骨骼肌1型11β-羟基类固醇脱氢酶在2型糖尿病发病机制中的作用
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摘要
糖尿病的发病率呈逐年上升趋势,而其发病机制尚未彻底阐明。建立有效模型,深入探讨糖尿病的发病机制是当前糖尿病研究的基础。目前应用的糖尿病模型主要包括自发性糖尿病模型及诱导性糖尿病模型。由于环境因素(高脂饮食、高果糖饮食)在成人普通2型糖尿病发生过程中起到至关重要的作用,诱导性糖尿病大鼠模型更能够模拟2型糖尿病的发病病因及机制,且具有造价低廉,易于饲养的特点。诱导性2型糖尿病模型的建立方法多样,目前高脂饮食联合链脲佐菌素(streptozotocin, STZ)注射建立2型糖尿病模型已经应用于基础研究,但多重因素影响2型糖尿病动物模型的建立,且多存在成模率低、血糖稳定性差、胰岛素抵抗不明显等不足。因此,建立具有高成模率,血糖稳定,模拟2型糖尿病胰岛素抵抗及胰岛素分泌不足的临床病理特征的动物模型是糖尿病发病机制及药物治疗研究的重要基础。
1型11β-羟基类固醇脱氢酶(11β-HSD1)是目前胰岛素抵抗、肥胖、代谢紊乱综合征发病机制治疗靶点研究的热点。11β-HSD1对糖皮质激素进行组织特异性调节,使其由无活性的糖皮质激素转化为有活性的糖皮质激素,并通过糖皮质激素受体(GR)介导发挥其生物学效应。已有文献报道11β-HSD1在肝脏、网状脂肪组织中发生变化。而对于GR及11β-HSD1在胰岛素抵抗重要靶器官骨骼肌中的变化及其与骨骼肌胰岛素抵抗的关系还不是很清楚。
鉴于上述分析,本文进行了如下研究:
1.建立模拟2型糖尿病临床特征的实验性2型糖尿病大鼠模型,探讨高脂饮食喂养大鼠STZ注射的合理剂量及方法,观察不同剂量STZ(25mg/kg, 30mg/kg, 35mg/kg, 45mg/kg)一次注射诱导模型的成模率及高成模率组(45mg/kgSTZ注射组)的胰岛素敏感性,并对低剂量注射组(25mg/kg, 30mg/kg)实施2次STZ注射,以达到渐进性破坏胰岛细胞,合并有高脂饮食诱导的胰岛素抵抗,观察其成模率、血糖稳定性,并在成模后4周及8周时进行葡萄糖耐量及胰岛素耐量实验。进而考察高成模率组的血糖稳定性。结果表明高脂饮食联合小剂量两次腹腔注射STZ(30mg/kg)建立2型糖尿病模型具有胰岛素抵抗及胰岛素分泌不足并存的特征,并且通过这种方法建立的模型具有高成模率,血糖稳定的优点,为2型糖尿病的发病机制及治疗研究奠定基础。
2.探讨糖皮质激素代谢酶11β-HSD1及其受体在2型糖尿病大鼠骨骼肌的改变:通过HE染色及免疫组化观察胰岛的破坏程度及胰岛素分泌情况。用荧光测定法检测血清中皮质酮含量的改变,RT-PCR法检测11β-HSD1及GR的mRNA表达,Westernblot检测11β-HSD1、GR、胰岛素受体(IR-β)、蛋白激酶B(AKT)及葡萄糖转运子4(GLUT4)的蛋白表达。结果显示,模型组胰岛有轻度的破坏,胰岛素阳性面积占胰岛的比例较正常组明显降低,胰岛素阳性面积占胰腺的比例及胰岛形态因子在模型组有下降的趋势但是没有统计学差异。血清中皮质酮含量模型组与对照组没有统计学差异,11β-HSD1及GR的蛋白表达增加,胰岛素信号传导关键蛋白(IR-β, AKT, p-AKT, GLUT4)在接受胰岛素刺激后与刺激前没有差异,说明我们建立的2型糖尿病大鼠模型存在骨骼肌胰岛素信号传导障碍,表现为胰岛素抵抗,伴有11β-HSD1及GR的蛋白表达增加,为11β-HSD1抑制剂成为新型胰岛素增敏剂提供理论依据。
Now there has been a tragedy increase in diabetes across the world, paralleling the overweight and obesity epidemic. There are 95 percent of those people belonging to type 2 diabetes. Therefore, finding better treatments and novel prevention strategies for type 2 diabetes is a matter of great urgency. To accomplish this goal, appropriate experimental models are considered as essential tools for understanding the molecular basis, pathogenesis of the vascular and neural lesions, actions of therapeutic agents and genetic or environmental influences that increase the risks of type 2 diabetes.
Although there are numerous animal models (natural as well as developed) available for the study of type 2 diabetes, the pattern of disease establishment and progress in most of them did not appear to be similar to the clinical situation in humans. Thus, there is a continued quest among the investigators with respect to establishment of better animal model for type 2 diabetes either by adjusting the existing methods or/and by developing new methodologies or a combination of both.
Many studies have reported that the rats fed with high-fat diet (HFD) develop insulin resistance but not frank hyperglycemia or diabetes. Suggesting that the HFD might be a better way to initiate the insulin resistance which is one of the important features of type 2 diabetes. At the same time, Streptozotocin (STZ) is widely used to reproducibly induce both insulin-dependent and non- insulin-dependent diabetes mellitus presently by inducingβcell death through alkylation of DNA. Although high-dose STZ severely impairs insulin secretion mimicking type 1 DM, low dose STZ has been known to induce a mild impairment of insulin secretion which is similar to the feature of the later stage of type 2 diabetes. Therefore, investigators have started to develop a rat model by feeding the animal with high-fat diet following low-dose STZ that would closely mimic the natural history of the disease events (from insulin resistance toβcell dysfunction) as well as metabolic characteristics of human type 2 diabetes. The successful establishment of such a model would be cheaper, easily accessible and practical for the investigation as well as testing of various compounds for the treatment of type 2 diabetes. Although the appearance of the type 2 diabetes pattern was achieved by combining the feeding of HFD and low dose of STZ treatment in non-genetic, out-bred rats, the injection dose of STZ and its methodologies were not consistent in those studies. Others reported that STZ may also be given in multiple low doses. It has been extensively used in the development of type 1 diabetes in rats and mice to study immune response in pancreas, since the multiple low-dose injections of STZ could induce a gradual, autoimmune destruction ofβcells instead of the rapid destruction induced by single high dose injection. However, it has not been reported whether the high fat diet has synergistic effect on speedying the development of type 2 diabetes with multiple low doses STZ.
Glucocorticoid has been documented for a long time as a key regulator of salt and water metabolism, blood pressure, immune function and metabolism. Recent evidence suggests that the action of glucocorticoid is regulated by glucocorticoid receptors and 11β-Hydroxysteroid dehydrogenase (11β-HSD), both of which play key roles in the pathophysiology of type 2 diabetes and metabolic syndrome. At present, a great deal of research is focused on the management of local glucocorticoid action as a therapeutic strategy. It has been reported that the most classical actions of glucocorticoids were regulated principally via the activation of intracellular receptors (glucocorticoid receptor). The interaction of intracellular cortisol/corticosterone with glucocorticoid receptor is mainly mediated by 11β-HSD1, which offers a key advantage for regulating glucocorticoid action. It reduces glucocorticoid action selectively without influencing the central negative feedback. A substantial data have demonstrated that inhibition of 11β-HSD1 activity can increase insulin sensitivity without the consequences of changing the circulating glucocorticoid levels in liver and adipose tissues. Beneficial effects of inhibiting 11β-HSD1 in adipose tissue have been estimated from in vitro studies.
Skeletal muscle is an important target tissue for insulin stimulated glucose consumption. The molecular mechanisms of insulin-dependent glucose uptake in skeletal muscle have been broadly explored. Normally, circulating insulin binding to the insulin receptor (IR), phosphorylatesβ-subunit and causes insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, which binds to the p85 subunit of phosphatidyl inositol 3-kinase (PI3K). This in turn activates Akt, leading to glucose transporter-4 (GLUT-4) translocation. It has been proved that this insulin signaling pathway present abnormally in the skeletal muscle of obesity and diabetic patient. The change on the insulin signaling pathway related protein has been verified to be the key point in the pathogenesis of insulin resistance and diabetes. Therefore, it is really important to investigate theeffect of alteration of 11β-HSD1 in the skeletal muscle of type 2 diabetes.
Present study attempt to develop an ideal type 2 diabetes animal models, explore the optame dosage of STZ injection and method, observed the successful rate of diabetic model. Meanwhile the IPGTT and ITT were also performed, find the level of insulin resistance, and adjust the times of STZ injection. High fat diet combined once STZ injection with moderate low dose to induce diabetic and no damage on the pancreas. However, in the first section, we found that 45 mg/kg STZ is too much to induce type 2 diabetes. The 25, 30, 35 mg/kg are not enough to induce type 2 diabetes with lower diabetic successful rate, therefore we examined in the second section with multiple low dose STZ injection (25, 30 mg/kg, twice i.p.). In the second section, we found 25mg/kg twice ip has low successful rate, so we focus on the 30mg/kg twice injection group, the IPGTT and ITT have been carried out. Following this section, we continued the third section experiments. We use multiple low dose STZ injection to destroy the pancreaseβcell, combined with insulin resistance induced by high fat diet. Our study demonstrates that a combination of HFD and multiple low dose of STZ (30mg/kg, twice) injection could be effectively used to generate a rat model that mimics the natural history and metabolic characteristics of type 2 diabetes in humans. This method will successfully produce type 2 diabeteic rat models, as well as provide the enough number of diabetic rats once which will make the investigation more convincing. It was also useful in exploring the pathogensis of type 2 diabetes and evaluating the effect of therapeutic compounds on the treatment of type 2 diabetes.
The present study also observe the pancrease morphology, the corticosterone level in the blood, the alteration of 11β-HSD1 and GR in this type 2diabetic model in skeletal muscle, and study the abnormality of insulin signal transduction pathway related protein. RT-PCR was used to evaluate the mRNA level of 11β-HSD1 and GR,western blot was used to study the protein level of 11β-HSD1, GR, insulin receptor, AKT and GLUT4. Spectrofluorometric determination analysis examined the alteration of corticosterone level in the serum. We found that corticosterone level in the serum was no changed in the model and control group, the protein level of 11β-HSD1 and glucocorticoid receptor was significantly increased. The mRNA level of 11β-HSD1 was also elevated. The mRNA level of glucocorticoid receptor was decreased. After insulin stimulation, diabetic rats had no significant changes in the level of the insulin receptorβ-subunit (IR-β), AKT, as in phosphorylated AKT in the gastrocnemius muscle compared to its basal state. Similar results were observed in the protein expression level of glucose transporter 4 (GLUT4). Our data indicate that the alteration of 11β-HSD1 at protein and mRNA level may be related to the abnormality of insulin signal pathway in skeletal muscle.This effect may be mediated by glucocorticoid receptor.
Conclusively, based on the others’study, the present study develop a type 2 diabetes animal model by a combination of HFD and multiple low dose of STZ injection could be effectively used to generate a rat model that mimics the natural history and metabolic characteristics of type 2 diabetes in humans, which present high diabetic incidency, low expence and enough number of models can be developed at the same time.Meanwhile, the insulin signaling pathway related protein present abnormally in this model which indicate the decrease of insulin sensitivity, and the key enzyme of glucocorticoid(11β-HSD1) and glucocorticoid receptor were changed in the skeletal muscle as well. It may provide theory basis to produce 11β-HSD1 inhibitory drugs interfering with the pathogenesis of type 2 diabetes.
1型11β-羟基类固醇脱氢酶(11β-HSD1)是目前胰岛素抵抗、肥胖、代谢紊乱综合征发病机制治疗靶点研究的热点。11β-HSD1对糖皮质激素进行组织特异性调节,使其由无活性的糖皮质激素转化为有活性的糖皮质激素,并通过糖皮质激素受体(GR)介导发挥其生物学效应。已有文献报道11β-HSD1在肝脏、网状脂肪组织中发生变化。而对于GR及11β-HSD1在胰岛素抵抗重要靶器官骨骼肌中的变化及其与骨骼肌胰岛素抵抗的关系还不是很清楚。
鉴于上述分析,本文进行了如下研究:
1.建立模拟2型糖尿病临床特征的实验性2型糖尿病大鼠模型,探讨高脂饮食喂养大鼠STZ注射的合理剂量及方法,观察不同剂量STZ(25mg/kg, 30mg/kg, 35mg/kg, 45mg/kg)一次注射诱导模型的成模率及高成模率组(45mg/kgSTZ注射组)的胰岛素敏感性,并对低剂量注射组(25mg/kg, 30mg/kg)实施2次STZ注射,以达到渐进性破坏胰岛细胞,合并有高脂饮食诱导的胰岛素抵抗,观察其成模率、血糖稳定性,并在成模后4周及8周时进行葡萄糖耐量及胰岛素耐量实验。进而考察高成模率组的血糖稳定性。结果表明高脂饮食联合小剂量两次腹腔注射STZ(30mg/kg)建立2型糖尿病模型具有胰岛素抵抗及胰岛素分泌不足并存的特征,并且通过这种方法建立的模型具有高成模率,血糖稳定的优点,为2型糖尿病的发病机制及治疗研究奠定基础。
2.探讨糖皮质激素代谢酶11β-HSD1及其受体在2型糖尿病大鼠骨骼肌的改变:通过HE染色及免疫组化观察胰岛的破坏程度及胰岛素分泌情况。用荧光测定法检测血清中皮质酮含量的改变,RT-PCR法检测11β-HSD1及GR的mRNA表达,Westernblot检测11β-HSD1、GR、胰岛素受体(IR-β)、蛋白激酶B(AKT)及葡萄糖转运子4(GLUT4)的蛋白表达。结果显示,模型组胰岛有轻度的破坏,胰岛素阳性面积占胰岛的比例较正常组明显降低,胰岛素阳性面积占胰腺的比例及胰岛形态因子在模型组有下降的趋势但是没有统计学差异。血清中皮质酮含量模型组与对照组没有统计学差异,11β-HSD1及GR的蛋白表达增加,胰岛素信号传导关键蛋白(IR-β, AKT, p-AKT, GLUT4)在接受胰岛素刺激后与刺激前没有差异,说明我们建立的2型糖尿病大鼠模型存在骨骼肌胰岛素信号传导障碍,表现为胰岛素抵抗,伴有11β-HSD1及GR的蛋白表达增加,为11β-HSD1抑制剂成为新型胰岛素增敏剂提供理论依据。
Now there has been a tragedy increase in diabetes across the world, paralleling the overweight and obesity epidemic. There are 95 percent of those people belonging to type 2 diabetes. Therefore, finding better treatments and novel prevention strategies for type 2 diabetes is a matter of great urgency. To accomplish this goal, appropriate experimental models are considered as essential tools for understanding the molecular basis, pathogenesis of the vascular and neural lesions, actions of therapeutic agents and genetic or environmental influences that increase the risks of type 2 diabetes.
Although there are numerous animal models (natural as well as developed) available for the study of type 2 diabetes, the pattern of disease establishment and progress in most of them did not appear to be similar to the clinical situation in humans. Thus, there is a continued quest among the investigators with respect to establishment of better animal model for type 2 diabetes either by adjusting the existing methods or/and by developing new methodologies or a combination of both.
Many studies have reported that the rats fed with high-fat diet (HFD) develop insulin resistance but not frank hyperglycemia or diabetes. Suggesting that the HFD might be a better way to initiate the insulin resistance which is one of the important features of type 2 diabetes. At the same time, Streptozotocin (STZ) is widely used to reproducibly induce both insulin-dependent and non- insulin-dependent diabetes mellitus presently by inducingβcell death through alkylation of DNA. Although high-dose STZ severely impairs insulin secretion mimicking type 1 DM, low dose STZ has been known to induce a mild impairment of insulin secretion which is similar to the feature of the later stage of type 2 diabetes. Therefore, investigators have started to develop a rat model by feeding the animal with high-fat diet following low-dose STZ that would closely mimic the natural history of the disease events (from insulin resistance toβcell dysfunction) as well as metabolic characteristics of human type 2 diabetes. The successful establishment of such a model would be cheaper, easily accessible and practical for the investigation as well as testing of various compounds for the treatment of type 2 diabetes. Although the appearance of the type 2 diabetes pattern was achieved by combining the feeding of HFD and low dose of STZ treatment in non-genetic, out-bred rats, the injection dose of STZ and its methodologies were not consistent in those studies. Others reported that STZ may also be given in multiple low doses. It has been extensively used in the development of type 1 diabetes in rats and mice to study immune response in pancreas, since the multiple low-dose injections of STZ could induce a gradual, autoimmune destruction ofβcells instead of the rapid destruction induced by single high dose injection. However, it has not been reported whether the high fat diet has synergistic effect on speedying the development of type 2 diabetes with multiple low doses STZ.
Glucocorticoid has been documented for a long time as a key regulator of salt and water metabolism, blood pressure, immune function and metabolism. Recent evidence suggests that the action of glucocorticoid is regulated by glucocorticoid receptors and 11β-Hydroxysteroid dehydrogenase (11β-HSD), both of which play key roles in the pathophysiology of type 2 diabetes and metabolic syndrome. At present, a great deal of research is focused on the management of local glucocorticoid action as a therapeutic strategy. It has been reported that the most classical actions of glucocorticoids were regulated principally via the activation of intracellular receptors (glucocorticoid receptor). The interaction of intracellular cortisol/corticosterone with glucocorticoid receptor is mainly mediated by 11β-HSD1, which offers a key advantage for regulating glucocorticoid action. It reduces glucocorticoid action selectively without influencing the central negative feedback. A substantial data have demonstrated that inhibition of 11β-HSD1 activity can increase insulin sensitivity without the consequences of changing the circulating glucocorticoid levels in liver and adipose tissues. Beneficial effects of inhibiting 11β-HSD1 in adipose tissue have been estimated from in vitro studies.
Skeletal muscle is an important target tissue for insulin stimulated glucose consumption. The molecular mechanisms of insulin-dependent glucose uptake in skeletal muscle have been broadly explored. Normally, circulating insulin binding to the insulin receptor (IR), phosphorylatesβ-subunit and causes insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, which binds to the p85 subunit of phosphatidyl inositol 3-kinase (PI3K). This in turn activates Akt, leading to glucose transporter-4 (GLUT-4) translocation. It has been proved that this insulin signaling pathway present abnormally in the skeletal muscle of obesity and diabetic patient. The change on the insulin signaling pathway related protein has been verified to be the key point in the pathogenesis of insulin resistance and diabetes. Therefore, it is really important to investigate theeffect of alteration of 11β-HSD1 in the skeletal muscle of type 2 diabetes.
Present study attempt to develop an ideal type 2 diabetes animal models, explore the optame dosage of STZ injection and method, observed the successful rate of diabetic model. Meanwhile the IPGTT and ITT were also performed, find the level of insulin resistance, and adjust the times of STZ injection. High fat diet combined once STZ injection with moderate low dose to induce diabetic and no damage on the pancreas. However, in the first section, we found that 45 mg/kg STZ is too much to induce type 2 diabetes. The 25, 30, 35 mg/kg are not enough to induce type 2 diabetes with lower diabetic successful rate, therefore we examined in the second section with multiple low dose STZ injection (25, 30 mg/kg, twice i.p.). In the second section, we found 25mg/kg twice ip has low successful rate, so we focus on the 30mg/kg twice injection group, the IPGTT and ITT have been carried out. Following this section, we continued the third section experiments. We use multiple low dose STZ injection to destroy the pancreaseβcell, combined with insulin resistance induced by high fat diet. Our study demonstrates that a combination of HFD and multiple low dose of STZ (30mg/kg, twice) injection could be effectively used to generate a rat model that mimics the natural history and metabolic characteristics of type 2 diabetes in humans. This method will successfully produce type 2 diabeteic rat models, as well as provide the enough number of diabetic rats once which will make the investigation more convincing. It was also useful in exploring the pathogensis of type 2 diabetes and evaluating the effect of therapeutic compounds on the treatment of type 2 diabetes.
The present study also observe the pancrease morphology, the corticosterone level in the blood, the alteration of 11β-HSD1 and GR in this type 2diabetic model in skeletal muscle, and study the abnormality of insulin signal transduction pathway related protein. RT-PCR was used to evaluate the mRNA level of 11β-HSD1 and GR,western blot was used to study the protein level of 11β-HSD1, GR, insulin receptor, AKT and GLUT4. Spectrofluorometric determination analysis examined the alteration of corticosterone level in the serum. We found that corticosterone level in the serum was no changed in the model and control group, the protein level of 11β-HSD1 and glucocorticoid receptor was significantly increased. The mRNA level of 11β-HSD1 was also elevated. The mRNA level of glucocorticoid receptor was decreased. After insulin stimulation, diabetic rats had no significant changes in the level of the insulin receptorβ-subunit (IR-β), AKT, as in phosphorylated AKT in the gastrocnemius muscle compared to its basal state. Similar results were observed in the protein expression level of glucose transporter 4 (GLUT4). Our data indicate that the alteration of 11β-HSD1 at protein and mRNA level may be related to the abnormality of insulin signal pathway in skeletal muscle.This effect may be mediated by glucocorticoid receptor.
Conclusively, based on the others’study, the present study develop a type 2 diabetes animal model by a combination of HFD and multiple low dose of STZ injection could be effectively used to generate a rat model that mimics the natural history and metabolic characteristics of type 2 diabetes in humans, which present high diabetic incidency, low expence and enough number of models can be developed at the same time.Meanwhile, the insulin signaling pathway related protein present abnormally in this model which indicate the decrease of insulin sensitivity, and the key enzyme of glucocorticoid(11β-HSD1) and glucocorticoid receptor were changed in the skeletal muscle as well. It may provide theory basis to produce 11β-HSD1 inhibitory drugs interfering with the pathogenesis of type 2 diabetes.
引文
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