目的探讨血管紧张素Ⅱ受体阻滞剂(氯沙坦)对链脲佐菌素诱导的糖尿病大鼠胰岛功能、胰岛纤维化的影响及机制。方法Wistar雄性大鼠以高脂高热量饲料喂养,配合小剂量链脲佐菌素腹腔注射建立糖尿病大鼠模型,随机分为糖尿病对照组和氯沙坦干...目的探讨血管紧张素Ⅱ受体阻滞剂(氯沙坦)对链脲佐菌素诱导的糖尿病大鼠胰岛功能、胰岛纤维化的影响及机制。方法Wistar雄性大鼠以高脂高热量饲料喂养,配合小剂量链脲佐菌素腹腔注射建立糖尿病大鼠模型,随机分为糖尿病对照组和氯沙坦干预组,同时设立正常对照组。氯沙坦干预组用氯沙坦30mg/(kg·d)灌胃。检测各组大鼠的血糖、血清胰岛素,计算胰岛素抵抗指数。实验结束后取胰腺组织,HE染色观察形态学变化,分别用免疫组化法和实时荧光定量PCR技术检测胰岛组织转化生长因子-β1(TGF-β1)、Smad7、纤维化的I型胶原(Collagen I)的蛋白和mRNA表达。结果糖尿病对照组与正常对照组相比,血糖增高,血胰岛素水平降低,胰岛素抵抗指数增高,并有明显的体重减轻,差异有统计学意义(P<0.05);氯沙坦干预组与糖尿病对照组相比,除体重无明显变化外,血糖、胰岛素及胰岛素抵抗指数均有明显改善(P<0.05)。HE染色结果显示:糖尿病对照组的胰岛结构紊乱,出现纤维化;氯沙坦干预组胰岛形态结构有所恢复,纤维化减轻,但未完全恢复正常。免疫组化结果显示:糖尿病对照组TGF-β1及Collagen I蛋白表达较正常对照组增加(P<0.05),Smad7蛋白表达较正常对照组减少(P<0.05);氯沙坦干预组TGF-β1及Collagen I蛋白表达较糖尿病对照组减少(P<0.05),Smad7蛋白表达增加(P<0.05)。实时荧光定量PCR结果显示:糖尿病对照组TGF-β1及Collagen I mRNA表达较正常对照组增加,Smad7mRNA表达较正常对照组减少(P<0.05);氯沙坦干预组TGF-β1及Collagen I mRNA表达较糖尿病对照组减少,Smad7mRNA表达增加(P<0.05)。结论血管紧张素Ⅱ受体阻滞剂氯沙坦能够改善糖尿病大鼠胰岛纤维化,保护胰岛功能,发挥抗糖尿病效应,其作用可能是通过调节TGF-β1/Smads信号转导途径,进而降低Collagen I的表达来实现的。展开更多
Insulin resistance is the major feature of the metabolic syndrome and depends on insulin secretion and insulin sensitivity. In chronic hepatitis C, insulin resistance and type 2 diabetes mellitus are more often seen t...Insulin resistance is the major feature of the metabolic syndrome and depends on insulin secretion and insulin sensitivity. In chronic hepatitis C, insulin resistance and type 2 diabetes mellitus are more often seen than in healthy controls or chronic hepatitis B patients. Hepatitis C virus （HCV） infection promotes insulin resistance, mainly by increased TNF production together with enhancement of suppressor of cytokine （SOC-3）; both events block PI3K and Akt phosphorylation. Two types of insulin resistance could be found in chronic hepatitis C patients＇. ＂viral＂ and ＂metabolic＂ insulin resistance. Insulin resistance in chronic hepatitis C is relevant because it promotes steatosis and fibrosis. The mechanisms by which insulin resistance promotes fibrosis progression include： （1） steatosis, （2） hyperleptinemia, （3） increased TNF production, （4） impaired expression of PPARy receptors. Lastly, insulin resistance has been found as a common denominator in patients difficult-to-treat like cirrhotics, overweight, HIV coinfected and Afro-American. Insulin resistance together with fibrosis and genotype has been found to be independently associated with impaired response rate to peginterferon plus ribavirin. Indeed, in genotype 1, the sustained response rate was twice （60%） in patients with HOMA ≤ 2 than patients with HOMA 〉 2. In experiments carried out on Huh-7 cells transfected by full length HCVRNA, interferon alpha blocks HCV replication. However, when insulin （at doses of 128 μU/mL, similar that seen in the hyperinsulinemic state） was added to interferon, the ability to block HCV replication disappeared, and the PKR synthesis was abolished. In summary, hepatitis C promotes insulin resistance and insulin resistance induces interferon resistance, steatosis and fibrosis progression.展开更多
This review focuses on the relationship between hepatitis C virus(HCV) infection and glucose metabolism derangements.Cross-sectional and longitudinal studies have shown that the chronic HCV infection is associated wit...This review focuses on the relationship between hepatitis C virus(HCV) infection and glucose metabolism derangements.Cross-sectional and longitudinal studies have shown that the chronic HCV infection is associated with an increased risk of developing insulin resistance(IR) and type 2 diabetes(T2D).The direct effect of HCV on the insulin signaling has been analyzed in experimental models.Although currently available data should be considered as preliminary,HCV seems to affect glucose metabolism via mechanisms that involve cellular pathways that have been implicated in the host innate immune response.IR and T2D not only accelerate the histological and clinical progression of chronic hepatitis C,but also reduce the early and sustained virological response to interferon-alpha-based therapy.Thus,a detailed knowledge of the mechanisms underlying the HCV-associated glucose metabolism derangements is warranted,in order to improve the clinical management of chronic hepatitis C patients.展开更多
Steatosis is a common feature of many liver diseases,namely non-alcoholic steatohepatitis(NASH) and hepatitis C virus(HCV) infection,but the pathogenic mechanisms differ.Insulin resistance(IR),a key feature of metabol...Steatosis is a common feature of many liver diseases,namely non-alcoholic steatohepatitis(NASH) and hepatitis C virus(HCV) infection,but the pathogenic mechanisms differ.Insulin resistance(IR),a key feature of metabolic syndrome,is crucial for NASH development,associated with many underlying genetically determined or acquired mitochondrial and metabolic defects and culminates to inflammation and progression to fibrosis.This may have potential implications for new drug therapy.In HCV-related disease,steatosis impacts both fibrosis progression and response to treatment.Steatosis in HCV-related disease relates to both viral factors(HCV genotype 3),and host factors(alcohol consumption,overweight,hyperlipidemia,diabetes).Among others,IR is a recognized factor.Hepatic steatosis is reported to be associated with disturbance in the signaling cascade of interferon and downregulation of its receptors.Thus,hepatic steatosis should not be considered a benign feature,but rather a silent killer.展开更多
文摘目的探讨血管紧张素Ⅱ受体阻滞剂(氯沙坦)对链脲佐菌素诱导的糖尿病大鼠胰岛功能、胰岛纤维化的影响及机制。方法Wistar雄性大鼠以高脂高热量饲料喂养,配合小剂量链脲佐菌素腹腔注射建立糖尿病大鼠模型,随机分为糖尿病对照组和氯沙坦干预组,同时设立正常对照组。氯沙坦干预组用氯沙坦30mg/(kg·d)灌胃。检测各组大鼠的血糖、血清胰岛素,计算胰岛素抵抗指数。实验结束后取胰腺组织,HE染色观察形态学变化,分别用免疫组化法和实时荧光定量PCR技术检测胰岛组织转化生长因子-β1(TGF-β1)、Smad7、纤维化的I型胶原(Collagen I)的蛋白和mRNA表达。结果糖尿病对照组与正常对照组相比,血糖增高,血胰岛素水平降低,胰岛素抵抗指数增高,并有明显的体重减轻,差异有统计学意义(P<0.05);氯沙坦干预组与糖尿病对照组相比,除体重无明显变化外,血糖、胰岛素及胰岛素抵抗指数均有明显改善(P<0.05)。HE染色结果显示:糖尿病对照组的胰岛结构紊乱,出现纤维化;氯沙坦干预组胰岛形态结构有所恢复,纤维化减轻,但未完全恢复正常。免疫组化结果显示:糖尿病对照组TGF-β1及Collagen I蛋白表达较正常对照组增加(P<0.05),Smad7蛋白表达较正常对照组减少(P<0.05);氯沙坦干预组TGF-β1及Collagen I蛋白表达较糖尿病对照组减少(P<0.05),Smad7蛋白表达增加(P<0.05)。实时荧光定量PCR结果显示:糖尿病对照组TGF-β1及Collagen I mRNA表达较正常对照组增加,Smad7mRNA表达较正常对照组减少(P<0.05);氯沙坦干预组TGF-β1及Collagen I mRNA表达较糖尿病对照组减少,Smad7mRNA表达增加(P<0.05)。结论血管紧张素Ⅱ受体阻滞剂氯沙坦能够改善糖尿病大鼠胰岛纤维化,保护胰岛功能,发挥抗糖尿病效应,其作用可能是通过调节TGF-β1/Smads信号转导途径,进而降低Collagen I的表达来实现的。
基金Supported by a grant of PAI-CTS-532 from Junta de Andalucía, Andalucía, Spain
文摘Insulin resistance is the major feature of the metabolic syndrome and depends on insulin secretion and insulin sensitivity. In chronic hepatitis C, insulin resistance and type 2 diabetes mellitus are more often seen than in healthy controls or chronic hepatitis B patients. Hepatitis C virus （HCV） infection promotes insulin resistance, mainly by increased TNF production together with enhancement of suppressor of cytokine （SOC-3）; both events block PI3K and Akt phosphorylation. Two types of insulin resistance could be found in chronic hepatitis C patients＇. ＂viral＂ and ＂metabolic＂ insulin resistance. Insulin resistance in chronic hepatitis C is relevant because it promotes steatosis and fibrosis. The mechanisms by which insulin resistance promotes fibrosis progression include： （1） steatosis, （2） hyperleptinemia, （3） increased TNF production, （4） impaired expression of PPARy receptors. Lastly, insulin resistance has been found as a common denominator in patients difficult-to-treat like cirrhotics, overweight, HIV coinfected and Afro-American. Insulin resistance together with fibrosis and genotype has been found to be independently associated with impaired response rate to peginterferon plus ribavirin. Indeed, in genotype 1, the sustained response rate was twice （60%） in patients with HOMA ≤ 2 than patients with HOMA 〉 2. In experiments carried out on Huh-7 cells transfected by full length HCVRNA, interferon alpha blocks HCV replication. However, when insulin （at doses of 128 μU/mL, similar that seen in the hyperinsulinemic state） was added to interferon, the ability to block HCV replication disappeared, and the PKR synthesis was abolished. In summary, hepatitis C promotes insulin resistance and insulin resistance induces interferon resistance, steatosis and fibrosis progression.
基金Supported by Grant No. 320000-116544 from the Swiss National Science Foundationa research award from the Leenaards Foundation
文摘This review focuses on the relationship between hepatitis C virus(HCV) infection and glucose metabolism derangements.Cross-sectional and longitudinal studies have shown that the chronic HCV infection is associated with an increased risk of developing insulin resistance(IR) and type 2 diabetes(T2D).The direct effect of HCV on the insulin signaling has been analyzed in experimental models.Although currently available data should be considered as preliminary,HCV seems to affect glucose metabolism via mechanisms that involve cellular pathways that have been implicated in the host innate immune response.IR and T2D not only accelerate the histological and clinical progression of chronic hepatitis C,but also reduce the early and sustained virological response to interferon-alpha-based therapy.Thus,a detailed knowledge of the mechanisms underlying the HCV-associated glucose metabolism derangements is warranted,in order to improve the clinical management of chronic hepatitis C patients.
文摘Steatosis is a common feature of many liver diseases,namely non-alcoholic steatohepatitis(NASH) and hepatitis C virus(HCV) infection,but the pathogenic mechanisms differ.Insulin resistance(IR),a key feature of metabolic syndrome,is crucial for NASH development,associated with many underlying genetically determined or acquired mitochondrial and metabolic defects and culminates to inflammation and progression to fibrosis.This may have potential implications for new drug therapy.In HCV-related disease,steatosis impacts both fibrosis progression and response to treatment.Steatosis in HCV-related disease relates to both viral factors(HCV genotype 3),and host factors(alcohol consumption,overweight,hyperlipidemia,diabetes).Among others,IR is a recognized factor.Hepatic steatosis is reported to be associated with disturbance in the signaling cascade of interferon and downregulation of its receptors.Thus,hepatic steatosis should not be considered a benign feature,but rather a silent killer.
