脂毒性对胰岛β细胞去分化的影响及胰岛局部GLP-1的保护作用及机制
发布时间：2018-09-06 18:06
【摘要】：第一部分：脂毒性诱导β细胞去分化 目的：在离体模型中观察脂毒性对小鼠胰岛功能状态的影响和在体模型中探讨高脂饮食对胰岛p细胞功能及其分化状态的影响。 方法：分离C57BL/6J小鼠胰岛,加棕榈酸培养24h、48h、72h, MTT检测细胞活性,ELISA测细胞凋亡,定量PCR和免疫印记分别测定PDX1mRNA(?)口蛋白表达情况；高脂饮食喂养C57BL/6J小鼠8周,4周和8周时行腹腔葡萄糖耐量试验(IPGTT)与胰岛素释放试验(IPITT)观察糖代谢情况以及ELISA法检测血浆胰岛素水平,共聚焦结合免疫荧光观察胰岛结构及各种细胞标记物(p细胞：FoxO1、胰岛素和PDX1; α细胞：胰高血糖素；干细胞：OCT4、 Nanog)的表达,并检测Ki67和Caspase-3分别观察胰岛细胞增殖和凋亡。 结果：0.5mmol/L的棕榈酸培养24小时,48小时或72小时均降低胰岛细胞活力和增加细胞凋亡,并呈现时间依赖性(p0.05)。48小时的棕榈酸暴露显著降低胰岛细胞PDX1mRNA和蛋白水平(p0.05),但对胰岛素mRNA表达无影响(p0.05)。高脂饮食增加胰岛素的分泌(p0.01)；计算曲线下面积(AUC)显示高脂饮食组中AUCIPGTT和AUCIPITT增加,8周相对于4周时更明显(p0.05)；高脂饮食喂养增加HOMA-IR指数(p0.05)。高脂饮食降低β细胞表达FoxO1、胰岛素和PDX1,增加干细胞标记物OCT4和Nanog的表达。高脂饮食促进胰岛细胞Caspase-3表达；高脂饮食增加胰岛细胞表达Ki67,但所示增殖的胰岛细胞总体数量仍极少。 结论：1.离体和在体模型中脂毒性诱导胰岛功能损伤和胰岛素抵抗,呈现时间依赖性； 2.高脂饮食促进胰岛细胞增殖,诱导细胞凋亡； 3.高脂饮食损伤β细胞,促使胰岛细胞去分化成为骨髓干细胞。 第二部分：前α细胞形成与胰岛内源性GLP-1系统的激活及机制 目的：在离体和在体脂毒性模型,通过观察胰岛内GLP-1和GLP-1形成关键酶PC1/3表达变化,探讨胰岛内GLP-1系统激活水平及氧化应激在其中扮演的作用。 方法：分离正常C57BL/6J小鼠胰岛,棕榈酸培养胰岛24-72h,ELISA法观察培养液和细胞裂解液中GLP-1水平,定量PCR和免疫印记观察PC1/3mRNA和蛋白水平变化情况,藉此获得最佳的胰岛内GLP-1系统激活的刺激条件。高脂饮食喂养C57BL/6J小鼠8周,ELISA法测空腹状态下血清中GLP-1浓度,Q-PCR胰腺组织PC1/3mRNA表达,免疫荧光观察前a细胞形成情况。并采用DCFH-DA法检测棕榈酸诱导生成活性氧(ROS)水平,添加抗氧化剂N-乙酰半胱氨酸(NAC)进一步观察细胞裂解液中PCl/3mRNA和GLP-1水平变化。 结果：0.5mmol/L的棕榈酸培养离体胰岛24小时,48小时或72小时分别增加细胞培养中的GLP-1水平3.15-,6.55-和5.62倍(p0.05)。在胰岛细胞裂解中PC1/3mRNA和蛋白水平及GLP-1的浓度与细胞培养液中结果呈现相似的变化(p0.05)。相对于棕榈酸处理离体胰岛48小时,72小时后GLP-1和PC1/3表达水平呈现下降趋势。8周高脂饮食喂养显著促进前a细胞形成,以及增加小鼠胰岛细胞PC1/3的表达及血浆GLP-1浓度(p0.05)。相对于对照组,0.5mmol/L棕榈酸培养胰岛24小时,48小时或72小时分别增加ROS水平3.01-,5.12-和6.45倍。在棕榈酸培养胰岛之前添加0.5mmol/LNAC使胰岛细胞活性从59.56%增加至84.94%,而凋亡降低64.84%。NAC也显著降低细胞裂解物中PC1/3mRNA水平和GLP-1的浓度,但不能完全恢复正常(p0.05)。 结论：1.无论长期暴露于棕榈酸还是高脂饮食均上调胰岛GLP-1及其关键酶PC1/3表达,即激活胰岛内GLP-1系统； 2.棕榈酸增加活性氧生成,拮抗氧化应激减轻胰岛细胞损伤和部分逆转胰岛内GLP-1系统活化,表明氧化应激部分介导脂毒性激活胰岛内GLP-1系统。 第三部分：胰岛内源性的GLP-1的保护作用及机制 目的：在脂毒性模型中,改变GLP-1受体的活性观察胰岛内源性的GLP-1对胰岛细胞的保护作用,以及通过检测氧化应激和炎症反应探讨GLP-1的作用机制。 方法：分离正常C57BL/6J小鼠胰岛并棕榈酸培养,通过添加GLP-1R受体拮抗剂Exendin9-39或激动剂利纳鲁肽,观察胰岛细胞活性、凋亡水平及PDX1表达的变化,检测ROS水平、NA(D)PH氧化酶成分(NOX4, p22phox和gp91phox)和抗氧化基因(SOD2和Gpx-1)的mRNA表达水平以及炎症因子(TNF-a, IL-1β和IL-6)表达水平。高脂喂养C57BL/6J小鼠8周,于第4周开始皮下注射利纳鲁肽4周,免疫荧光观察胰岛细胞结构改变及炎症信号通路NF-κB的改变。结果：联合棕榈酸和Exendin9-39培养48小时,胰岛细胞活性从57.82%降至40.28%,细胞凋亡从0.48至0.72(p0.05)。联合棕榈酸和利纳鲁肽培养离体胰岛,显著增加胰岛的生存能力和降低胰岛细胞凋亡,并均接近对照组水平(p0.05)；也显著地上调PDX1mRNA表达7.70倍,均能被Exendin9-39所逆转(p0.05)。Exendin9-39阻断GLP-1受体信号增加ROS生成,而利纳鲁肽抑制NA(D)PH氧化酶成分和上调抗氧化基因(SOD2和Gpx-1) mRNA的表达,进而降低ROS生成(p0.05)。利纳鲁肽还抑制棕榈酸诱导的炎症因子(TNF-a,IL-1β和IL-6)表达(p0.05)。利拉鲁肽显著增加β细胞标记物PDX1, NKX6.1和GLUT2的mRNA的表达(p0.05)。低脂喂养组中,胰岛结构呈现α细胞外周和β细胞核心的特性,而高脂喂养使得α细胞分散且比例增高,增加中小胰岛的面积。利纳鲁肽恢复胰岛的正常结构和胰岛素的表达,降低α细胞/β细胞比例和α重量的变化。利纳鲁肽还可抑制胰岛内p65的表达。 结论：1.拮抗GLP-1受体活性,加重细胞损伤,恶化β细胞功能； 2.胰岛内源性的GLP-1通过维持胰岛内氧化应激的平衡和抑制炎症信号通路保护p细胞和维持正常胰岛结构。
[Abstract]:Part I: lipotoxicity induced dedifferentiation of beta cells
AIM: To observe the effect of lipid toxicity on the function and differentiation of mouse pancreatic islets in vitro and in vivo.
Methods: Islets of C57BL/6J mice were isolated and cultured with palmitic acid for 24 hours, 48 hours, 72 hours, MTT assay for cell activity, ELISA for cell apoptosis, quantitative PCR and immunoblotting for the expression of PDX1 mRNA (?) oral protein, and high fat diet for 8 weeks, 4 weeks and 8 weeks for intraperitoneal glucose tolerance test (IPGTT) and insulin release test (IPITT). Glucose metabolism and plasma insulin levels were measured by ELISA. Confocal and immunofluorescence were used to observe the structure of islets and the expression of various cell markers (p cells: FoxO1, insulin and PDX1; alpha cells: glucagon; stem cells: OCT4, Nanog), and the proliferation and apoptosis of islets were observed by Ki67 and Caspase-3, respectively.
Results: 0.5mmol/L palmitic acid culture for 24 hours, 48 hours or 72 hours decreased the activity of islet cells and increased cell apoptosis, and showed a time-dependent (p0.05). 48 hours palmitic acid exposure significantly decreased the levels of PDX1 mRNA and protein in islet cells (p0.05), but had no effect on insulin mRNA expression (p0.05). High-fat diet increased insulin expression. Secretion (p0.01); calculated area under curve (AUC) showed that AUCIPGTT and AUCIPITT increased in the high-fat diet group, especially at 8 weeks compared with 4 weeks (p0.05); high-fat diet increased HOMA-IR index (p0.05). High-fat diet decreased the expression of FoxO1, insulin and PDX1 in beta cells, and increased the expression of stem cell markers OCT4 and Nanog. High-fat diet promoted pancreas. Caspase-3 expression in islet cells and Ki67 expression in islet cells were increased by high-fat diet, but the total number of proliferated islet cells was still very small.
Conclusion: 1. In vitro and in vivo, lipotoxicity induces islet dysfunction and insulin resistance in a time-dependent manner.
2. high fat diet promotes islet cell proliferation and induces apoptosis.
3. high fat diet damages beta cells and promotes islet cells to dedifferentiate into bone marrow stem cells.
The second part: the formation of pre alpha cells and the activation and mechanism of islet endogenous GLP-1 system.
AIM: To investigate the expression of PC1/3, the key enzyme of GLP-1 and GLP-1 formation, and the role of oxidative stress in the activation of GLP-1 system.
Methods: Islets of normal C57BL/6J mice were isolated and cultured with palmitic acid for 24-72 hours. The levels of GLP-1 in culture medium and cell lysate were observed by ELISA. The changes of PC1/3 mRNA and protein levels were observed by quantitative PCR and immunoblotting. The optimal stimulating conditions for activation of GLP-1 system in islets were obtained. The concentration of GLP-1 in serum, the expression of PC1/3 mRNA in pancreatic tissue by Q-PCR and the formation of pre-A cells were detected by immunofluorescence. The levels of reactive oxygen species (ROS) induced by palmitic acid were detected by DCFH-DA method, and the levels of PCl/3 mRNA and GLP-1 in cell lysate were further observed by adding antioxidant N-acetylcysteine (NAC).
Results: The levels of GLP-1 in islets cultured with 0.5mmol/L palmitic acid for 24 hours, 48 hours or 72 hours increased by 3.15-, 6.55-and 5.62 times respectively (p0.05). The levels of PC1/3 mRNA and protein and the concentration of GLP-1 in islets lysis were similar to those in cell culture medium (p0.05) compared with those treated with palmitic acid in vitro. The expression of GLP-1 and PC1/3 in islets decreased after 48 hours and 72 hours. High-fat diet significantly promoted the formation of pre-A cells and increased the expression of PC1/3 in islet cells and plasma GLP-1 concentration (p0.05). Compared with the control group, the ROS level of islets cultured with 0.5mmol/L palmitic acid for 24 hours, 48 hours or 72 hours increased by 3.01-, 5.05-, respectively. The addition of 0.5mmol/LNAC before palmitic acid culture increased the activity of islet cells from 59.56% to 84.94% and decreased apoptosis by 64.84%. NAC also significantly decreased the levels of PC1/3 mRNA and GLP-1 in the lysates, but could not completely recover to normal (p0.05).
Conclusion: 1. Both long-term exposure to palmitic acid and high-fat diet up-regulate the expression of GLP-1 and its key enzyme PC1/3 in islets, that is, activate the GLP-1 system in islets.
2. Palmitic acid increases ROS production, antagonizes antioxidant stress to alleviate islet cell injury and partially reverses the activation of GLP-1 system in islets, suggesting that oxidative stress partially mediates lipid toxicity to activate GLP-1 system in islets.
The third part: the protective effect and mechanism of endogenous GLP-1 in islets.
AIM: To observe the protective effect of endogenous GLP-1 on islet cells by altering the activity of GLP-1 receptor in a lipotoxic model, and to explore the mechanism of GLP-1 by detecting oxidative stress and inflammation.
Methods: Islets of normal C57BL/6J mice were isolated and cultured with palmitic acid. The activity, apoptosis and PDX1 expression of islet cells were observed by adding GLP-1R receptor antagonist Exendin 9-39 or agonist Linalopeptide. The levels of ROS, NA (D) PH oxidase (NOX4, p22phox and gp91phox) and the mRNA expression of antioxidant genes (SOD2 and Gpx-1) were detected. Levels of inflammatory factors (TNF-a, IL-1beta and IL-6) were measured. High-fat-fed C57BL/6J mice were subcutaneously injected with linalopeptide for 8 weeks and 4 weeks. Immunofluorescence was used to observe the changes of islet cell structure and inflammation signal pathway NF-kappa B. Results: After 48 hours of culture with palmitic acid and Exendin 9-39, the activity of islet cells decreased from 57.82%. By 40.28%, the apoptosis was from 0.48 to 0.72 (p0.05). The combination of palmitic acid and linalopeptide significantly increased the viability of islets and decreased the apoptosis of islets, which were close to the level of control group (p0.05). The expression of PDX1 mRNA was also significantly up-regulated by 7.70 times and could be reversed by Exendin 9-39 (p0.05). Exendin 9-39 blocked the GLP-1 receptor signaling. Liraglutide also inhibited the expression of inflammatory factors (TNF-a, IL-1beta and IL-6) induced by palmitic acid (p0.05). Liraglutide significantly increased the mRNAs of beta cell markers PDX1, NKX6.1 and GLUT2. In low-fat diet group, the structure of pancreatic islets showed the characteristics of periphery of alpha cells and core of beta cells, while high-fat diet made alpha cells disperse and increase the proportion of small and medium-sized islets, increased the area of small and medium-sized islets. It can also inhibit the expression of p65 in islets.
Conclusion: 1. antagonizing the activity of GLP-1 receptor, aggravating cell damage and worsening the function of beta cell.
2. Endogenous GLP-1 protects P cells and maintains normal islet structure by maintaining the balance of oxidative stress and inhibiting inflammation signaling in islets.
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R587.1
本文编号：2227114
[Abstract]:Part I: lipotoxicity induced dedifferentiation of beta cells
AIM: To observe the effect of lipid toxicity on the function and differentiation of mouse pancreatic islets in vitro and in vivo.
Methods: Islets of C57BL/6J mice were isolated and cultured with palmitic acid for 24 hours, 48 hours, 72 hours, MTT assay for cell activity, ELISA for cell apoptosis, quantitative PCR and immunoblotting for the expression of PDX1 mRNA (?) oral protein, and high fat diet for 8 weeks, 4 weeks and 8 weeks for intraperitoneal glucose tolerance test (IPGTT) and insulin release test (IPITT). Glucose metabolism and plasma insulin levels were measured by ELISA. Confocal and immunofluorescence were used to observe the structure of islets and the expression of various cell markers (p cells: FoxO1, insulin and PDX1; alpha cells: glucagon; stem cells: OCT4, Nanog), and the proliferation and apoptosis of islets were observed by Ki67 and Caspase-3, respectively.
Results: 0.5mmol/L palmitic acid culture for 24 hours, 48 hours or 72 hours decreased the activity of islet cells and increased cell apoptosis, and showed a time-dependent (p0.05). 48 hours palmitic acid exposure significantly decreased the levels of PDX1 mRNA and protein in islet cells (p0.05), but had no effect on insulin mRNA expression (p0.05). High-fat diet increased insulin expression. Secretion (p0.01); calculated area under curve (AUC) showed that AUCIPGTT and AUCIPITT increased in the high-fat diet group, especially at 8 weeks compared with 4 weeks (p0.05); high-fat diet increased HOMA-IR index (p0.05). High-fat diet decreased the expression of FoxO1, insulin and PDX1 in beta cells, and increased the expression of stem cell markers OCT4 and Nanog. High-fat diet promoted pancreas. Caspase-3 expression in islet cells and Ki67 expression in islet cells were increased by high-fat diet, but the total number of proliferated islet cells was still very small.
Conclusion: 1. In vitro and in vivo, lipotoxicity induces islet dysfunction and insulin resistance in a time-dependent manner.
2. high fat diet promotes islet cell proliferation and induces apoptosis.
3. high fat diet damages beta cells and promotes islet cells to dedifferentiate into bone marrow stem cells.
The second part: the formation of pre alpha cells and the activation and mechanism of islet endogenous GLP-1 system.
AIM: To investigate the expression of PC1/3, the key enzyme of GLP-1 and GLP-1 formation, and the role of oxidative stress in the activation of GLP-1 system.
Methods: Islets of normal C57BL/6J mice were isolated and cultured with palmitic acid for 24-72 hours. The levels of GLP-1 in culture medium and cell lysate were observed by ELISA. The changes of PC1/3 mRNA and protein levels were observed by quantitative PCR and immunoblotting. The optimal stimulating conditions for activation of GLP-1 system in islets were obtained. The concentration of GLP-1 in serum, the expression of PC1/3 mRNA in pancreatic tissue by Q-PCR and the formation of pre-A cells were detected by immunofluorescence. The levels of reactive oxygen species (ROS) induced by palmitic acid were detected by DCFH-DA method, and the levels of PCl/3 mRNA and GLP-1 in cell lysate were further observed by adding antioxidant N-acetylcysteine (NAC).
Results: The levels of GLP-1 in islets cultured with 0.5mmol/L palmitic acid for 24 hours, 48 hours or 72 hours increased by 3.15-, 6.55-and 5.62 times respectively (p0.05). The levels of PC1/3 mRNA and protein and the concentration of GLP-1 in islets lysis were similar to those in cell culture medium (p0.05) compared with those treated with palmitic acid in vitro. The expression of GLP-1 and PC1/3 in islets decreased after 48 hours and 72 hours. High-fat diet significantly promoted the formation of pre-A cells and increased the expression of PC1/3 in islet cells and plasma GLP-1 concentration (p0.05). Compared with the control group, the ROS level of islets cultured with 0.5mmol/L palmitic acid for 24 hours, 48 hours or 72 hours increased by 3.01-, 5.05-, respectively. The addition of 0.5mmol/LNAC before palmitic acid culture increased the activity of islet cells from 59.56% to 84.94% and decreased apoptosis by 64.84%. NAC also significantly decreased the levels of PC1/3 mRNA and GLP-1 in the lysates, but could not completely recover to normal (p0.05).
Conclusion: 1. Both long-term exposure to palmitic acid and high-fat diet up-regulate the expression of GLP-1 and its key enzyme PC1/3 in islets, that is, activate the GLP-1 system in islets.
2. Palmitic acid increases ROS production, antagonizes antioxidant stress to alleviate islet cell injury and partially reverses the activation of GLP-1 system in islets, suggesting that oxidative stress partially mediates lipid toxicity to activate GLP-1 system in islets.
The third part: the protective effect and mechanism of endogenous GLP-1 in islets.
AIM: To observe the protective effect of endogenous GLP-1 on islet cells by altering the activity of GLP-1 receptor in a lipotoxic model, and to explore the mechanism of GLP-1 by detecting oxidative stress and inflammation.
Methods: Islets of normal C57BL/6J mice were isolated and cultured with palmitic acid. The activity, apoptosis and PDX1 expression of islet cells were observed by adding GLP-1R receptor antagonist Exendin 9-39 or agonist Linalopeptide. The levels of ROS, NA (D) PH oxidase (NOX4, p22phox and gp91phox) and the mRNA expression of antioxidant genes (SOD2 and Gpx-1) were detected. Levels of inflammatory factors (TNF-a, IL-1beta and IL-6) were measured. High-fat-fed C57BL/6J mice were subcutaneously injected with linalopeptide for 8 weeks and 4 weeks. Immunofluorescence was used to observe the changes of islet cell structure and inflammation signal pathway NF-kappa B. Results: After 48 hours of culture with palmitic acid and Exendin 9-39, the activity of islet cells decreased from 57.82%. By 40.28%, the apoptosis was from 0.48 to 0.72 (p0.05). The combination of palmitic acid and linalopeptide significantly increased the viability of islets and decreased the apoptosis of islets, which were close to the level of control group (p0.05). The expression of PDX1 mRNA was also significantly up-regulated by 7.70 times and could be reversed by Exendin 9-39 (p0.05). Exendin 9-39 blocked the GLP-1 receptor signaling. Liraglutide also inhibited the expression of inflammatory factors (TNF-a, IL-1beta and IL-6) induced by palmitic acid (p0.05). Liraglutide significantly increased the mRNAs of beta cell markers PDX1, NKX6.1 and GLUT2. In low-fat diet group, the structure of pancreatic islets showed the characteristics of periphery of alpha cells and core of beta cells, while high-fat diet made alpha cells disperse and increase the proportion of small and medium-sized islets, increased the area of small and medium-sized islets. It can also inhibit the expression of p65 in islets.
Conclusion: 1. antagonizing the activity of GLP-1 receptor, aggravating cell damage and worsening the function of beta cell.
2. Endogenous GLP-1 protects P cells and maintains normal islet structure by maintaining the balance of oxidative stress and inhibiting inflammation signaling in islets.
【学位授予单位】：华中科技大学
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R587.1
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