牛初乳类胰岛素生长因子-Ⅰ提取物在大鼠糖尿病治疗和预防中的作用及机理研究
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摘要
本课题对牛初乳IGF-I的分离制备、稳定性、药物代谢动力学进行了研究,并对其在大鼠糖尿病治疗与预防中的作用和机理进行了分析。
牛初乳与过渡乳中IGF-I的含量测定结果表明,乳牛分娩后随泌乳天数的推移,乳中IGF-I的含量急剧下降,总含量由第一天的25141.28 ng/ml下降到十四天的77.95ng/ml。泌乳前五天,乳中的IGF-I主要以游离形态存在,游离态IGF-I占总IGF-I的比例由第一天的71.10%下降到第五天的50.64%,之后乳中的IGF-I主要以结合形态存在,结合态IGF-I占总IGF-I的比例由第六天的51.41%上升到十四天的63.63%。
采用酸-乙醇前处理工艺和Sephedex G-15凝胶过滤层析从牛初乳中分离得到IGF-I,前处理过程的收率平均为95.26%,层析过程的收率平均为58.84%,工艺总收率平均为56.05%,分离物中IGF-I的含量平均达到2.137mg/g。
牛初乳IGF-I的热稳定性研究表明,IGF-I在UHT乳和PBS中的热变性反应级数均为1.1级,在UHT乳中的热稳定性明显强于PBS;65℃、72℃、80℃及90℃条件下在PBS中的热变性D值分别为33193s、19580s、7906s和3127s,此温度范围内Z值为24.41℃,表观活化能为98.02KJ/mol;相同条件下在UHT乳中的D值分别为43732s、21199s、10591s和5577s,Z值为27.12℃,表观活化能为83.86KJ/mol。
牛初乳IGF-I的pH稳定性表明,37℃、30min条件下,当pH在2～7的范围内时,活性保留率在89.92%～88.51%之间变化;当pH在8～12的范围内时,活性保留率在46.86%～45.47%之间变化。
分离的牛初乳IGF-I在人工胃液中的稳定性随胃液pH值的升高而增加,0.5h～4h内,胃液pH值为2,3,4时的活性保留率变化范围分别为40.25%～0.25%,50.40%～0.60%和93.34%～8.40%;初乳乳清粉中的IGF-I对胃液消化的耐受性远远高于分离的IGF-I,相同条件下,pH2,3,4时的活性保留率变化范围分别为67.72%～45.14%,84.59%～58.41%和94.21%～63.35%;分离的牛初乳IGF-I对pH8的人工肠液的耐受性相对较差,0.5h～4h内活性保留率变化范围为33.20%～0.46%,而初乳乳清粉中的IGF-I活性保留率变化范围为87.80%～24.28%。
常用的酸乳生产发酵过程和储存过程对牛初乳IGF-I的活性影响不大,6小时发酵结束时活性保留率平均为70.61%,4℃储存20天后活性保留率平均为45.99%。
正常大鼠和糖尿病大鼠单次静脉注射牛初乳IGF-I的药代动力学方程均符合二室模型;正常和糖尿病大鼠的IGF-I药代动力学方程分别为C=1791.72e~(-2.82t)+456.96e~(-0.112t)和C=1879.56e~(-2.46t)+169.84e~(-0.125t);IGF-I在糖尿病大鼠体内的分布和消除速率均快于正常大鼠,表观分布容积Vd、总消除率CL显著高于正常大鼠(P<0.01),药时曲线下面积AUC、平均残留时间MRT、消除速率常数K12和K21则低于正常大鼠(P<0.05)。
口服或腹腔注射牛初乳IGF-I均能有效降低糖尿病大鼠的血糖水平。30天治疗结束时15ug、10ug、5ugIGF-I/kg口服组和腹腔注射10ugIGF-I/kg组糖尿病大鼠的血糖值分别较基础值下降18.21%、14.96%、14.55%和43.23%,停止治疗15天后降糖效应仍有一定的持续性。血清激素测定结果表明,牛初乳IGF-I能够升高糖尿病大鼠的血清胰岛素水平和血清游离IGF-I,下调生长激素水平。糖耐量动物实验表明,牛初乳IGF-I治疗能有效改善糖尿病大鼠的糖耐量。大鼠胰腺组织病理切片和免疫组织化学染色表明,牛初乳IGF-I能够明显增加糖尿病大鼠的胰岛β细胞数量和胰岛细胞IGF-I受体数量。
与牛初乳IGF-I相比,口服降糖药物盐酸二甲双胍的前期降糖效果明显,治疗20天时大鼠血糖值下降39.66%,后期逐渐出现继发性失效,而牛初乳IGF-I的降糖效果呈现缓慢和温和的趋势;动物实验表明,牛初乳IGF-I与胰岛素合用10天后出现协同降糖效应。
预防性口服牛初乳IGF-I可以有效控制STZ所致大鼠血糖水平、糖化血清蛋白水平、血清总胆固醇水平、血清甘油三酯水平、血清生长激素水平的升高,抑制血清胰岛素、血清IGF-I水平的下降,增加大鼠胰腺/体重比值,改善糖耐量,抵抗STZ所致大鼠胰岛β细胞数量和胰岛细胞IGF-I受体数量的下降。
细胞实验表明,牛初乳IGF-I对鼠NIT-1胰腺β细胞的增殖活力依赖于细胞所处环境的葡萄糖浓度和IGF-I浓度,在葡萄糖浓度为15.3mM和牛初乳IGF-I浓度为400ng/ml时细胞活力相对较强。
基因芯片检测结果表明,TGF-β、Wnt、PI3K/AKT、NF-kB和Jak-Stat这5条信号转导通路的共同激活调控了牛初乳IGF-I对胰腺β细胞的促增殖效应。
Isolation, stability and pharmacokinetics of bovine colostrums insulin-like growth factor-I (bc-IGF-I) were analyzed. The preventive and therapeutic effect of bc-IGF-I on rat Diabetic and its mechanism were also investigated. The results are as follow:
Concentrations of free and bound IGF-I were measured in bovine colostrums from the first milkings to 14 day postpartum. Rapid decrease was found during this period. Free form IGF-I appeared mainly in 1 to 5 day colostrums and the ratio varied from 71.10% to 50.64%. After that, bound form dominated and the ratio varied from 51.41% to 63.63%.
Extraction of acid-ethanol and gel filtration chromatography methods were used to isolate bc-IGF-I from bovine colostrums. The recovery of was 95.26% and 58.84% in two process, respectively. The final content of IGF-I was 2.137mg/g.
kinetic and thermodynamic parameters for heat denaturation of bc-IGF-I in phosphate buffer saline (PBS) and ultra high temperature (UHT) milk showed that more significant thermal stability of IGF-I in milk than in PBS. The D-values were higher in UHT milk than in PBS at all temperatures. The Z-values and energies of activation were 24.41℃and 27.12℃, 98.02KJ/mol and 83.86KJ/mol in PBS and UHT milk, respectively. Heat denaturation of IGF-I followed a reaction order of n=1.1.
The activity of bc-IGF-I were relatively higher at pH 2 to 7, varied from 89.92% to 88.51%, than at pH 8 to 12, varied from 46.86% to 45.47%.
The stability of bc-IGF-I was increased with pH value of artificial gastric juice. The activity of IGF-I at pH 2,3,4 between 0.5h and 4h varied from 40.25% to 0.25%,50.40% to 0.60% and 93.34% to 8.40%, respectively. The activity of IGF-I in colostrums whey power were higher and ranged from 67.72% to 45.14%,84.59% to 58.41% and 94.21% to 63.35% at the same condition. The stability of bc-IGF-I was relatively poor in artificial intestinal juice and the retention rate changed from 33.20% to 0.46%, but the value for IGF-I in colostrums whey power were from 87.80% to 24.28%.
Pharmacokinetic formula of bc-IGF-I in normal or diabetic rat correspond to two- compartment model. The Pharmacokinetic formula of bc-IGF-I in normal and diabetic rat were C=1791.72e~(-2.82t) + 456.96e~(-0.112t) and C=1879.56e~(-2.46t) + 169.84e~(-0.125t), respectively. Pharmacokinetic parameters showed that the distribution and elimination rate of IGF-I were faster in diabetic rat than in normal rat. The distribution volume (Vd) and total body clearance (CL) of IGF-I were significantly higher in diabetic rat (P<0.01) than in normal rat, while area under curve (AUC), main residence time (MRT), elimination rate constant K12 and K21 were significantly lower in diabetic rat (P<0.05).
The therapeutic effect of bc-IGF-I on streptozotocin-induced diabetic rats was evaluated. The results indicated that the bc-IGF-I had obvious glucose-lowered effect on diabetic rats. Compared with basic value, plasma glucose level was decreased about 18.21%, 14.96%, 14.55% and 43.23% in 15ug, 10ug, 5ug IGF-I/kg oral group and 10ug IGF-I/kg intraperitoneal group at the end of treatment, respectively. Furthermore, glucose-lowered effect of IGF-I had persistence and stability to some extent. Serum homone level of all rats were measured by radioimmunoassay and showed that bc-IGF-I could increase serum insulin and free IGF-I level significantly and decrease growth homone level. Moreover, bc-IGF-I treatment improved the oral glucose tolerance of diabetic rat. Pathological section and immunohistochemical localization of rat pancreas showed that bc-IGF-I treatment increased the amount of beta-Cell and IGF-I receptor obviously.
The glucose-lowered effect of metformin was obvious in early days and plasma glucose value of diabetic rat was decreased about 39.66% at 20th days. After that, metformin began to lose efficacy gradually until out of service at 45th days. However, bc-IGF-I presented the slow and mild glucose-lowered effect. The combination of bc-IGF-I and insulin demonstrated the synergistic effect after ten days.
Preventive oral administration of bc-IGF-I could restrain the increase of plasma glucose level, glycolated serum protein (GSP) level, serum total cholesterol (T-CHO) level, serum triglyceride level and serum growth hormone level, delay the decrease of serum IGF-I and insulin level, raise the ratio of pancreas and body weight and improve glucose tolerance, and also resist the diminish of beta-Cell and IGF-I receptor amount in STZ-induced diabetic rats.
Bc-IGF-I-stimulated pancreatic beta-Cell growth depended on environmental IGF-I and glucose concentration in mouse NIT-1 beta-cells. The relatively high proliferation activity was found at 15.3mM glucose and 400ng/ml IGF-I concentration.
Gene microarray detection suggested that the coactivation of TGF-β、Wnt、PI3K/AKT、NF-kB and Jak-Stat signal transduction pathways regulated the promoting-proliferation effect of Bc-IGF-I.
牛初乳与过渡乳中IGF-I的含量测定结果表明,乳牛分娩后随泌乳天数的推移,乳中IGF-I的含量急剧下降,总含量由第一天的25141.28 ng/ml下降到十四天的77.95ng/ml。泌乳前五天,乳中的IGF-I主要以游离形态存在,游离态IGF-I占总IGF-I的比例由第一天的71.10%下降到第五天的50.64%,之后乳中的IGF-I主要以结合形态存在,结合态IGF-I占总IGF-I的比例由第六天的51.41%上升到十四天的63.63%。
采用酸-乙醇前处理工艺和Sephedex G-15凝胶过滤层析从牛初乳中分离得到IGF-I,前处理过程的收率平均为95.26%,层析过程的收率平均为58.84%,工艺总收率平均为56.05%,分离物中IGF-I的含量平均达到2.137mg/g。
牛初乳IGF-I的热稳定性研究表明,IGF-I在UHT乳和PBS中的热变性反应级数均为1.1级,在UHT乳中的热稳定性明显强于PBS;65℃、72℃、80℃及90℃条件下在PBS中的热变性D值分别为33193s、19580s、7906s和3127s,此温度范围内Z值为24.41℃,表观活化能为98.02KJ/mol;相同条件下在UHT乳中的D值分别为43732s、21199s、10591s和5577s,Z值为27.12℃,表观活化能为83.86KJ/mol。
牛初乳IGF-I的pH稳定性表明,37℃、30min条件下,当pH在2～7的范围内时,活性保留率在89.92%～88.51%之间变化;当pH在8～12的范围内时,活性保留率在46.86%～45.47%之间变化。
分离的牛初乳IGF-I在人工胃液中的稳定性随胃液pH值的升高而增加,0.5h～4h内,胃液pH值为2,3,4时的活性保留率变化范围分别为40.25%～0.25%,50.40%～0.60%和93.34%～8.40%;初乳乳清粉中的IGF-I对胃液消化的耐受性远远高于分离的IGF-I,相同条件下,pH2,3,4时的活性保留率变化范围分别为67.72%～45.14%,84.59%～58.41%和94.21%～63.35%;分离的牛初乳IGF-I对pH8的人工肠液的耐受性相对较差,0.5h～4h内活性保留率变化范围为33.20%～0.46%,而初乳乳清粉中的IGF-I活性保留率变化范围为87.80%～24.28%。
常用的酸乳生产发酵过程和储存过程对牛初乳IGF-I的活性影响不大,6小时发酵结束时活性保留率平均为70.61%,4℃储存20天后活性保留率平均为45.99%。
正常大鼠和糖尿病大鼠单次静脉注射牛初乳IGF-I的药代动力学方程均符合二室模型;正常和糖尿病大鼠的IGF-I药代动力学方程分别为C=1791.72e~(-2.82t)+456.96e~(-0.112t)和C=1879.56e~(-2.46t)+169.84e~(-0.125t);IGF-I在糖尿病大鼠体内的分布和消除速率均快于正常大鼠,表观分布容积Vd、总消除率CL显著高于正常大鼠(P<0.01),药时曲线下面积AUC、平均残留时间MRT、消除速率常数K12和K21则低于正常大鼠(P<0.05)。
口服或腹腔注射牛初乳IGF-I均能有效降低糖尿病大鼠的血糖水平。30天治疗结束时15ug、10ug、5ugIGF-I/kg口服组和腹腔注射10ugIGF-I/kg组糖尿病大鼠的血糖值分别较基础值下降18.21%、14.96%、14.55%和43.23%,停止治疗15天后降糖效应仍有一定的持续性。血清激素测定结果表明,牛初乳IGF-I能够升高糖尿病大鼠的血清胰岛素水平和血清游离IGF-I,下调生长激素水平。糖耐量动物实验表明,牛初乳IGF-I治疗能有效改善糖尿病大鼠的糖耐量。大鼠胰腺组织病理切片和免疫组织化学染色表明,牛初乳IGF-I能够明显增加糖尿病大鼠的胰岛β细胞数量和胰岛细胞IGF-I受体数量。
与牛初乳IGF-I相比,口服降糖药物盐酸二甲双胍的前期降糖效果明显,治疗20天时大鼠血糖值下降39.66%,后期逐渐出现继发性失效,而牛初乳IGF-I的降糖效果呈现缓慢和温和的趋势;动物实验表明,牛初乳IGF-I与胰岛素合用10天后出现协同降糖效应。
预防性口服牛初乳IGF-I可以有效控制STZ所致大鼠血糖水平、糖化血清蛋白水平、血清总胆固醇水平、血清甘油三酯水平、血清生长激素水平的升高,抑制血清胰岛素、血清IGF-I水平的下降,增加大鼠胰腺/体重比值,改善糖耐量,抵抗STZ所致大鼠胰岛β细胞数量和胰岛细胞IGF-I受体数量的下降。
细胞实验表明,牛初乳IGF-I对鼠NIT-1胰腺β细胞的增殖活力依赖于细胞所处环境的葡萄糖浓度和IGF-I浓度,在葡萄糖浓度为15.3mM和牛初乳IGF-I浓度为400ng/ml时细胞活力相对较强。
基因芯片检测结果表明,TGF-β、Wnt、PI3K/AKT、NF-kB和Jak-Stat这5条信号转导通路的共同激活调控了牛初乳IGF-I对胰腺β细胞的促增殖效应。
Isolation, stability and pharmacokinetics of bovine colostrums insulin-like growth factor-I (bc-IGF-I) were analyzed. The preventive and therapeutic effect of bc-IGF-I on rat Diabetic and its mechanism were also investigated. The results are as follow:
Concentrations of free and bound IGF-I were measured in bovine colostrums from the first milkings to 14 day postpartum. Rapid decrease was found during this period. Free form IGF-I appeared mainly in 1 to 5 day colostrums and the ratio varied from 71.10% to 50.64%. After that, bound form dominated and the ratio varied from 51.41% to 63.63%.
Extraction of acid-ethanol and gel filtration chromatography methods were used to isolate bc-IGF-I from bovine colostrums. The recovery of was 95.26% and 58.84% in two process, respectively. The final content of IGF-I was 2.137mg/g.
kinetic and thermodynamic parameters for heat denaturation of bc-IGF-I in phosphate buffer saline (PBS) and ultra high temperature (UHT) milk showed that more significant thermal stability of IGF-I in milk than in PBS. The D-values were higher in UHT milk than in PBS at all temperatures. The Z-values and energies of activation were 24.41℃and 27.12℃, 98.02KJ/mol and 83.86KJ/mol in PBS and UHT milk, respectively. Heat denaturation of IGF-I followed a reaction order of n=1.1.
The activity of bc-IGF-I were relatively higher at pH 2 to 7, varied from 89.92% to 88.51%, than at pH 8 to 12, varied from 46.86% to 45.47%.
The stability of bc-IGF-I was increased with pH value of artificial gastric juice. The activity of IGF-I at pH 2,3,4 between 0.5h and 4h varied from 40.25% to 0.25%,50.40% to 0.60% and 93.34% to 8.40%, respectively. The activity of IGF-I in colostrums whey power were higher and ranged from 67.72% to 45.14%,84.59% to 58.41% and 94.21% to 63.35% at the same condition. The stability of bc-IGF-I was relatively poor in artificial intestinal juice and the retention rate changed from 33.20% to 0.46%, but the value for IGF-I in colostrums whey power were from 87.80% to 24.28%.
Pharmacokinetic formula of bc-IGF-I in normal or diabetic rat correspond to two- compartment model. The Pharmacokinetic formula of bc-IGF-I in normal and diabetic rat were C=1791.72e~(-2.82t) + 456.96e~(-0.112t) and C=1879.56e~(-2.46t) + 169.84e~(-0.125t), respectively. Pharmacokinetic parameters showed that the distribution and elimination rate of IGF-I were faster in diabetic rat than in normal rat. The distribution volume (Vd) and total body clearance (CL) of IGF-I were significantly higher in diabetic rat (P<0.01) than in normal rat, while area under curve (AUC), main residence time (MRT), elimination rate constant K12 and K21 were significantly lower in diabetic rat (P<0.05).
The therapeutic effect of bc-IGF-I on streptozotocin-induced diabetic rats was evaluated. The results indicated that the bc-IGF-I had obvious glucose-lowered effect on diabetic rats. Compared with basic value, plasma glucose level was decreased about 18.21%, 14.96%, 14.55% and 43.23% in 15ug, 10ug, 5ug IGF-I/kg oral group and 10ug IGF-I/kg intraperitoneal group at the end of treatment, respectively. Furthermore, glucose-lowered effect of IGF-I had persistence and stability to some extent. Serum homone level of all rats were measured by radioimmunoassay and showed that bc-IGF-I could increase serum insulin and free IGF-I level significantly and decrease growth homone level. Moreover, bc-IGF-I treatment improved the oral glucose tolerance of diabetic rat. Pathological section and immunohistochemical localization of rat pancreas showed that bc-IGF-I treatment increased the amount of beta-Cell and IGF-I receptor obviously.
The glucose-lowered effect of metformin was obvious in early days and plasma glucose value of diabetic rat was decreased about 39.66% at 20th days. After that, metformin began to lose efficacy gradually until out of service at 45th days. However, bc-IGF-I presented the slow and mild glucose-lowered effect. The combination of bc-IGF-I and insulin demonstrated the synergistic effect after ten days.
Preventive oral administration of bc-IGF-I could restrain the increase of plasma glucose level, glycolated serum protein (GSP) level, serum total cholesterol (T-CHO) level, serum triglyceride level and serum growth hormone level, delay the decrease of serum IGF-I and insulin level, raise the ratio of pancreas and body weight and improve glucose tolerance, and also resist the diminish of beta-Cell and IGF-I receptor amount in STZ-induced diabetic rats.
Bc-IGF-I-stimulated pancreatic beta-Cell growth depended on environmental IGF-I and glucose concentration in mouse NIT-1 beta-cells. The relatively high proliferation activity was found at 15.3mM glucose and 400ng/ml IGF-I concentration.
Gene microarray detection suggested that the coactivation of TGF-β、Wnt、PI3K/AKT、NF-kB and Jak-Stat signal transduction pathways regulated the promoting-proliferation effect of Bc-IGF-I.
引文
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