantitatively, respectively. Flow cytometry was used to detect cell apoptosis. Real-time quantitative PCR was used to detect the mRNA expression of the main proteins that are associated with the transport of cholesterol, such as CD36, SRB1, ABCA1 and ABCG1. Western blot analysis was used to detect the protein expression of certain apoptosis-related proteins, such as caspase-9, caspase-3, p38 MAPK/p-p38 MAPK and JNK/p-JNK. RESULTS: Beta2-GPI or reduced beta2-GPI decreased ox-LDL-induced cholesterol accumulation (96.45 ± 8.51 µg/mg protein vs. 114.35 ± 10.38 µg/mg protein, p < 0.05;74.44 ± 5.27 µg/mg protein vs. 114.35 ± 10.38 µg/mg protein, p < 0.01) and cell apoptosis (30.00 ± 5.10% vs. 38.70 ± 7.76%, p < 0.05; 20.66 ± 2.50% vs. 38.70 ± 7.76%, p < 0.01), and there are significant differences between beta2-GPI and reduced beta2-GPI (p < 0.05). Reduced beta2-GPI decreased the ox-LDL-induced expression of CD36 mRNA and ABCA1 mRNA (p < 0.05), as well as CD36, cleaved caspase-9, cleaved caspase-3, p-p38 MAPK and p-JNK proteins (p < 0.05 or p < 0.01). Beta2-GPI did not significantly decrease the expression of ABCA1 mRNA and the p-p38 MAPK protein. CONCLUSIONS: Both beta2-GPI and reduced beta2-GPI inhibit ox-LDL-induced foam cell formation and cell apoptosis, and the latter exhibits a stronger inhibition effect. Both of these glycoproteins reduce the lipid intake of macrophages by downregulating CD36 as well as protein expression. Reduced beta2-GPI inhibits cell apoptosis by reducing the ox-LDL-induced phosphorylation of p38 MAPK and JNK, and the amount of cleaved caspase-3 and caspase-9. Beta2-GPI does not inhibit the ox-LDL-induced phosphorylation of p38 MAPK.
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Colesterol/metabolismo , Células Espumosas/efeitos dos fármacos , Lipoproteínas LDL/farmacologia , beta 2-Glicoproteína I/farmacologia , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Antígenos CD36/antagonistas & inibidores , Antígenos CD36/genética , Antígenos CD36/metabolismo , Caspases/genética , Caspases/metabolismo , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Células Espumosas/metabolismo , Células Espumosas/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Lipoproteínas/genética , Lipoproteínas/metabolismo , Lipoproteínas LDL/antagonistas & inibidores , MAP Quinase Quinase 4/genética , MAP Quinase Quinase 4/metabolismo , Camundongos , Oxirredução , Fosforilação/efeitos dos fármacos , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
BACKGROUND: The aim of this study was to investigate the effect of C-reactive protein/oxidised low-density lipoprotein/ß2-glycoprotein I (CRP/oxLDL/ß2GPI) complex on atherosclerosis (AS) in diabetic BALB/c mice. METHODS: BALB/c mice were fed high-fat and normal diet. Eight weeks later, the mice fed with high-fat diet were injected with streptozotocin (STZ) to induce diabetes. The diabetic mice were respectively injected twice monthly with 20 µg oxLDL, 20 µg ß2GPI, 40 µg oxLDL/ß2GPI complex, 44 µg CRP/oxLDL/ß2GPI complex, and PBS. Aortas were stained with Sudan IV to investigate lipid plaque formation. The infiltration condition of smooth muscle cells (SMCs), macrophages, and T cells in the aortas were determined by immunohistochemistry (IH). The mRNA expressions of receptors associated with lipid metabolism were quantified by real-time PCR. The phosphorylation of p38 mitogen-activated protein kinase (p38MAPK) and MKK3/6 in aorta tissues were assessed by Western blot. The expression of inflammation cytokines was evaluated by protein chip. RESULTS: The lipid plaques were more extensive, the lumen area was obviously narrower, the ratio of intima and media thickness were increased, and the normal internal elastic lamia structure and endothelial cell disappeared (P < 0.05) in the oxLDL and CRP/oxLDL/ß2GPI groups (P < 0.05). CRP/oxLDL/ß2GPI complex dramatically promoted infiltration of SMCs, macrophages, and T cells, improved the mRNA expression of ABCA1 and ABCG1, but reduced the mRNA expression of SR-BI and CD36 and increased the phosphorylation of p38MAPK and MKK3/6 (all P < 0.05). The highest expression levels of IL-1, IL-9, PF-4, bFGF, and IGF-II were detected in the CRP/oxLDL/ß2GPI group (P < 0.05). CONCLUSIONS: CRP/oxLDL/ß2GPI complex aggravated AS in diabetic BALB/c mice by increasing lipid uptake, the mechanism of which may be mediated by the p38MAPK signal pathway.
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Aterosclerose/etiologia , Aterosclerose/genética , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/genética , Placa Aterosclerótica/etiologia , Placa Aterosclerótica/genética , Transdução de Sinais , Animais , Aorta/metabolismo , Aorta/patologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Proteína C-Reativa/farmacologia , Citocinas/genética , Citocinas/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica , Regulação da Expressão Gênica , Lipoproteínas LDL/farmacologia , MAP Quinase Quinase 3/genética , MAP Quinase Quinase 3/metabolismo , MAP Quinase Quinase 6/genética , MAP Quinase Quinase 6/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Estreptozocina , Linfócitos T/metabolismo , Linfócitos T/patologia , beta 2-Glicoproteína I/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
OBJECTIVE: The aims of this study were to determine the association of skeletal muscle mass with three cardiovascular risk factors and explore a simple and clinically feasible indicator for identifying high-risk groups of cardiovascular diseases in occupational sedentary population. METHODS: We recruited 7316 occupational sedentary participants older than 18 years from the Health Management Center of Tianjin Union Medical Center. Age-adjusted logistic regression was used to analyze the association between skeletal muscle mass index (SMI) and cardiovascular risk factors. RESULTS: There were significant positive associations between SMI, especially arm SMI, and cardiovascular risk factors in both male and female subjects (odds ratio, 1.28 to 5.02; P < 0.001). CONCLUSIONS: Our findings suggest that measurements of skeletal muscle mass, particularly in the arms, may help identify individuals at high risk for cardiovascular disease in an occupationally sedentary population.
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Doenças Cardiovasculares , Sarcopenia , Humanos , Masculino , Feminino , Músculo Esquelético , Sarcopenia/epidemiologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/patologia , Estudos Transversais , Fatores de Risco , Fatores de Risco de Doenças CardíacasRESUMO
BACKGROUND: The purpose of the study was to compare the efficacy of two novel obesity indices, lipid accumulation product (LAP) and visceral adiposity index (VAI), with traditional obesity indices in predicting early-onset type 2 diabetes (T2DM). METHODS: In this cross-sectional study, a total of 744 participants, including 605 patients newly diagnosed with T2DM and 139 non-diabetic control subjects, were enrolled from a tertiary care hospital in Tianjin, China. Participants with T2DM were divided into two groups based on their age at diagnosis, namely early-onset T2DM (age less than 40 years, n = 154) and late-onset T2DM (age 40 years or older, n = 451). The predictive power of each obesity index was evaluated using receiver operating characteristic (ROC) curve analysis. Furthermore, binary logistic regression analysis was conducted to examine the independent relationship between LAP and VAI with early-onset T2DM risk. The relationship between novel obesity indices and the age of T2DM onset was also evaluated through correlation and multiple linear regression analysis. RESULTS: In males, LAP had the highest predictive power for early-onset T2DM with an area under the ROC curve (AUC) of 0.742 (95% CI 0.684-0.799, P < 0.001). In females, VAI had the highest AUC for early-onset T2DM with a value of 0.748 (95% CI 0.657-0.839, P < 0.001), which was superior to traditional indices. Patients in the 4th quartile of LAP and VAI had 2.257 (95% CI 1.116-4.563, P = 0.023) and 4.705 (95% CI 2.132-10.384, P < 0.001) times higher risk of T2DM before age 40, compared to those in the 1st quartile, respectively. A tenfold increase in LAP was associated with a decrease in T2DM onset age of 12.862 years in males (ß = -12.862, P < 0.001) and 6.507 years in females (ß = -6.507, P = 0.013). A similar decrease in T2DM onset age was observed for each tenfold increase in VAI in both male (ß = -15.222, P < 0.001) and female (ß = -12.511, P < 0.001) participants. CONCLUSIONS: In young Chinese individuals, LAP and VAI are recommended over traditional obesity indices for improved prediction of early-onset T2DM risk.
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BACKGROUND: Alpha-lipoic acid (ALA), a naturally occurring compound, exerts powerful protective effects in various cardiovascular disease models. However, its role in protecting against diabetic cardiomyopathy (DCM) has not been elucidated. In this study, we have investigated the effects of ALA on cardiac dysfunction, mitochondrial oxidative stress (MOS), extracellular matrix (ECM) remodeling and interrelated signaling pathways in a diabetic rat model. METHODS: Diabetes was induced in rats by I.V. injection of streptozotocin (STZ) at 45 mg/kg. The animals were randomly divided into 4 groups: normal groups with or without ALA treatment, and diabetes groups with or without ALA treatment. All studies were carried out 11 weeks after induction of diabetes. Cardiac catheterization was performed to evaluate cardiac function. Mitochondrial oxidative biochemical parameters were measured by spectophotometeric assays. Extracellular matrix content (total collagen, type I and III collagen) was assessed by staining with Sirius Red. Gelatinolytic activity of Pro- and active matrix metalloproteinase-2 (MMP-2) levels were analyzed by a zymogram. Cardiac fibroblasts differentiation to myofibroblasts was evaluated by Western blot measuring smooth muscle actin (α-SMA) and transforming growth factor-ß (TGF-ß). Key components of underlying signaling pathways including the phosphorylation of c-Jun N-terminal kinase (JNK), p38 MAPK and ERK were also assayed by Western blot. RESULTS: DCM was successfully induced by the injection of STZ as evidenced by abnormal heart mass and cardiac function, as well as the imbalance of ECM homeostasis. After administration of ALA, left ventricular dysfunction greatly improved; interstitial fibrosis also notably ameliorated indicated by decreased collagen deposition, ECM synthesis as well as enhanced ECM degradation. To further assess the underlying mechanism of improved DCM by ALA, redox status and cardiac remodeling associated signaling pathway components were evaluated. It was shown that redox homeostasis was disturbed and MAPK signaling pathway components activated in STZ-induced DCM animals. While ALA treatment favorably shifted redox homeostasis and suppressed JNK and p38 MAPK activation. CONCLUSIONS: These results, coupled with the excellent safety and tolerability profile of ALA in humans, demonstrate that ALA may have therapeutic potential in the treatment of DCM by attenuating MOS, ECM remodeling and JNK, p38 MAPK activation.
Assuntos
Cardiotônicos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Cardiomiopatias Diabéticas/prevenção & controle , Miocárdio/patologia , Ácido Tióctico/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Actinas/metabolismo , Animais , Western Blotting , Cateterismo Cardíaco , Diferenciação Celular/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Colágeno Tipo II/metabolismo , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Cardiomiopatias Diabéticas/fisiopatologia , Ativação Enzimática , Precursores Enzimáticos/metabolismo , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Fibrose , Gelatinases/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Miocárdio/metabolismo , Miofibroblastos/efeitos dos fármacos , Miofibroblastos/metabolismo , Miofibroblastos/patologia , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Espectrofotometria , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
OBJECTIVE: To assess the efficacy and safety of adding liraglutide to established insulin therapy in poorly controlled Chinese subjects with type 2 diabetes and abdominal obesity compared with increasing insulin dose. METHODS: A 12-week, randomized, parallel-group study was carried out. A total of 84 patients completed the trial who had been randomly assigned to either the liraglutide-added group or the insulin-increasing group while continuing current insulin based treatment. Insulin dose was reduced by 0-30% upon the initiation of liraglutide. Insulin doses were subsequently adjusted to optimized glycemic control. Glycosylated hemoglobin (HbA1c) values, blood glucose, total daily insulin dose, body weight, waist circumference, and the number of hypoglycemic events and adverse events were evaluated. RESULTS: At the end of study, the mean reduction in HbA1c between the liraglutide-added group and the insulin-increasing group was not significantly different (1.9% vs. 1.77%, p>0.05). However, the percentage of subjects reaching the composite endpoint of HbA1c ≤ 7.0% with no weight gain and no hypoglycemia, was significantly higher in the liraglutide-added group than in the insulin-increasing group (67% vs. 19%, p<0.001). Add-on liraglutide treatment significantly reduced mean body weight (5.62 kg, p<0.01), waist circumference (5.70 cm, p<0.01), body mass index (BMI) (1.93 kg/m2, p<0.01) and daily total insulin dose (dropped by 66%) during 12-week treatment period, while all of these significantly increased with insulin increasing treatment. Add-on liraglutide treated patients had lower rate of hypoglycemic events and greater insulin and oral antidiabetic drugs discontinuation. Gastrointestinal disorders were the most common adverse events in the liraglutide added treatment, but were transient. CONCLUSIONS: Addition of liraglutide to abdominally obese, insulin-treated patients led to improvement in glycemic control similar to that achieved by increasing insulin dosage, but with a lower daily dose of insulin and fewer hypoglycemic events. Adding liraglutide to insulin also induced a significant reduction in body weight and waist circumference. Liraglutide combined with insulin may be the best treatment option for poorly controlled type 2 diabetes and abdominal obesity.
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Povo Asiático , Diabetes Mellitus Tipo 2/tratamento farmacológico , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Obesidade Abdominal/etnologia , Adulto , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , China/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etnologia , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Peptídeo 1 Semelhante ao Glucagon/administração & dosagem , Peptídeo 1 Semelhante ao Glucagon/efeitos adversos , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemia/sangue , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Liraglutida , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/sangue , Obesidade Abdominal/diagnóstico , Fatores de Tempo , Resultado do Tratamento , Circunferência da Cintura , Aumento de Peso/efeitos dos fármacosRESUMO
INTRODUCTION: Adipose tissue deposited on the viscera is the main culprit in the development of insulin resistance (IR) and cardiometabolic diseases, whereas subcutaneous adipose tissue may have a protective role. This study aimed to propose a new predictive index - the visceral-fat area (VFA)-to-hip-circumference ratio (VHR) and explore its efficacy for prediction of IR in a Chinese population with type 2 diabetes mellitus. METHODS: A total of 643 patients with newly diagnosed diabetes were enrolled in this study. Body composition, anthropometrical, and biochemical measurements were performed. IR was defined as homeostatic model assessment of IR (HOMA-IR) > 2.69. The association between VHR and IR was analyzed. RESULTS: Regardless of gender, subjects in the IR group had higher VHR, body mass index (BMI), VFA, body fat percentage, systolic blood pressure, diastolic blood pressure (DBP), fasting blood glucose, fasting insulin, triglyceride (TG), uric acid (UA), homocysteine, and aminotransferases than those in the non-IR group. The other concomitant metabolic disorders were more common in the IR group. Further analysis showed that with the increase of VHR, the levels of HOMA-IR, BMI, VFA, DBP, TG, UA and the prevalence of nonalcoholic fatty-liver disease, hypertension, and hyperuricemia increased continuously (p trend <0.01). The linear trend test showed that VHR and IR remained closely correlated after adjusting for possible confounders (p trend <0.05). The receiver operating characteristic curve analysis showed that the area under the curve was 0.69, and the optimal cutoff of VHR was 0.89 (sensitivity 79.3%, specificity 61.5%). CONCLUSION: VHR was positively associated with IR regardless of gender, and it might be a reliable predictor for IR.
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Diabetes Mellitus Tipo 2 , Resistência à Insulina , Índice de Massa Corporal , China/epidemiologia , Humanos , Insulina , Gordura Intra-Abdominal/metabolismo , TriglicerídeosRESUMO
Background: Visceral adiposity plays a key role in the development of insulin resistance (IR), so surrogate index that can indicate visceral obesity may have higher predictive value for IR. This study aimed to establish and validate a new predictive model including indicator of visceral obesity for IR. Methods: The study population consisted of two cohorts. The derivation cohort was a group of 667 patients with newly diagnosed type 2 diabetes and the population undergoing a routine health checkup was the validation cohort. The predictive model was established by the logistic regression analysis. Its value for predicting IR was compared with other surrogate indices by the receiver operating characteristic curve. Results: The odds ratio (OR) of age, visceral fat area (VFA), triglyceride (TG), fasting plasma glucose (FPG), and alanine aminotransferase (ALT) for IR was 1.028 (95% CI, 1.008-1.048) (P < 0.01), 1.016 (95% CI, 1.009-1.023) (P < 0.001), 1.184 (95% CI, 1.005-1.396) (P < 0.05), 1.334 (95% CI, 1.225-1.451) (P < 0.001), and 1.021 (95% CI, 1.001-1.040) (P < 0.05). The formula of the predictive model was (0.0293 × age + 1.4892 × Ln VFA + 0.4966 × Ln TG + 2.784 × Ln FPG + 0.6906 × Ln ALT)/2. The area under the curve was the largest among all the previously reported predictors. Conclusions: This study established and validated a predicting model for IR and confirmed its predictive value in comparison with other surrogate indicators, which will offer a simple and effective tool to measure IR in future large population studies.
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Medium-chain acyl-CoA dehydrogenase (MCAD) is one of the significant enzymes involved in the ß-oxidation of mitochondrial fatty acids. MCAD deficiency affects the ß-oxidation of fatty acid and leads to lipid deposition in multiple organs, but little is known about its importance in nonalcoholic steatohepatitis (NASH). Empagliflozin is revealed to effectively improve NASH by increasing research, whereas the specific mechanism still has to be explored. Human liver tissues of patients with or without NASH were obtained for proteomic analysis to screen proteins of interest. db/db mice were given empagliflozin by gavage for 8 weeks. The expression of MCAD and signaling molecules involved in hepatic lipid metabolism was evaluated in human liver, mice and HL7702 cells. We found that the MCAD levels in the liver were significantly reduced in NASH patients compared to patients without NASH. Protein-protein interaction network analysis showed that MCAD was highly correlated with forkhead box A2 (FOXA2) and protein kinase AMP-activated catalytic subunit alpha (PRKAA). AMPK/FOXA2/MCAD signaling pathway was detected to be inhibited in the liver of NASH patients. Decreased expression of MCAD was also observed in the livers of db/db mice and hepatocyte treated with palmitic acid and glucose. Of note, empagliflozin could upregulate MCAD expression by activating AMPK/FOXA2 signaling pathway, reduce lipid deposition and improve NASH in vivo and in vitro. This research demonstrated that MCAD is a key player of hepatic lipid deposition and its targeting partially corrects NASH. MCAD thus may be a potential therapeutic target for the treatment of NASH.