胞外5’-AMP信号与2型糖尿病的发病机制
摘要
2型糖尿病是一种严重威胁人类健康的慢性疾病,其患者数量迅速增加且发病年龄有日益年轻化的趋势,已经成为全世界共同面临的主要公共健康问题之一。高脂饮食和肥胖被认为是诱发胰岛素抵抗及2型糖尿病的最重要因素。目前公认的2型糖尿病发病机制是增多的脂肪细胞释放出高浓度的游离脂肪酸(FFA),使血浆中的FFA水平异常升高,从而导致胰岛素抵抗的发生。但是FFA引起胰岛素抵抗的具体机制到目前为止还未完全阐明。因此深入探索FFA诱导胰岛素抵抗的作用机制从而寻找相应的靶点对于预防和治疗胰岛素抵抗和2型糖尿病有着重要的意义。
本研究首先发现在2型糖尿病小鼠模型和2型糖尿病病人中,血浆5'-AMP (pAMP)水平异常升高,形成一个新的特定的2型糖尿病特征。用HPLC方法检测了两种不同2型糖尿病小鼠模型的血浆核苷酸和2型糖尿病病人的血浆核苷酸。自发性2型糖尿病小鼠模型——db/db小鼠的pAMP和血浆尿酸(UA)水平明显上升；在高脂食物喂养建立的诱导性2型糖尿病小鼠模型中,其pAMP和血浆UA水平也明显上升；在2型糖尿病病人中,其pAMP水平也异常上升。通过在正常小鼠中强化5'-AMP信号,发现5'-AMP是升高血糖和产生胰岛素抵抗的重要信号分子。葡萄糖耐受性实验和胰岛素耐受性实验显示5’-AMP可以降低正常小鼠的葡萄糖耐受性和胰岛素敏感性,使正常小鼠产生胰岛素抵抗；丙酮酸耐受性实验显示5’-AMP可以升高丙酮酸作为底物的糖异生；并且5'-AMP可以诱导正常小鼠产生高胰岛素和降低其氧代谢水平,这些症状与2型糖尿病小鼠所呈现的相关症状相一致。
进一步研究发现,高浓度FFA诱发的血管内皮细胞的损伤和凋亡是胞外5'-AMP水平升高的原因。体外实验显示FFA可以诱导人脐静脉血管内皮细胞(HUVECs)的损伤和凋亡,从而增加胞外5’-AMP水平；体内实验显示对小鼠施行手术损伤也可以使得胞外的5'-AMP水平增加同时血糖水平也增加。这些数据表明细胞损伤可以导致胞内5'-AMP的释放,从而升高胞外5'-AMP水平,加强5’-AMP信号强度。腺苷受体基因敲除的小鼠实验证明pAMP升高血糖的作用是通过升高胞内腺苷的浓度来实现的。在四种腺苷受体基因敲除的小鼠(A1-/-,A2a-/-,A2b-/-,A3-/-)中,5'-AMP诱导的血糖变化与野生型小鼠基本一致,这说明5'-AMP信号并不是通过腺苷受体起作用的。在给小鼠注射5'-AMP后1h,HPLC数据显示胞内的腺苷含量明显上升,使得S-腺苷-L-蛋氨酸(AdoMet)与S-腺苷高半胱氨酸(AdoHcy)的比例降低,进一步减少了叉头蛋白家族1(Foxo1)、葡萄糖-6-磷酸酶(G6Pase)和磷酸烯醇式丙酮酸羧激酶(PEPCK)基因启动子区域的组蛋白H3K9二甲基化(Me2-H3K9)水平,导致Foxo1、G6Pase和PEPCK基因表达的增加,从而使血糖含量上升。而在5'-AMP作用前期(15min时),荧光定量PCR结果显示G6Pase基因表达没有变化,但是检测到了G6Pase酶活的增加,HPLC数据显示胞内腺苷的含量明显上升。通过体外实验证明腺苷可以直接升高G6Pase的酶活,因此5'-AMP信号作用前期是通过升高胞内的腺苷含量而直接增加G6Pase酶活来使血糖含量增加。同时,5'-AMP信号可以使骨骼肌中的GLUT4基因表达减少,免疫荧光数据显示5'-AMP信号也可能使GLUT4蛋白易位减少,从而减少了小鼠体内葡萄糖的利用。综上所述,血浆中升高的5'-AMP导致了小鼠高血糖症状的发生。
5'-AMP诱导产生的高血糖可以通过2型糖尿病治疗药物二甲双胍来降低,证明二甲双胍是通过降低胞内腺苷的浓度这一新的药物作用机制来起作用的。HPLC数据显示二甲双胍降低了5'-AMP信号诱导升高的胞内腺苷浓度,而降低Foxo1、G6Pase和PEPCK的基因表达,从而干预5'-AMP信号诱导的小鼠高血糖作用。这为二甲双胍的作用初步提出了一个新的潜在的机制。接着发现,合并索拉胶喂养可以减弱单纯高脂喂养引起的胞外5'-AMP信号的增强,证实索拉胶是通过影响脂肪的吸收,降低血浆中FFA的浓度,从而减少细胞的损伤和凋亡来起作用的。索拉胶是本实验室制得的一种新型葡聚糖,体内实验表明,给小鼠喂养高脂食物建立小鼠肥胖模型,结果显示合并索拉胶喂养显著改善了高脂食物喂养引起的一系列生理特征(如小鼠体重、体脂的增加,肝脏和脂肪组织重量的增加,血脂和肝脂的增加)以及葡萄糖耐受性的降低,并且索拉胶的改善作用呈现剂量依赖性。HPLC数据显示,索拉胶干预了高脂食物喂养引起的血浆UA水平的增加。索拉胶合并高脂喂养组小鼠粪便中的总甘油三酯含量明显上升,乳化实验显示索拉胶可以影响胆汁对脂肪的乳化作用,使乳化颗粒的直径变大。这些数据显示索拉胶通过抑制脂肪的乳化而减少脂肪的吸收,从而抑制了脂肪在小鼠体内的累积,减少了FFA诱导的细胞损伤,表现为减少了血浆中UA的水平。新型葡聚糖索拉胶的这一功能为预防高脂饮食诱发的2型糖尿病提供了一个潜在的手段。
Type2diabetes is one of the most common chronic diseases affecting people and the prevalence of diabetes increases with age. The number of diabetes cases has increased dramatically in recent decades, and type2diabetes has become one of the world's top health problems. High-fat diet and obesity play an important role in leading to insulin resistance and type2diabetes. The most widely accepted pathogenesis of type2diabetes is that expanded fat mass releases high amount of free fatty acids (FFA), abnormal elevating of plasma FFA levels, can produce insulin resistance. However, precise mechanism by which FFA cause insulin resistance has not yet been fully elucidated. Exploring mechanisms underlying FFA-induced insulin resistance in order to find a therapeutic target is very important in prevention and treatment of insulin resistance and type2diabetes.
First, abnormally elevated levels of plasma5'-AMP (pAMP) were found in mouse models of type2diabetes and in patients with type2diabetes, forming a new and specific characteristic of type2diabetes. HPLC analysis were performed to investigate the plasma nucleotides in two different mouse models of type2diabetes and in patients with type2diabetes. The results demonstrated that pAMP and UA levels were elevated in spontaneous diabetic db/db mice; In high-fat diet-induced type2diabetic mice, the levels of pAMP and plasma UA were elevated; and the pAMP level was also increased in patients with type2diabetes. Through strengthen the5'-AMP signals in normal mice, we found that5'-AMP is an important signaling molecule that elevated blood sugar and cause insulin resistance. Glucose tolerance test and insulin tolerance test indicated that5'-AMP treatment reduced glucose tolerance and insulin sensitivity in normal mice, and induced insulin resistance; pyruvate tolerance test showed that5'-AMP increased pyruvate-induced gluconeogenesis; and5'-AMP treatment caused hyperinsulimia and lowered oxygen consumption in normal mice. All these phenotypes are similar to diabetic phenotypes in diabetic mice.
We further found that vein endothelial cells injury and apoptosis induced by high levels of FFA contributed to the increase in pAMP. In vitro, FFA induced damage and apoptosis in human umbilical vein endothelial cells (HUVECs) and contributed to an increase in pAMP. In vivo, surgery-induced injury increased pAMP level and also blood glucose level in mice. Our data indicated that cell injury caused the release of intracellular5'-AMP and increased the extracellular5'-AMP level. Studies on adenosine receptor knockout mice show that pAMP-induced hyperglycemia was achieved by increasing the concentration of intracellular adenosine.5'-AMP elevated blood glucose in mice deficient in adenosine receptors (A1-/-, A2a-/-, A2b-/-, A3-/-) with equal efficiency as wild-type mice. The findings suggested that5'-AMP-induced hyperglycemia was not directly related to adenosine receptor pathways. At1h after5'-AMP injection, HPLC analysis demonstrated that the function of5'-AMP was initiated by the elevation of cellular adenosine levels. It was followed by the decreased dimethylation of histone H3K9related Foxol, G6Pase and PEPCK promoter through declining ratio of S-adenosylmethionine (AdoMet) to S-adenosylhomocysteine (AdoHcy), resulting in high blood glucose levels. At the early stage (15min) of5'-AMP injection, our results demonstrated that5'-AMP treatment dramatically increased G6Pase activity but had no effect on G6Pase mRNA abundance. And HPLC data indicated that adenosine levels increased after5'-AMP treatment. Our in vitro experiments showed that adenosine directly increased the activity of G6Pase. Our results revealed that the function of pAMP was initiated by the elevation of cellular adenosine levels, directly stimulating G6Pase enzyme activity. On the other side,5'-AMP treatment decreased the expression of GLUT4and attenuated insulin-dependent GLUT4translocation in skeletal muscle, resulting in decreased glucose utilization. Collectively, mice treated with5'-AMP displayed a rapid and steep increase in blood glucose.
Metformin improved5'-AMP-induced hyperglycemia by a new mechanism of reducing5'-AMP-induced increase in adenosine content. HPLC data showed that metformin reduced5'-AMP-induced increase in adenosine content, and QRT-PCR analysis showed that mRNA levels of Foxol, G6Pase and PEPCK were significantly decreased in5'-AMP-treated mice, resulting in lower blood glucose level. These results suggested a new potential mechanism for metformin action. By reducing fat absorption and plasma FFA level, Salecan reduced cell injury and apoptosis to weaken high-fat diet-enhanced extracellular5'-AMP signals. Salecan is a novel glucan that isolated by our group recently. Using a high-fat diet-induced obese mouse model, we found that Salecan dose-dependent improved high-fat diet-induced increases in body weight, body fat, liver and adipose weight, lipid profiles of plasma and liver, and a decrease in glucose tolerance. HPLC analysis showed that Salecan reduced high-fat diet-induced increase in plasma UA level in mice. Dietary Salecan intake caused an obvious elevation of fat in feces. Presence of Salecan disturbed bile acid-promoted emulsification and reduced the size of emulsion droplets in vitro. These results indicated that Salecan decreases fat absorption by disturbing bile acid-promoted emulsification of fat and reduced fat accumulation in mice, resulting in a decrease in FFA-induced cell injury and plasma UA level. These findings suggested that Salecan qualify to be useful for treating high fat-induced obesity, indicating a potential application in treating high-fat diet-induced type2diabetes.
本研究首先发现在2型糖尿病小鼠模型和2型糖尿病病人中,血浆5'-AMP (pAMP)水平异常升高,形成一个新的特定的2型糖尿病特征。用HPLC方法检测了两种不同2型糖尿病小鼠模型的血浆核苷酸和2型糖尿病病人的血浆核苷酸。自发性2型糖尿病小鼠模型——db/db小鼠的pAMP和血浆尿酸(UA)水平明显上升；在高脂食物喂养建立的诱导性2型糖尿病小鼠模型中,其pAMP和血浆UA水平也明显上升；在2型糖尿病病人中,其pAMP水平也异常上升。通过在正常小鼠中强化5'-AMP信号,发现5'-AMP是升高血糖和产生胰岛素抵抗的重要信号分子。葡萄糖耐受性实验和胰岛素耐受性实验显示5’-AMP可以降低正常小鼠的葡萄糖耐受性和胰岛素敏感性,使正常小鼠产生胰岛素抵抗；丙酮酸耐受性实验显示5’-AMP可以升高丙酮酸作为底物的糖异生；并且5'-AMP可以诱导正常小鼠产生高胰岛素和降低其氧代谢水平,这些症状与2型糖尿病小鼠所呈现的相关症状相一致。
进一步研究发现,高浓度FFA诱发的血管内皮细胞的损伤和凋亡是胞外5'-AMP水平升高的原因。体外实验显示FFA可以诱导人脐静脉血管内皮细胞(HUVECs)的损伤和凋亡,从而增加胞外5’-AMP水平；体内实验显示对小鼠施行手术损伤也可以使得胞外的5'-AMP水平增加同时血糖水平也增加。这些数据表明细胞损伤可以导致胞内5'-AMP的释放,从而升高胞外5'-AMP水平,加强5’-AMP信号强度。腺苷受体基因敲除的小鼠实验证明pAMP升高血糖的作用是通过升高胞内腺苷的浓度来实现的。在四种腺苷受体基因敲除的小鼠(A1-/-,A2a-/-,A2b-/-,A3-/-)中,5'-AMP诱导的血糖变化与野生型小鼠基本一致,这说明5'-AMP信号并不是通过腺苷受体起作用的。在给小鼠注射5'-AMP后1h,HPLC数据显示胞内的腺苷含量明显上升,使得S-腺苷-L-蛋氨酸(AdoMet)与S-腺苷高半胱氨酸(AdoHcy)的比例降低,进一步减少了叉头蛋白家族1(Foxo1)、葡萄糖-6-磷酸酶(G6Pase)和磷酸烯醇式丙酮酸羧激酶(PEPCK)基因启动子区域的组蛋白H3K9二甲基化(Me2-H3K9)水平,导致Foxo1、G6Pase和PEPCK基因表达的增加,从而使血糖含量上升。而在5'-AMP作用前期(15min时),荧光定量PCR结果显示G6Pase基因表达没有变化,但是检测到了G6Pase酶活的增加,HPLC数据显示胞内腺苷的含量明显上升。通过体外实验证明腺苷可以直接升高G6Pase的酶活,因此5'-AMP信号作用前期是通过升高胞内的腺苷含量而直接增加G6Pase酶活来使血糖含量增加。同时,5'-AMP信号可以使骨骼肌中的GLUT4基因表达减少,免疫荧光数据显示5'-AMP信号也可能使GLUT4蛋白易位减少,从而减少了小鼠体内葡萄糖的利用。综上所述,血浆中升高的5'-AMP导致了小鼠高血糖症状的发生。
5'-AMP诱导产生的高血糖可以通过2型糖尿病治疗药物二甲双胍来降低,证明二甲双胍是通过降低胞内腺苷的浓度这一新的药物作用机制来起作用的。HPLC数据显示二甲双胍降低了5'-AMP信号诱导升高的胞内腺苷浓度,而降低Foxo1、G6Pase和PEPCK的基因表达,从而干预5'-AMP信号诱导的小鼠高血糖作用。这为二甲双胍的作用初步提出了一个新的潜在的机制。接着发现,合并索拉胶喂养可以减弱单纯高脂喂养引起的胞外5'-AMP信号的增强,证实索拉胶是通过影响脂肪的吸收,降低血浆中FFA的浓度,从而减少细胞的损伤和凋亡来起作用的。索拉胶是本实验室制得的一种新型葡聚糖,体内实验表明,给小鼠喂养高脂食物建立小鼠肥胖模型,结果显示合并索拉胶喂养显著改善了高脂食物喂养引起的一系列生理特征(如小鼠体重、体脂的增加,肝脏和脂肪组织重量的增加,血脂和肝脂的增加)以及葡萄糖耐受性的降低,并且索拉胶的改善作用呈现剂量依赖性。HPLC数据显示,索拉胶干预了高脂食物喂养引起的血浆UA水平的增加。索拉胶合并高脂喂养组小鼠粪便中的总甘油三酯含量明显上升,乳化实验显示索拉胶可以影响胆汁对脂肪的乳化作用,使乳化颗粒的直径变大。这些数据显示索拉胶通过抑制脂肪的乳化而减少脂肪的吸收,从而抑制了脂肪在小鼠体内的累积,减少了FFA诱导的细胞损伤,表现为减少了血浆中UA的水平。新型葡聚糖索拉胶的这一功能为预防高脂饮食诱发的2型糖尿病提供了一个潜在的手段。
Type2diabetes is one of the most common chronic diseases affecting people and the prevalence of diabetes increases with age. The number of diabetes cases has increased dramatically in recent decades, and type2diabetes has become one of the world's top health problems. High-fat diet and obesity play an important role in leading to insulin resistance and type2diabetes. The most widely accepted pathogenesis of type2diabetes is that expanded fat mass releases high amount of free fatty acids (FFA), abnormal elevating of plasma FFA levels, can produce insulin resistance. However, precise mechanism by which FFA cause insulin resistance has not yet been fully elucidated. Exploring mechanisms underlying FFA-induced insulin resistance in order to find a therapeutic target is very important in prevention and treatment of insulin resistance and type2diabetes.
First, abnormally elevated levels of plasma5'-AMP (pAMP) were found in mouse models of type2diabetes and in patients with type2diabetes, forming a new and specific characteristic of type2diabetes. HPLC analysis were performed to investigate the plasma nucleotides in two different mouse models of type2diabetes and in patients with type2diabetes. The results demonstrated that pAMP and UA levels were elevated in spontaneous diabetic db/db mice; In high-fat diet-induced type2diabetic mice, the levels of pAMP and plasma UA were elevated; and the pAMP level was also increased in patients with type2diabetes. Through strengthen the5'-AMP signals in normal mice, we found that5'-AMP is an important signaling molecule that elevated blood sugar and cause insulin resistance. Glucose tolerance test and insulin tolerance test indicated that5'-AMP treatment reduced glucose tolerance and insulin sensitivity in normal mice, and induced insulin resistance; pyruvate tolerance test showed that5'-AMP increased pyruvate-induced gluconeogenesis; and5'-AMP treatment caused hyperinsulimia and lowered oxygen consumption in normal mice. All these phenotypes are similar to diabetic phenotypes in diabetic mice.
We further found that vein endothelial cells injury and apoptosis induced by high levels of FFA contributed to the increase in pAMP. In vitro, FFA induced damage and apoptosis in human umbilical vein endothelial cells (HUVECs) and contributed to an increase in pAMP. In vivo, surgery-induced injury increased pAMP level and also blood glucose level in mice. Our data indicated that cell injury caused the release of intracellular5'-AMP and increased the extracellular5'-AMP level. Studies on adenosine receptor knockout mice show that pAMP-induced hyperglycemia was achieved by increasing the concentration of intracellular adenosine.5'-AMP elevated blood glucose in mice deficient in adenosine receptors (A1-/-, A2a-/-, A2b-/-, A3-/-) with equal efficiency as wild-type mice. The findings suggested that5'-AMP-induced hyperglycemia was not directly related to adenosine receptor pathways. At1h after5'-AMP injection, HPLC analysis demonstrated that the function of5'-AMP was initiated by the elevation of cellular adenosine levels. It was followed by the decreased dimethylation of histone H3K9related Foxol, G6Pase and PEPCK promoter through declining ratio of S-adenosylmethionine (AdoMet) to S-adenosylhomocysteine (AdoHcy), resulting in high blood glucose levels. At the early stage (15min) of5'-AMP injection, our results demonstrated that5'-AMP treatment dramatically increased G6Pase activity but had no effect on G6Pase mRNA abundance. And HPLC data indicated that adenosine levels increased after5'-AMP treatment. Our in vitro experiments showed that adenosine directly increased the activity of G6Pase. Our results revealed that the function of pAMP was initiated by the elevation of cellular adenosine levels, directly stimulating G6Pase enzyme activity. On the other side,5'-AMP treatment decreased the expression of GLUT4and attenuated insulin-dependent GLUT4translocation in skeletal muscle, resulting in decreased glucose utilization. Collectively, mice treated with5'-AMP displayed a rapid and steep increase in blood glucose.
Metformin improved5'-AMP-induced hyperglycemia by a new mechanism of reducing5'-AMP-induced increase in adenosine content. HPLC data showed that metformin reduced5'-AMP-induced increase in adenosine content, and QRT-PCR analysis showed that mRNA levels of Foxol, G6Pase and PEPCK were significantly decreased in5'-AMP-treated mice, resulting in lower blood glucose level. These results suggested a new potential mechanism for metformin action. By reducing fat absorption and plasma FFA level, Salecan reduced cell injury and apoptosis to weaken high-fat diet-enhanced extracellular5'-AMP signals. Salecan is a novel glucan that isolated by our group recently. Using a high-fat diet-induced obese mouse model, we found that Salecan dose-dependent improved high-fat diet-induced increases in body weight, body fat, liver and adipose weight, lipid profiles of plasma and liver, and a decrease in glucose tolerance. HPLC analysis showed that Salecan reduced high-fat diet-induced increase in plasma UA level in mice. Dietary Salecan intake caused an obvious elevation of fat in feces. Presence of Salecan disturbed bile acid-promoted emulsification and reduced the size of emulsion droplets in vitro. These results indicated that Salecan decreases fat absorption by disturbing bile acid-promoted emulsification of fat and reduced fat accumulation in mice, resulting in a decrease in FFA-induced cell injury and plasma UA level. These findings suggested that Salecan qualify to be useful for treating high fat-induced obesity, indicating a potential application in treating high-fat diet-induced type2diabetes.
引文
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