PI3KP85α、AKT2在高脂高糖喂养妊娠期大鼠肝脏、肾周脂肪中的表达及其与胰岛素抵抗的关系
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摘要
背景与目的
妊娠期糖尿病(GDM)是一种特殊类型的糖尿病,对孕妇、胎儿、新生儿均可产生严重危害,且近年来其发病率明显上升。研究认为GDM与2型糖尿病(T2DM)有共同的病理学和遗传学特征,对GDM进行研究可为T2DM的早期预防和干预提供依据。GDM的病因和发病机制尚未明确,胰岛素抵抗(IR)可能是其发生的关键环节之一,而胰岛素信号传导过程发生障碍可能处于妊娠期胰岛素抵抗发生的中心环节,成为近年来研究的热点。
国内外研究认为胰岛素受体后信号转导障碍与妊娠期胰岛素抵抗关系密切,磷脂酰肌醇3-激酶-蛋白激酶B(PI3K-AKT)途径是胰岛素信号下游的重要信号通路,它与IR的发生密切相关。磷脂酰肌醇-3激酶p85α调节亚基(PI-3KP85α),蛋白激酶Bβ(AKT2)是此信号通路上的重要信号分子,PI-3KP85α, AKT2与妊娠期胰岛素抵抗的关系国内外研究较少。
本实验通过高糖高脂喂养建立妊娠期胰岛素抵抗大鼠模型,通过对肝脏、肾周脂肪中PI3K/AKT通路中关键因子p85α、AKT2的检测,探讨p85α、AKT2表达与正常妊娠和妊娠期糖尿病IR的关系,为GDM发病机制的研究提供新的思路。
材料与方法
健康6周龄雌性SD大鼠40只,雄性10只(清洁级),体质量190-200g。所有雌性大鼠,普通饲料适应性喂养一周后,按随机数字表法分为四组,即高糖高脂饮食-孕鼠组(SFP)和未孕组(SFV),普通饮食-孕鼠组(NP)和未孕鼠(NV),各10只,孕鼠组：未孕组=1：1。相应组受孕,各组继续给予高糖高脂或普通饲料喂养。4组大鼠于妊娠组大鼠妊娠第18天,行OGTT。在妊娠组大鼠妊娠第20天实验结束时,心内取血,测空腹血糖、胰岛素,血清总甘油三酯、胆固醇、血清游离脂肪酸水平。采血后处死大鼠,切取肝脏、肾周脂肪组织,分为两份,一份行苏木精-伊红(HE)染色,另一份采用半定量逆转录-聚合酶链反应(RT-PCR)方法测定P13KP85αmRNA, AKT2mRNA的表达。血清游离脂肪酸采用酶联免疫吸附铜染色法,血清胰岛素测定使用ELISA法。计量资料以(均数±s)表示,多组间均数比较采用方差分析及LSD检验,相关性检验用Pearson相关分析,以a=0.05为检验水准。所有数据采用SPSS for windows13.0统计软件进行分析。
结果
1 OGTT
SFP组大鼠0、30、60、120min血糖均高于其他各组,差异有统计学意义(P<0.01)；NP组、SFV组在60min时血糖高于对照组(NV)大鼠,差异有统计学意义(P<0.05),在余时间点三组间血糖无明显差异(P>0.05)。
2各组大鼠空腹血糖、空腹胰岛素、胰岛素抵抗指数TG、TC、FFA的比较
SFP组空腹胰岛素、TG、TC、FFA胰岛素抵抗指数较其他三组升高(P<0.01)；SFV组、NP组上述各项指标均较NV明显升高(p<0.05),但两组间差异无统计学意义(P>0.05)；在SFP组空腹血糖水平较其他组明显升高(P<0.01); SFV组、NP组、NV组之间空腹血糖水平差异无统计学意义(P>0.05)。
3肝脏组织HE染色结果
肝脏组织：HE染色后光镜下(x400倍)可见NV组各小叶结构清晰,细胞板排列整齐,肝细胞形态正常,大小均匀；SFV、NP组肝小叶结构基本正常,肝细胞大小尚均匀,部分细胞浊肿,胞浆内可见少量脂肪空泡；SFP组大鼠肝细胞大小不一,部分细胞体积增大,胞浆内可见大量大小不等的脂肪空泡。
4 RT-PCR结果
肝脏、肾周脂肪组织中,p85 a mRNA表达水平在SFP组较其它三组明显升高(P<0.01); SFV组和NP组p85αmRNA表达较NV升高(P<0.05),但两组之间差异无统计学意义(P>0.05); AKT2mRNA的表达水平在SFP明显减低,与其它三组相比差异具有统计学意义(P<0.01), SFV组和NP组AKT2mRNA表达水平均较NV组降低(P<0.05),但两组之间差异无统计学意义(P>0.05)。
5单因素相关分析显示：在SFP组、NP组和SFV组,肝脏和肾周脂肪组织中p85 a mRNA的表达量与胰岛素抵抗指数(HOMA-IR)均呈正相关(P<0.01或P<0.05);AKT2mRNA的表达量与HOMA-IR均呈负相关(P<0.01或P<0.05)；在NV组p85αmRNA、AKT2mRNA表达量与HOMA-IR均无相关性(P>0.05)。血清FFA水平与HOMA-IR在SFP组、NP组和SFV组呈正相关(P<0.01或P<0.05),在NV组无相关性(p>0.05)。
在SFP组、NP组和SFV组,血清FFA水平与肝脏和肾周脂肪组织中p85αmRNA的表达量均呈正相关(P<0.05或P<0.01)；与AKT2mRNA的表达量均呈负相关(P<0.05或P<0.01)；在NV组FFA与p85αmRNA、AKT2mRNA表达量均无相关性(P>0.05)。
结论
1高脂高糖喂养的妊娠期胰岛素抵抗大鼠模型符合人类妊娠期糖尿病胰岛素抵抗的特征,此模型出现糖脂代谢异常；
2肝脏、肾周脂肪中p85α表达上调和AKT2表达下调可能是导致妊娠期糖尿病胰岛素抵抗的分子机制之一；
3高脂高糖饮食和妊娠均可能是引起p85α表达上调和AKT2表达下调进而导致妊娠期胰岛素抵抗的因素；
4血清游离脂肪酸可能通过影响胰岛素信号通路的关键分子PI3Kp85α、AKT2的表达而导致妊娠期胰岛素抵抗。
Background
Gestational diabetes mellitus(GDM) is a special kind of diabetes mellitus.GDM is associated with serious hazardes to pregnant women, fetal and newborns.GDM morbidity has increased dramatically in recent years.GDM appears to result from the same spectrum of physiological and genetic abnormality that characterize diabetes outside of pregnancy. So GDM provides a unique chance to study pathogenesis of diabetes and to develop early interventions to prevent the type 2 diabetes.Severe insulin resistance is a defining attribute of GDM.The etiology and pathogenesis of insulin resistance is unclear,which may be induced by abnormal insulin signaling pathway.In currently studies,the relations between abnormal insulin signaling pathway and pregnancy insulin resistance became a focus.It was kown that the key reason of pregnancy insulin resistance was dysfunction afer insulin receptor of insulin signaling transmission.Phosphoinositide 3-kinase p85 alpha and Akt2/PKB beta are two importance molecules proteins in phosphatidylinositol 3-kinase-dependent signaling pathways,which was the major pathway in insulin-signaling transmission afer insulin receptor.
Objective
In the study,we made the model of pregnancy insulin resistance rats by sucrose and fat diet.the model is similar to human in insulin resistance of gestational diabetes mellitus.we discussed the expression of PI3Kp85 alpha and AKT2 in liver and perinephric adipose in model.The aim of this study was to determine whether the expression of p85 alpha and Akt2 were associated with insulin resistance in normal pregnancy and gestational diabetes mellitus.
Subjects and Methods
Forty female SD rats were divided into four groups:sucrose and fat diet pregnant rats (SFP),sucrose and fat diet virgin rats (SFV), normal diet pregnant rats (NP),normal diet virgin rats (NV). (n=10 per group).High-sucrose-fat diet or normal diet were given according to group. Oral Glucose Tolerance Test (OGTT)were performed at 18 days of gestation.On days 20 of gestation, we measured followed serologic parameters such as FPG,FINS,triglyceride,cholerterol,and free fatty acids.Then executed rats, Liver and perinephric adipose were divided into two parts:one was used to observed the morphological changes in liver,perinephric adipose and pancreatic tissue by HE staining,another was used to measure the level of PI3KP85alpha mRNA and AKT2 mRNA by RT-PCR.Fasting plasma glucose (FPG) and fasting insulin(FINS)were measured by oxidized assay and ELISA.Insulin resistance index (HOMA-IR) was calculated according FPG and FINS.All statistical analyses were carried out with the SPSS 13.0.
Results
1 OGTT:In the SPF group,the levels of glucose at 0min,30min,60min and120min were higher than other groups.In the SFV and NP group the levels of glucose are higher than control group (NV) at 60min(P<0.05).But the levels of glucose at 0,30,120min glucose were no difference among the three groups (P>0.05)
2 In the SFP group,the levels of FIN,TG,TC,FFA and HOMA-IR were significantly higher than that of other groups(P<0.01),these were higher than control group(NV) in the SFV and NP group (P<0.05),but no difference between each other (P>0.05).The levels of FBG in the SFP group was significantly higher than other groups(P<0.01); But fasting blood glucose was no difference among the SFV,NP and NVgroups.
3 HE stain analysis:Examined under microscope,in liver of the SFP group, hepatic cells were different in size and volume compare with other groups. Lots of hepatic cell were getting fatty degeneration, translucent spaces and vacuoles in cytoplasm. In the NP and SFV group, a few hepatic cell were getting fatty degeneration and cell size are arranged disorders.
4 In liver and perinephric adipose tissue, the expression levels of P85 alpha mRNA in SPF group were obviously higher than that of other groups (P<0.01); The level of P85 alpha mRNA in SFV group and NP group were higher than that of NV group (P<0.05).No differences were found in mRNA expression of p85 alpha between SFV and NP group(P>0.05); The mRNA expression levels of AKT2 in liver and perinephric adipose tissue were significally lower in SFP group than other groups (P<0.01),The mRNA expression of AKT2 was decreased in SFV or NP compared to NV group(P<0.05),However,expression of AKT2 mRNA were no differ between SFV and NP group(P>0.05).
5 In liver and perinephric adipose,the expression levels of p85 alpha mRNA was significantly correlated positively with HOMA-IR in the SFP,NP and SFV groups (P<0.01 or P<0.05);The expression levels of AKT2 mRNA was significantly correlated negatively with HOMA-IR in the SFP,NP and SFV groups (P<0.01 or P<0.05); However,expression levels of p85 alpha and AKT2 mRNA were not correlated with HOMA-IR in the NV group(P>0.05).
In the SFP,NP and SFV groups, the expression levels of P85 alpha mRNA was correlated positively with the levels of FFA(P<0.01 or P<0.05) and the expression levels of AKT2 mRNA was correlated negatively with the levels of FFA(P<0.01 or P<0.05);However,expression levels of p85 alpha and AKT2 mRNA were not correlated with the levels of FFA in the NV group(P>0.05).
Conclusions
1 We made a success of the pregnancy insulin resistance rats model induced by high-sucrose-fat diet.The model was similar to human gestational diabetes mellitus in insulin resistance and metabolic characters of glucose and lipid;
2.The overexpression p85amRNA and low expression AKT2mRNA may be one of the molecular mechanisms leading to insulin resistance of gestational diabetes mellitus;
3 High-Sucrose-fat diet and pregnancy may contribute to increase the expression of p85a and decrease the expression of AKT2, leading to insulin resistance;
4 FFA may contribute to the insulin resistance of gestational diabetes mellitus by increasing the expression of p85a and decreasing the expression of AKT2
妊娠期糖尿病(GDM)是一种特殊类型的糖尿病,对孕妇、胎儿、新生儿均可产生严重危害,且近年来其发病率明显上升。研究认为GDM与2型糖尿病(T2DM)有共同的病理学和遗传学特征,对GDM进行研究可为T2DM的早期预防和干预提供依据。GDM的病因和发病机制尚未明确,胰岛素抵抗(IR)可能是其发生的关键环节之一,而胰岛素信号传导过程发生障碍可能处于妊娠期胰岛素抵抗发生的中心环节,成为近年来研究的热点。
国内外研究认为胰岛素受体后信号转导障碍与妊娠期胰岛素抵抗关系密切,磷脂酰肌醇3-激酶-蛋白激酶B(PI3K-AKT)途径是胰岛素信号下游的重要信号通路,它与IR的发生密切相关。磷脂酰肌醇-3激酶p85α调节亚基(PI-3KP85α),蛋白激酶Bβ(AKT2)是此信号通路上的重要信号分子,PI-3KP85α, AKT2与妊娠期胰岛素抵抗的关系国内外研究较少。
本实验通过高糖高脂喂养建立妊娠期胰岛素抵抗大鼠模型,通过对肝脏、肾周脂肪中PI3K/AKT通路中关键因子p85α、AKT2的检测,探讨p85α、AKT2表达与正常妊娠和妊娠期糖尿病IR的关系,为GDM发病机制的研究提供新的思路。
材料与方法
健康6周龄雌性SD大鼠40只,雄性10只(清洁级),体质量190-200g。所有雌性大鼠,普通饲料适应性喂养一周后,按随机数字表法分为四组,即高糖高脂饮食-孕鼠组(SFP)和未孕组(SFV),普通饮食-孕鼠组(NP)和未孕鼠(NV),各10只,孕鼠组：未孕组=1：1。相应组受孕,各组继续给予高糖高脂或普通饲料喂养。4组大鼠于妊娠组大鼠妊娠第18天,行OGTT。在妊娠组大鼠妊娠第20天实验结束时,心内取血,测空腹血糖、胰岛素,血清总甘油三酯、胆固醇、血清游离脂肪酸水平。采血后处死大鼠,切取肝脏、肾周脂肪组织,分为两份,一份行苏木精-伊红(HE)染色,另一份采用半定量逆转录-聚合酶链反应(RT-PCR)方法测定P13KP85αmRNA, AKT2mRNA的表达。血清游离脂肪酸采用酶联免疫吸附铜染色法,血清胰岛素测定使用ELISA法。计量资料以(均数±s)表示,多组间均数比较采用方差分析及LSD检验,相关性检验用Pearson相关分析,以a=0.05为检验水准。所有数据采用SPSS for windows13.0统计软件进行分析。
结果
1 OGTT
SFP组大鼠0、30、60、120min血糖均高于其他各组,差异有统计学意义(P<0.01)；NP组、SFV组在60min时血糖高于对照组(NV)大鼠,差异有统计学意义(P<0.05),在余时间点三组间血糖无明显差异(P>0.05)。
2各组大鼠空腹血糖、空腹胰岛素、胰岛素抵抗指数TG、TC、FFA的比较
SFP组空腹胰岛素、TG、TC、FFA胰岛素抵抗指数较其他三组升高(P<0.01)；SFV组、NP组上述各项指标均较NV明显升高(p<0.05),但两组间差异无统计学意义(P>0.05)；在SFP组空腹血糖水平较其他组明显升高(P<0.01); SFV组、NP组、NV组之间空腹血糖水平差异无统计学意义(P>0.05)。
3肝脏组织HE染色结果
肝脏组织：HE染色后光镜下(x400倍)可见NV组各小叶结构清晰,细胞板排列整齐,肝细胞形态正常,大小均匀；SFV、NP组肝小叶结构基本正常,肝细胞大小尚均匀,部分细胞浊肿,胞浆内可见少量脂肪空泡；SFP组大鼠肝细胞大小不一,部分细胞体积增大,胞浆内可见大量大小不等的脂肪空泡。
4 RT-PCR结果
肝脏、肾周脂肪组织中,p85 a mRNA表达水平在SFP组较其它三组明显升高(P<0.01); SFV组和NP组p85αmRNA表达较NV升高(P<0.05),但两组之间差异无统计学意义(P>0.05); AKT2mRNA的表达水平在SFP明显减低,与其它三组相比差异具有统计学意义(P<0.01), SFV组和NP组AKT2mRNA表达水平均较NV组降低(P<0.05),但两组之间差异无统计学意义(P>0.05)。
5单因素相关分析显示：在SFP组、NP组和SFV组,肝脏和肾周脂肪组织中p85 a mRNA的表达量与胰岛素抵抗指数(HOMA-IR)均呈正相关(P<0.01或P<0.05);AKT2mRNA的表达量与HOMA-IR均呈负相关(P<0.01或P<0.05)；在NV组p85αmRNA、AKT2mRNA表达量与HOMA-IR均无相关性(P>0.05)。血清FFA水平与HOMA-IR在SFP组、NP组和SFV组呈正相关(P<0.01或P<0.05),在NV组无相关性(p>0.05)。
在SFP组、NP组和SFV组,血清FFA水平与肝脏和肾周脂肪组织中p85αmRNA的表达量均呈正相关(P<0.05或P<0.01)；与AKT2mRNA的表达量均呈负相关(P<0.05或P<0.01)；在NV组FFA与p85αmRNA、AKT2mRNA表达量均无相关性(P>0.05)。
结论
1高脂高糖喂养的妊娠期胰岛素抵抗大鼠模型符合人类妊娠期糖尿病胰岛素抵抗的特征,此模型出现糖脂代谢异常；
2肝脏、肾周脂肪中p85α表达上调和AKT2表达下调可能是导致妊娠期糖尿病胰岛素抵抗的分子机制之一；
3高脂高糖饮食和妊娠均可能是引起p85α表达上调和AKT2表达下调进而导致妊娠期胰岛素抵抗的因素；
4血清游离脂肪酸可能通过影响胰岛素信号通路的关键分子PI3Kp85α、AKT2的表达而导致妊娠期胰岛素抵抗。
Background
Gestational diabetes mellitus(GDM) is a special kind of diabetes mellitus.GDM is associated with serious hazardes to pregnant women, fetal and newborns.GDM morbidity has increased dramatically in recent years.GDM appears to result from the same spectrum of physiological and genetic abnormality that characterize diabetes outside of pregnancy. So GDM provides a unique chance to study pathogenesis of diabetes and to develop early interventions to prevent the type 2 diabetes.Severe insulin resistance is a defining attribute of GDM.The etiology and pathogenesis of insulin resistance is unclear,which may be induced by abnormal insulin signaling pathway.In currently studies,the relations between abnormal insulin signaling pathway and pregnancy insulin resistance became a focus.It was kown that the key reason of pregnancy insulin resistance was dysfunction afer insulin receptor of insulin signaling transmission.Phosphoinositide 3-kinase p85 alpha and Akt2/PKB beta are two importance molecules proteins in phosphatidylinositol 3-kinase-dependent signaling pathways,which was the major pathway in insulin-signaling transmission afer insulin receptor.
Objective
In the study,we made the model of pregnancy insulin resistance rats by sucrose and fat diet.the model is similar to human in insulin resistance of gestational diabetes mellitus.we discussed the expression of PI3Kp85 alpha and AKT2 in liver and perinephric adipose in model.The aim of this study was to determine whether the expression of p85 alpha and Akt2 were associated with insulin resistance in normal pregnancy and gestational diabetes mellitus.
Subjects and Methods
Forty female SD rats were divided into four groups:sucrose and fat diet pregnant rats (SFP),sucrose and fat diet virgin rats (SFV), normal diet pregnant rats (NP),normal diet virgin rats (NV). (n=10 per group).High-sucrose-fat diet or normal diet were given according to group. Oral Glucose Tolerance Test (OGTT)were performed at 18 days of gestation.On days 20 of gestation, we measured followed serologic parameters such as FPG,FINS,triglyceride,cholerterol,and free fatty acids.Then executed rats, Liver and perinephric adipose were divided into two parts:one was used to observed the morphological changes in liver,perinephric adipose and pancreatic tissue by HE staining,another was used to measure the level of PI3KP85alpha mRNA and AKT2 mRNA by RT-PCR.Fasting plasma glucose (FPG) and fasting insulin(FINS)were measured by oxidized assay and ELISA.Insulin resistance index (HOMA-IR) was calculated according FPG and FINS.All statistical analyses were carried out with the SPSS 13.0.
Results
1 OGTT:In the SPF group,the levels of glucose at 0min,30min,60min and120min were higher than other groups.In the SFV and NP group the levels of glucose are higher than control group (NV) at 60min(P<0.05).But the levels of glucose at 0,30,120min glucose were no difference among the three groups (P>0.05)
2 In the SFP group,the levels of FIN,TG,TC,FFA and HOMA-IR were significantly higher than that of other groups(P<0.01),these were higher than control group(NV) in the SFV and NP group (P<0.05),but no difference between each other (P>0.05).The levels of FBG in the SFP group was significantly higher than other groups(P<0.01); But fasting blood glucose was no difference among the SFV,NP and NVgroups.
3 HE stain analysis:Examined under microscope,in liver of the SFP group, hepatic cells were different in size and volume compare with other groups. Lots of hepatic cell were getting fatty degeneration, translucent spaces and vacuoles in cytoplasm. In the NP and SFV group, a few hepatic cell were getting fatty degeneration and cell size are arranged disorders.
4 In liver and perinephric adipose tissue, the expression levels of P85 alpha mRNA in SPF group were obviously higher than that of other groups (P<0.01); The level of P85 alpha mRNA in SFV group and NP group were higher than that of NV group (P<0.05).No differences were found in mRNA expression of p85 alpha between SFV and NP group(P>0.05); The mRNA expression levels of AKT2 in liver and perinephric adipose tissue were significally lower in SFP group than other groups (P<0.01),The mRNA expression of AKT2 was decreased in SFV or NP compared to NV group(P<0.05),However,expression of AKT2 mRNA were no differ between SFV and NP group(P>0.05).
5 In liver and perinephric adipose,the expression levels of p85 alpha mRNA was significantly correlated positively with HOMA-IR in the SFP,NP and SFV groups (P<0.01 or P<0.05);The expression levels of AKT2 mRNA was significantly correlated negatively with HOMA-IR in the SFP,NP and SFV groups (P<0.01 or P<0.05); However,expression levels of p85 alpha and AKT2 mRNA were not correlated with HOMA-IR in the NV group(P>0.05).
In the SFP,NP and SFV groups, the expression levels of P85 alpha mRNA was correlated positively with the levels of FFA(P<0.01 or P<0.05) and the expression levels of AKT2 mRNA was correlated negatively with the levels of FFA(P<0.01 or P<0.05);However,expression levels of p85 alpha and AKT2 mRNA were not correlated with the levels of FFA in the NV group(P>0.05).
Conclusions
1 We made a success of the pregnancy insulin resistance rats model induced by high-sucrose-fat diet.The model was similar to human gestational diabetes mellitus in insulin resistance and metabolic characters of glucose and lipid;
2.The overexpression p85amRNA and low expression AKT2mRNA may be one of the molecular mechanisms leading to insulin resistance of gestational diabetes mellitus;
3 High-Sucrose-fat diet and pregnancy may contribute to increase the expression of p85a and decrease the expression of AKT2, leading to insulin resistance;
4 FFA may contribute to the insulin resistance of gestational diabetes mellitus by increasing the expression of p85a and decreasing the expression of AKT2
引文
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