Free fatty acids are known to play a key role in promoting loss of insulin sensitivity in type 2 diabetes mellitus but the underlying mechanism is still unclear.It has been postulated that an increase in the intracell...Free fatty acids are known to play a key role in promoting loss of insulin sensitivity in type 2 diabetes mellitus but the underlying mechanism is still unclear.It has been postulated that an increase in the intracellular concentration of fatty acid metabolites activates a serine kinase cascade,which leads to defects in insu-lin signaling downstream to the insulin receptor.In addition,the complex network of adipokines released from adipose tissue modulates the response of tissues to insulin.Among the many molecules involved in the intracellular processing of the signal provided by insulin,the insulin receptor substrate-2,the protein kinase B and the forkhead transcription factor Foxo 1a are of particular interest,as recent data has provided strong evidence that dysfunction of these proteins results in insulin resistance in vivo.Recently,studies have revealed that phosphoinositidedependent kinase 1-independent phosphorylation of protein kinase Cε causes a reduction in insulin receptor gene expression.Additionally,it has been suggested that mitochondrial dysfunction triggers activation of several serine kinases,and weakens insulin signal transduction.Thus,in this review,the current developments in understanding the pathophysiological processes of insulin resistance in type 2 diabetes have been summarized.In addition,this study provides potential new targets for the treatment and prevention of type 2 diabetes.展开更多
BACKGROUND Despite effective prevention and screening methods,the incidence and mortality rates associated with colorectal cancer(CRC)are still high.Insulin receptor substrate 1(IRS-1),a signaling molecule involved in...BACKGROUND Despite effective prevention and screening methods,the incidence and mortality rates associated with colorectal cancer(CRC)are still high.Insulin receptor substrate 1(IRS-1),a signaling molecule involved in cell proliferation,survival and metabolic responses has been implicated in carcinogenic processes in various cellular and animal models.However,the role of IRS-1 in CRC biology and its value as a clinical CRC biomarker has not been well defined.AIM To evaluate if and how IRS-1 expression and its associations with the apoptotic and proliferation tumor markers,Bax,Bcl-xL and Ki-67 are related to clinicopathological features in human CRC.METHODS The expression of IRS-1,Bax,Bcl-xL and Ki-67 proteins was assessed in tissue samples obtained from 127 patients with primary CRC using immunohistochemical methods.The assays were performed using specific antibodies against IRS-1,Bax,Bcl-xL,Ki-67.The associations between the expression of IRS-1,Bax,Bcl-xL,Ki-67 were analyzed in relation to clinicopathological parameters,i.e.,patient age,sex,primary localization of tumor,histopathological type,grading,staging and lymph node spread.Correlations between variables were examined by Spearman rank correlation test and Fisher exact test with a level of significance at P<0.05.RESULTS Immunohistochemical analysis of 127 CRC tissue samples revealed weak cytoplasmatic staining for IRS-1 in 66 CRC sections and strong cytoplasmatic staining in 61 cases.IRS-1 expression at any level in primary CRC was associated with tumor grade(69%in moderately differentiated tumors,G2 vs 31%in poorly differentiated tumors,G3)and with histological type(81.9%in adenocarcinoma vs 18.1%in adenocarcinoma with mucosal component cases).Strong IRS-1 positivity was observed more frequently in adenocarcinoma cases(95.1%)and in moderately differentiated tumors(85.2%).We also found statistically significant correlations between expression of IRS-1 and both Bax and Bcl-xL in all CRC cases examined.The relationships between studied proteins were related to clinicopathological parameters of CRC.No significant correlation between the expression of IRS-1 and proliferation marker Ki-67,excluding early stage tumors,where the correlation was positive and on a high level(P=0.043,r=0.723).CONCLUSION This study suggests that IRS-1 is co-expressed with both pro-and antiapoptotic markers and all these proteins are more prevalent in more differentiated CRC than in poorly differentiated CRC.展开更多
目的:探讨石榴花水提物(pomegranate flower water extract,PFW)对2型糖尿病小鼠肝脏胰岛素信号传导的影响及机制。方法:将C57BL/6J随机分为正常组、模型组、二甲双胍组(Met)、石榴花水提物低剂量组(PFWL)和石榴花水提物高剂量组(PFWH)...目的:探讨石榴花水提物(pomegranate flower water extract,PFW)对2型糖尿病小鼠肝脏胰岛素信号传导的影响及机制。方法:将C57BL/6J随机分为正常组、模型组、二甲双胍组(Met)、石榴花水提物低剂量组(PFWL)和石榴花水提物高剂量组(PFWH)。连续给药11周后,称小鼠体质量,检测空腹血糖(FBG)、胰岛素(INS)、甘油三酯(TG)和总胆固醇(TC)的含量,计算胰岛素抵抗指数(HOMA-IR);苏木素-伊红(HE)染色观察肝组织病理变化;Western blot法检测肝组织中胰岛素受体底物1(IRS1)、p-IRS1(Ser307)、蛋白激酶B(AKT)、p-AKT(Ser473)、糖原合成酶激酶-3β(Gsk3β)、p-Gsk3β(S9)、芳香烃受体(AhR)、磷脂酰乙醇胺N-甲基转移酶(PEMT)、Bcl-2/腺病毒E1B-19kDa相互作用蛋白3(BNIP3)蛋白表达。结果:与模型组比较,PFWH组FBG、INS、HOMA-IR、TG和TC含量极显著降低(P<0.01);PFWH组小鼠肝细胞内脂肪滴明显减少;PFWH组极显著升高肝脏中IRS1、p-AKT(Ser473)/AKT、p-Gsk3β(S9)/Gsk3β、BNIP3蛋白表达(P<0.01),极显著降低p-IRS1(Ser307)/IRS1、AHR、PEMT蛋白表达(P<0.01)。结论:PFW可能通过调节AHR/BNIP3抑制肝脏脂质沉积,改善p-IRS1(Ser307)/p-AKT(Ser473)/p-GSK3β(S9)胰岛素信号通路转导。展开更多
文摘Free fatty acids are known to play a key role in promoting loss of insulin sensitivity in type 2 diabetes mellitus but the underlying mechanism is still unclear.It has been postulated that an increase in the intracellular concentration of fatty acid metabolites activates a serine kinase cascade,which leads to defects in insu-lin signaling downstream to the insulin receptor.In addition,the complex network of adipokines released from adipose tissue modulates the response of tissues to insulin.Among the many molecules involved in the intracellular processing of the signal provided by insulin,the insulin receptor substrate-2,the protein kinase B and the forkhead transcription factor Foxo 1a are of particular interest,as recent data has provided strong evidence that dysfunction of these proteins results in insulin resistance in vivo.Recently,studies have revealed that phosphoinositidedependent kinase 1-independent phosphorylation of protein kinase Cε causes a reduction in insulin receptor gene expression.Additionally,it has been suggested that mitochondrial dysfunction triggers activation of several serine kinases,and weakens insulin signal transduction.Thus,in this review,the current developments in understanding the pathophysiological processes of insulin resistance in type 2 diabetes have been summarized.In addition,this study provides potential new targets for the treatment and prevention of type 2 diabetes.
文摘BACKGROUND Despite effective prevention and screening methods,the incidence and mortality rates associated with colorectal cancer(CRC)are still high.Insulin receptor substrate 1(IRS-1),a signaling molecule involved in cell proliferation,survival and metabolic responses has been implicated in carcinogenic processes in various cellular and animal models.However,the role of IRS-1 in CRC biology and its value as a clinical CRC biomarker has not been well defined.AIM To evaluate if and how IRS-1 expression and its associations with the apoptotic and proliferation tumor markers,Bax,Bcl-xL and Ki-67 are related to clinicopathological features in human CRC.METHODS The expression of IRS-1,Bax,Bcl-xL and Ki-67 proteins was assessed in tissue samples obtained from 127 patients with primary CRC using immunohistochemical methods.The assays were performed using specific antibodies against IRS-1,Bax,Bcl-xL,Ki-67.The associations between the expression of IRS-1,Bax,Bcl-xL,Ki-67 were analyzed in relation to clinicopathological parameters,i.e.,patient age,sex,primary localization of tumor,histopathological type,grading,staging and lymph node spread.Correlations between variables were examined by Spearman rank correlation test and Fisher exact test with a level of significance at P<0.05.RESULTS Immunohistochemical analysis of 127 CRC tissue samples revealed weak cytoplasmatic staining for IRS-1 in 66 CRC sections and strong cytoplasmatic staining in 61 cases.IRS-1 expression at any level in primary CRC was associated with tumor grade(69%in moderately differentiated tumors,G2 vs 31%in poorly differentiated tumors,G3)and with histological type(81.9%in adenocarcinoma vs 18.1%in adenocarcinoma with mucosal component cases).Strong IRS-1 positivity was observed more frequently in adenocarcinoma cases(95.1%)and in moderately differentiated tumors(85.2%).We also found statistically significant correlations between expression of IRS-1 and both Bax and Bcl-xL in all CRC cases examined.The relationships between studied proteins were related to clinicopathological parameters of CRC.No significant correlation between the expression of IRS-1 and proliferation marker Ki-67,excluding early stage tumors,where the correlation was positive and on a high level(P=0.043,r=0.723).CONCLUSION This study suggests that IRS-1 is co-expressed with both pro-and antiapoptotic markers and all these proteins are more prevalent in more differentiated CRC than in poorly differentiated CRC.
文摘目的:探讨石榴花水提物(pomegranate flower water extract,PFW)对2型糖尿病小鼠肝脏胰岛素信号传导的影响及机制。方法:将C57BL/6J随机分为正常组、模型组、二甲双胍组(Met)、石榴花水提物低剂量组(PFWL)和石榴花水提物高剂量组(PFWH)。连续给药11周后,称小鼠体质量,检测空腹血糖(FBG)、胰岛素(INS)、甘油三酯(TG)和总胆固醇(TC)的含量,计算胰岛素抵抗指数(HOMA-IR);苏木素-伊红(HE)染色观察肝组织病理变化;Western blot法检测肝组织中胰岛素受体底物1(IRS1)、p-IRS1(Ser307)、蛋白激酶B(AKT)、p-AKT(Ser473)、糖原合成酶激酶-3β(Gsk3β)、p-Gsk3β(S9)、芳香烃受体(AhR)、磷脂酰乙醇胺N-甲基转移酶(PEMT)、Bcl-2/腺病毒E1B-19kDa相互作用蛋白3(BNIP3)蛋白表达。结果:与模型组比较,PFWH组FBG、INS、HOMA-IR、TG和TC含量极显著降低(P<0.01);PFWH组小鼠肝细胞内脂肪滴明显减少;PFWH组极显著升高肝脏中IRS1、p-AKT(Ser473)/AKT、p-Gsk3β(S9)/Gsk3β、BNIP3蛋白表达(P<0.01),极显著降低p-IRS1(Ser307)/IRS1、AHR、PEMT蛋白表达(P<0.01)。结论:PFW可能通过调节AHR/BNIP3抑制肝脏脂质沉积,改善p-IRS1(Ser307)/p-AKT(Ser473)/p-GSK3β(S9)胰岛素信号通路转导。
