糖尿病脑病的PET/CT显像及与IGF1R的相关性研究
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摘要
本文应用影像学、细胞生物学和分子生物学等技术，从整体水平、细胞水平和分子水平三个层次上，开展了“糖尿病脑病的PET/CT显像及与IGF1R的相关性研究”工作，探讨了PET/CT显像在糖尿病脑病诊断及机制研究中的可能性，同时揭示了IGF1R在糖尿病脑病发生、发展中的重要作用。
1.糖尿病脑病大鼠的PET/CT显像及免疫组化研究
通过STZ诱导及水迷宫筛选，建立糖尿病大鼠模型及糖尿病脑病大鼠模型。利用PET/CT检测模型大鼠脑部糖代谢水平，免疫组织化学技术检测IR、IGF1R和Glut4的含量变化情况。与正常对照组相比，糖尿病模型组与糖尿病脑病模型组SUV明显减低，糖尿病脑病模型组大鼠葡萄糖代谢率下降更为明显。糖尿病脑病组大鼠出现IGF1R表达增高而Glut4下降的现象，特别值得关注的是相对于正常对照组，只患有糖尿病而未患脑病的大鼠海马区IGF1R表达水平出现显著降低，各组IR表达量无明显差异。
2.IGF1R缺失的PC12细胞构建及筛选
利用慢病毒包装转染技术，抑制IGF1R在神经胶质瘤细胞PC12中的表达，为后续研究提供重要的研究模型。半定量RT-PCR、Western Blot法检测siRNA对IGF1R的影响，进一步通过G418筛选获得了IGF1R低表达的稳转细胞株ΔIGF1R-PC12。
3.IGF1R缺失对PC12细胞糖代谢及相关信号转导通路的影响
该部分研究在细胞水平上关注了IGF1R缺失对细胞糖代谢及Akt信号通路的影响。葡萄糖氧化酶法检测IGF1R缺失对PC12细胞消耗葡萄糖的影响；液体闪烁计数法检测IGF1R缺失对PC12细胞摄取葡萄糖的影响；实时定量PCR法检测IGF1R缺失对PC12细胞Glut4的mRNA表达的影响；免疫印迹法检测IGF1R缺失对PC12细胞Phospho-Insulin R、SRC、Phospho-SRC、Akt、Phospho-Akt、IGF1R、PI3K p85、Glut4等蛋白表达的影响。
IGF1R缺陷提高了PC12细胞葡萄糖消耗，但仍不能完全逆转Aβ25-35对细胞消耗葡萄糖能力的损害；IGF1R缺陷可促进胰岛素刺激下的PC12细胞葡萄糖摄取量，同时这种效应具有浓度和时间依赖性；IGF1R的缺失提高了胰岛素对PC12细胞IR和IRS磷酸化的敏感性，对本研究非常重要的是在ΔIGF1R-PC12细胞中，IR对胰岛素表现出的亲和力，仅需要正常PC12细胞感知胰岛素浓度的1/100（0.1nM）；在IGF1R敲除的PC12细胞中，Akt磷酸化通路被激活，引起胰岛素受体相关通路对胰岛素的敏感性被大幅提升。
本文应用PET/CT技术开展了糖尿病脑病的机制研究，发现了IGF1R信号通路在糖尿病脑病发病过程中的重要作用。此项研究，为相关神经系统疾病理论研究开辟了新方向，同时也为治疗糖尿病脑病及相关药物开发提供了新思路和靶位点。
As is well known, PET/CT has an important Clinical significance and value todiagnosis, decisions of treatment and efficacy evaluation for patient in a variety ofcentral nervous system diseases, such as epilepsy, senile dementia, Parkinson's disease.Neuroimaging could link changes in the structure of the brain with changes incognitive function. Brain scanning in real time on the brains of Patient with diabetesgiven in three-dimensional imaging of the amount of monitoring, which evaluates theneuroanatomical regions involved in the brains of patients with diabetes, it isimpossible in neuropathology research organizations.
Here, brain glucose metabolism levels in Diabetic encephalopathy rat modelwere detected with PET/CT. It is exerted and measured that related pathologicstructural changes and some major functional molecules expression in hippocampus.The results show that the abnormal expression increase of IGF1R or related pathwaysactivation is very related to the occurrence of diabetic encephalopathy. This issupported by the observation that the production of reactive oxygen species is reducedin brains of IGF1R knock-out mice compared with their WT counterparts followingMPTP treatment known to induce a Parkinson’s disease-like phenotype. On the otherside, an alternative model suggests that increased neuronal resilience associated withreduced IGF signaling is promoted by enhanced DNA repair capabilities. It isreasonable to speculate that the histone deacetylase SIRT1, an aging regulator thatplays roles in the maintenance of genomic stability may also be a mediator foranti-apoptosis of the reduced IGF signaling protective effect in Alzheimer’s disease.
In view of the importance of IGF1R knock-out to nerve cells, we inhibited ofIGF1R expression in PC12cells, and reduced the activating level of IGF1R pathwayusing the lentiviral packaging, picked stable transfected cells, namely ΔIGF1R-ofPC12cells. In the follow parts, to investigate underlying details in that IGF1R defectsaffecting the nerve cells consumption and glucose uptake, and take particular attentionto the effects and the interactions between IGF1R, IR, phosphorylation of Aktsignaling pathway.
The content of the issue is divided into three parts, the use of imaging, pathology,molecular biology, cell biology techniques，on individual, cell and molecular levels, we studied the important role of IGF1R to the development of diabeticencephalopathy, revealed the interaction between IGF1R signaling pathwaydiminishing, glucose metabolism and IR signaling pathway in nerve cells. Followingthis three-part research brief summary, as follows:
1. PET/CT Imaging and Immunohistochemical on DiabeticEncephalopathy in Rats
In this part, first of all, we have established a rat model of diabetes screening bybehavioral experiments, rats suffering from diabetic encephalopathy, and then detectthe level of rat brain glucose metabolism using PE/CT, the final study brainthepathological features of the hippocampus and IR, IGF1R and Glut4in tissue withpathological staining and immunohistochemical methods. The results show that,compared with the normal control group and diabetic group, the level of brain glucosemetabolism in diabetic encephalopathy rats significantly reduced amyloid calm,organization and the cytoplasm have a red dye, the nerve fiber thickening,swellingderangement and so on, like neuropathological characteristics; IR expressionlevel is basically the same among the experimental group, diabetic encephalopathyrats IGF1R expression increased Glut4but the phenomenon of decline, it isnoteworthy that relative to the normal control group, only sufferinghippocampus ofrats with diabetes without suffering from encephalopathy IGF1R expression levelswere significantly reduced.
2. IGF1R knock-out PC12cell obtaining and screening
In accordance with the findings of the first part, only those with diabetes withoutencephalopathy rat hippocampal IGF1R expression levels appear significantlyreduced brain glucose metabolism capacity remained at a high level. Therefore,lentiviral packaging transfection techniques has been used to inhibit IGF1Rexpression in glioma cells PC12, which provided an important model for furtherresearch. After a large number of molecular biology vector assembling and screening,we obtained the IGF1R low expression of the stable transfected celllines-ΔIGF1R-PC12ultimately.
3. Study on the Inhibiting IGF1R affected PC12cell glucose metabolismand signal pathways
The part of the research，at the cellular level, concerning to the IGF1R defectsacted in cell glucose metabolism and Akt signaling pathway, the major resultwas the IGF1R defects enhanced PC12cells glucose consumption, but still not completelyreversed damage triggered by Aβ25-35in cells; IGF1R defect could promote glucoseuptake in insulin-stimulated PC12cells inthe dose and time manner; IGF1R defectcould improve insulin sensitivity to IR and IRS phosphorylation in PC12cells;extremely important to this study, in ΔIGF1R-of PC12cells, IR showed only need thesense insulin concentration of1/100(0.1nM) of normal PC12cells; in IGF1Rknock-out PC12cells, when Aktphosphorylation pathway was activated, the insulinsensitivity of IR would be improved significantly.
This study revealed that IGF1R signaling pathway’s role in diabeticencephalopathy, opened up a new direction for related research in nervous systemdiseases, but also provided a new idea for the treatment of diabetic encephalopathy,relevant drug development and target sites.
1.糖尿病脑病大鼠的PET/CT显像及免疫组化研究
通过STZ诱导及水迷宫筛选，建立糖尿病大鼠模型及糖尿病脑病大鼠模型。利用PET/CT检测模型大鼠脑部糖代谢水平，免疫组织化学技术检测IR、IGF1R和Glut4的含量变化情况。与正常对照组相比，糖尿病模型组与糖尿病脑病模型组SUV明显减低，糖尿病脑病模型组大鼠葡萄糖代谢率下降更为明显。糖尿病脑病组大鼠出现IGF1R表达增高而Glut4下降的现象，特别值得关注的是相对于正常对照组，只患有糖尿病而未患脑病的大鼠海马区IGF1R表达水平出现显著降低，各组IR表达量无明显差异。
2.IGF1R缺失的PC12细胞构建及筛选
利用慢病毒包装转染技术，抑制IGF1R在神经胶质瘤细胞PC12中的表达，为后续研究提供重要的研究模型。半定量RT-PCR、Western Blot法检测siRNA对IGF1R的影响，进一步通过G418筛选获得了IGF1R低表达的稳转细胞株ΔIGF1R-PC12。
3.IGF1R缺失对PC12细胞糖代谢及相关信号转导通路的影响
该部分研究在细胞水平上关注了IGF1R缺失对细胞糖代谢及Akt信号通路的影响。葡萄糖氧化酶法检测IGF1R缺失对PC12细胞消耗葡萄糖的影响；液体闪烁计数法检测IGF1R缺失对PC12细胞摄取葡萄糖的影响；实时定量PCR法检测IGF1R缺失对PC12细胞Glut4的mRNA表达的影响；免疫印迹法检测IGF1R缺失对PC12细胞Phospho-Insulin R、SRC、Phospho-SRC、Akt、Phospho-Akt、IGF1R、PI3K p85、Glut4等蛋白表达的影响。
IGF1R缺陷提高了PC12细胞葡萄糖消耗，但仍不能完全逆转Aβ25-35对细胞消耗葡萄糖能力的损害；IGF1R缺陷可促进胰岛素刺激下的PC12细胞葡萄糖摄取量，同时这种效应具有浓度和时间依赖性；IGF1R的缺失提高了胰岛素对PC12细胞IR和IRS磷酸化的敏感性，对本研究非常重要的是在ΔIGF1R-PC12细胞中，IR对胰岛素表现出的亲和力，仅需要正常PC12细胞感知胰岛素浓度的1/100（0.1nM）；在IGF1R敲除的PC12细胞中，Akt磷酸化通路被激活，引起胰岛素受体相关通路对胰岛素的敏感性被大幅提升。
本文应用PET/CT技术开展了糖尿病脑病的机制研究，发现了IGF1R信号通路在糖尿病脑病发病过程中的重要作用。此项研究，为相关神经系统疾病理论研究开辟了新方向，同时也为治疗糖尿病脑病及相关药物开发提供了新思路和靶位点。
As is well known, PET/CT has an important Clinical significance and value todiagnosis, decisions of treatment and efficacy evaluation for patient in a variety ofcentral nervous system diseases, such as epilepsy, senile dementia, Parkinson's disease.Neuroimaging could link changes in the structure of the brain with changes incognitive function. Brain scanning in real time on the brains of Patient with diabetesgiven in three-dimensional imaging of the amount of monitoring, which evaluates theneuroanatomical regions involved in the brains of patients with diabetes, it isimpossible in neuropathology research organizations.
Here, brain glucose metabolism levels in Diabetic encephalopathy rat modelwere detected with PET/CT. It is exerted and measured that related pathologicstructural changes and some major functional molecules expression in hippocampus.The results show that the abnormal expression increase of IGF1R or related pathwaysactivation is very related to the occurrence of diabetic encephalopathy. This issupported by the observation that the production of reactive oxygen species is reducedin brains of IGF1R knock-out mice compared with their WT counterparts followingMPTP treatment known to induce a Parkinson’s disease-like phenotype. On the otherside, an alternative model suggests that increased neuronal resilience associated withreduced IGF signaling is promoted by enhanced DNA repair capabilities. It isreasonable to speculate that the histone deacetylase SIRT1, an aging regulator thatplays roles in the maintenance of genomic stability may also be a mediator foranti-apoptosis of the reduced IGF signaling protective effect in Alzheimer’s disease.
In view of the importance of IGF1R knock-out to nerve cells, we inhibited ofIGF1R expression in PC12cells, and reduced the activating level of IGF1R pathwayusing the lentiviral packaging, picked stable transfected cells, namely ΔIGF1R-ofPC12cells. In the follow parts, to investigate underlying details in that IGF1R defectsaffecting the nerve cells consumption and glucose uptake, and take particular attentionto the effects and the interactions between IGF1R, IR, phosphorylation of Aktsignaling pathway.
The content of the issue is divided into three parts, the use of imaging, pathology,molecular biology, cell biology techniques，on individual, cell and molecular levels, we studied the important role of IGF1R to the development of diabeticencephalopathy, revealed the interaction between IGF1R signaling pathwaydiminishing, glucose metabolism and IR signaling pathway in nerve cells. Followingthis three-part research brief summary, as follows:
1. PET/CT Imaging and Immunohistochemical on DiabeticEncephalopathy in Rats
In this part, first of all, we have established a rat model of diabetes screening bybehavioral experiments, rats suffering from diabetic encephalopathy, and then detectthe level of rat brain glucose metabolism using PE/CT, the final study brainthepathological features of the hippocampus and IR, IGF1R and Glut4in tissue withpathological staining and immunohistochemical methods. The results show that,compared with the normal control group and diabetic group, the level of brain glucosemetabolism in diabetic encephalopathy rats significantly reduced amyloid calm,organization and the cytoplasm have a red dye, the nerve fiber thickening,swellingderangement and so on, like neuropathological characteristics; IR expressionlevel is basically the same among the experimental group, diabetic encephalopathyrats IGF1R expression increased Glut4but the phenomenon of decline, it isnoteworthy that relative to the normal control group, only sufferinghippocampus ofrats with diabetes without suffering from encephalopathy IGF1R expression levelswere significantly reduced.
2. IGF1R knock-out PC12cell obtaining and screening
In accordance with the findings of the first part, only those with diabetes withoutencephalopathy rat hippocampal IGF1R expression levels appear significantlyreduced brain glucose metabolism capacity remained at a high level. Therefore,lentiviral packaging transfection techniques has been used to inhibit IGF1Rexpression in glioma cells PC12, which provided an important model for furtherresearch. After a large number of molecular biology vector assembling and screening,we obtained the IGF1R low expression of the stable transfected celllines-ΔIGF1R-PC12ultimately.
3. Study on the Inhibiting IGF1R affected PC12cell glucose metabolismand signal pathways
The part of the research，at the cellular level, concerning to the IGF1R defectsacted in cell glucose metabolism and Akt signaling pathway, the major resultwas the IGF1R defects enhanced PC12cells glucose consumption, but still not completelyreversed damage triggered by Aβ25-35in cells; IGF1R defect could promote glucoseuptake in insulin-stimulated PC12cells inthe dose and time manner; IGF1R defectcould improve insulin sensitivity to IR and IRS phosphorylation in PC12cells;extremely important to this study, in ΔIGF1R-of PC12cells, IR showed only need thesense insulin concentration of1/100(0.1nM) of normal PC12cells; in IGF1Rknock-out PC12cells, when Aktphosphorylation pathway was activated, the insulinsensitivity of IR would be improved significantly.
This study revealed that IGF1R signaling pathway’s role in diabeticencephalopathy, opened up a new direction for related research in nervous systemdiseases, but also provided a new idea for the treatment of diabetic encephalopathy,relevant drug development and target sites.
引文
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