新的糖尿病治疗靶点：肝脏中生产糖的开关
2012-04-11 17:02:53 来源：
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科学每日（2012年4月8日）——在研究人员解密人类代谢机制的非凡探索中，索尔克生物研究所的研究员们发现调节肝脏生成葡萄糖的一对分子——正是这种简单的糖成为人类细胞能量的来源，也是糖尿病致病的中心环节。
在4月8日发表在《科学》上的一篇文章提到，科学家们称控制这两个分子的活性——他们共同作用来控制葡萄糖生成量——可能提供一种新方法降低血糖以治疗胰岛素抵抗的二型糖尿病。他们通过实验在糖尿病小鼠身上证实了这个方法的可行性。
“如果你控制这些开关，你将能控制葡萄糖的生成，而这正是二型糖尿病问题的中心环节。”索尔克克莱顿基金肽生物学实验室负责人教授马斯·蒙特米尼说。
新药的需求逐渐增加，蒙特米尼教授说，将近2600万美国人有二型糖尿病，而且预计有7900万人有发展为糖尿病的危险。糖尿病是美国第六大死亡原因，治疗费用预计在1160亿元每年。
为了研究糖尿病治疗新方法，研究人员需要理解人类代谢背后复杂精妙的生物学机制，以及疾病发展中这种精细协调的系统失衡，蒙特米尼说。
白天，人体燃烧从食物中获取的葡萄糖。这提供给给肌肉和身体其他部位燃料以补充能量损耗。在晚间，当我们睡觉时，我们恢复为存储脂肪作为一种非常可靠且缓慢释放的能量。但人体一些特殊部分，特别是心脏，将葡萄糖作为一种能量来源，甚至我们饥饿时也如此。
胰岛细胞控制着能量增减的两方面。他们位于胰腺，当饥饿时分泌胰高血糖素，告诉肝脏制造葡萄糖供大脑使用。当我们进食时，这个过程变为胰岛细胞分泌胰岛素告诉肝脏停止制造葡萄糖。
因此胰高血糖素和胰岛素是为控制血糖在一个稳定水平而设计的反馈体系
蒙特米尼的实验室多年来致力于研究调控肝脏葡萄糖生成以及胰腺中控制葡萄糖敏感性和胰岛素产生的那些核心开关。他主要的发现之一，胰高血糖素——饥饿激素——打开一个基因开关（CRTC2），增高血液中葡萄糖的产生。反过来，当血中胰岛素升高，CRTC2活性抑制，肝脏生成葡萄糖量就减少。
“但在胰岛素抵抗的二型糖尿病中，因为胰岛素信号没有通过，因此CRTC2开关开得过大，”蒙特米尼说。“结果是肝脏产生过多葡萄糖，造成血糖水平过高。约10到20年后，葡萄糖的不正常升高导致心脏疾病、眼盲以及肾衰等慢性并发症。”
《自然》杂志的一些新发现识别出了一个传递系统，该传到系统能够解释胰高血糖素在饥饿时如何激活CRTC2开关，以及在糖尿病中该系统如何失效。
科学家们说这个传递系统包括一个存在肝细胞外的分子受体（IP3），被他们称为“龙头分子”。胰高血糖素在人饥饿时开启IP3龙头分子，使钙这一细胞中共同的信号分子浓度升高。它刺激众多不同气体分子踏板，也被称为钙调磷酸酶中的一种，使得CRTC2调高，活化的CRTC2使肝脏产生更多葡萄糖维持代谢。
这很重要，蒙特米尼说，因为这个团队也发现，肝脏中IP3受体和钙调磷酸酶的活化在胰岛素抵抗糖尿病中升高，导致了血糖的上升。
因此，这些发现提示那些能够选择性下调IP3龙头和钙调磷酸酶加速器的药品制剂可能会帮助关闭CRTC2开关，降低二型糖尿病人的血糖，他说。研究人员在肝细胞中应用这些复合物，这个过程确实精确地发生了。
“要在人体中验证这种机制是否能够运作，我们显然还有很多工作要做，”他说。
研究队伍包括索尔克机构、哥伦比亚大学、圣地亚哥加州大学和渥太华大学的研究员。除了蒙特米尼，合著者还包括Yiguo Wang, Gang Li, Jason Goode, Jose Paz, Kunfu Ouyang, Robert Screaton, Wolfgang Fischer, Ju Chen和Ira Tabas.
该项研究由国家卫生院，基克希弗基金，克莱顿医学研究基金以及利昂娜.M和哈利.B赫尔姆斯利公益信托赞助.
ScienceDaily (Apr. 8, 2012) — In their extraordinary quest to decode human metabolism, researchers at the Salk Institute for Biological Studies have discovered a pair of molecules that regulates the liver's production of glucose -- -- the simple sugar that is the source of energy in human cells and the central player in diabetes.
In a paper published April 8 in Nature, the scientists say that controlling the activity of these two molecules -- -- which work together to allow more or less glucose production -- -- could potentially offer a new way to lower blood sugar to treat insulin-resistant type II diabetes. They showed, through an experimental technique, that this was possible in diabetic mice.
"If you control these switches, you can control the production of glucose, which is really at the heart of the problem of type 2 diabetes," says Professor Marc Montminy, head of Salk's Clayton Foundation Laboratories for Peptide Biology.
The need for new drugs is accelerating, says Montminy, as almost 26 million Americans have type II diabetes, and an estimated 79 million people are at risk of developing the condition. Diabetes is the sixth leading cause of death in the United States, and treatment costs are estimated at $116 billion annually.
In order to develop new and effective treatments for diabetes, researchers need to understand the complex and delicate biology behind human metabolism as well as the disorders that develop when this finely tuned system is out of balance, Montminy says.
During the day, humans burn glucose, derived from the food we eat. This is the fuel that supplies the muscles and other parts of the body expending energy. At night, when we sleep, we revert to stored fat as a source of very dependable but slowly released energy. But certain parts of the body, most notably the brain, require glucose as a source of energy, even when we fast.
Pancreatic islet cells control both sides of this energy equation. Located in the pancreas, they produce glucagon, a hormone released during fasting, to tell the liver to make glucose for use by the brain. This process is reversed when we feed, and when the pancreatic islets release insulin, which tells the liver to stop making glucose.
Thus glucagon and insulin are part of a feedback system designed to keep blood glucose at a stable level.
Montminy's lab has for years focused on the central switches that control glucose production in the liver and others that control glucose sensing and insulin production in the pancreas. Among his key findings is that glucagon -- -- the fasting hormone -- -- turns on a genetic switch (CRTC2) that ramps up production of glucose in the blood. In turn, when insulin is increased in the blood, activity of CRTC2 is inhibited, and the liver produces less glucose.
"But in insulin-resistant type II diabetic individuals, the CRTC2 switch is turned on too strongly because the insulin signal is not getting through," Montminy says. "As a result, the liver produces too much glucose and the level of glucose in the blood stream is too high. Over a period of 10 to 20 years, the abnormal elevation of glucose leads to chronic complications including heart disease, blindness and kidney failure."
The new findings in the Nature study identify a relay system that explains how glucagon activates the CRTC2 switch during fasting, and how that system is compromised during diabetes.
The scientists say this relay system involves a molecular receptor (IP3) on the outside of liver cells that they call a "molecular spigot." Glucagon opens the IP3 spigot during fasting, allowing an increase in calcium, a common signaling molecule in the cell. This stimulates a molecular gas pedal, of sorts, known as calcineurin, which revs up CRTC2, activating genes that allow the liver to drive the metabolic engine by producing more glucose.
This is important, Montminy says, because the team also discovered that activity of the IP3 receptor and calcineurin in the liver are increased in diabetic insulin resistance, resulting in more blood sugar.
The findings therefore suggest that agents that can selectively damp down activity of the IP3 spigot and the calcineurin accelerator might help to shut down the CRTC2 switch and to lower blood sugar in type II diabetic patients, he says. That is precisely what happened when the researchers used these compounds on liver cells.
"We obviously have a lot of work to do to find out whether such a strategy might work in humans," he says.
The research team includes investigators from Salk Institute, Columbia University, University of California San Diego and University of Ottawa. In addition to Montminy, the coauthors on the paper are Yiguo Wang, Gang Li, Jason Goode, Jose Paz, Kunfu Ouyang, Robert Screaton, Wolfgang Fischer, Ju Chen and Ira Tabas.
The study was funded by grants from the National Institutes of Health, the Kieckhefer Foundation, the Clayton Foundation for Medical Research and the Leona M. and Harry B. Helmsley Charitable Trust.
在4月8日发表在《科学》上的一篇文章提到，科学家们称控制这两个分子的活性——他们共同作用来控制葡萄糖生成量——可能提供一种新方法降低血糖以治疗胰岛素抵抗的二型糖尿病。他们通过实验在糖尿病小鼠身上证实了这个方法的可行性。
“如果你控制这些开关，你将能控制葡萄糖的生成，而这正是二型糖尿病问题的中心环节。”索尔克克莱顿基金肽生物学实验室负责人教授马斯·蒙特米尼说。
新药的需求逐渐增加，蒙特米尼教授说，将近2600万美国人有二型糖尿病，而且预计有7900万人有发展为糖尿病的危险。糖尿病是美国第六大死亡原因，治疗费用预计在1160亿元每年。
为了研究糖尿病治疗新方法，研究人员需要理解人类代谢背后复杂精妙的生物学机制，以及疾病发展中这种精细协调的系统失衡，蒙特米尼说。
白天，人体燃烧从食物中获取的葡萄糖。这提供给给肌肉和身体其他部位燃料以补充能量损耗。在晚间，当我们睡觉时，我们恢复为存储脂肪作为一种非常可靠且缓慢释放的能量。但人体一些特殊部分，特别是心脏，将葡萄糖作为一种能量来源，甚至我们饥饿时也如此。
胰岛细胞控制着能量增减的两方面。他们位于胰腺，当饥饿时分泌胰高血糖素，告诉肝脏制造葡萄糖供大脑使用。当我们进食时，这个过程变为胰岛细胞分泌胰岛素告诉肝脏停止制造葡萄糖。
因此胰高血糖素和胰岛素是为控制血糖在一个稳定水平而设计的反馈体系
蒙特米尼的实验室多年来致力于研究调控肝脏葡萄糖生成以及胰腺中控制葡萄糖敏感性和胰岛素产生的那些核心开关。他主要的发现之一，胰高血糖素——饥饿激素——打开一个基因开关（CRTC2），增高血液中葡萄糖的产生。反过来，当血中胰岛素升高，CRTC2活性抑制，肝脏生成葡萄糖量就减少。
“但在胰岛素抵抗的二型糖尿病中，因为胰岛素信号没有通过，因此CRTC2开关开得过大，”蒙特米尼说。“结果是肝脏产生过多葡萄糖，造成血糖水平过高。约10到20年后，葡萄糖的不正常升高导致心脏疾病、眼盲以及肾衰等慢性并发症。”
《自然》杂志的一些新发现识别出了一个传递系统，该传到系统能够解释胰高血糖素在饥饿时如何激活CRTC2开关，以及在糖尿病中该系统如何失效。
科学家们说这个传递系统包括一个存在肝细胞外的分子受体（IP3），被他们称为“龙头分子”。胰高血糖素在人饥饿时开启IP3龙头分子，使钙这一细胞中共同的信号分子浓度升高。它刺激众多不同气体分子踏板，也被称为钙调磷酸酶中的一种，使得CRTC2调高，活化的CRTC2使肝脏产生更多葡萄糖维持代谢。
这很重要，蒙特米尼说，因为这个团队也发现，肝脏中IP3受体和钙调磷酸酶的活化在胰岛素抵抗糖尿病中升高，导致了血糖的上升。
因此，这些发现提示那些能够选择性下调IP3龙头和钙调磷酸酶加速器的药品制剂可能会帮助关闭CRTC2开关，降低二型糖尿病人的血糖，他说。研究人员在肝细胞中应用这些复合物，这个过程确实精确地发生了。
“要在人体中验证这种机制是否能够运作，我们显然还有很多工作要做，”他说。
研究队伍包括索尔克机构、哥伦比亚大学、圣地亚哥加州大学和渥太华大学的研究员。除了蒙特米尼，合著者还包括Yiguo Wang, Gang Li, Jason Goode, Jose Paz, Kunfu Ouyang, Robert Screaton, Wolfgang Fischer, Ju Chen和Ira Tabas.
该项研究由国家卫生院，基克希弗基金，克莱顿医学研究基金以及利昂娜.M和哈利.B赫尔姆斯利公益信托赞助.
ScienceDaily (Apr. 8, 2012) — In their extraordinary quest to decode human metabolism, researchers at the Salk Institute for Biological Studies have discovered a pair of molecules that regulates the liver's production of glucose -- -- the simple sugar that is the source of energy in human cells and the central player in diabetes.
In a paper published April 8 in Nature, the scientists say that controlling the activity of these two molecules -- -- which work together to allow more or less glucose production -- -- could potentially offer a new way to lower blood sugar to treat insulin-resistant type II diabetes. They showed, through an experimental technique, that this was possible in diabetic mice.
"If you control these switches, you can control the production of glucose, which is really at the heart of the problem of type 2 diabetes," says Professor Marc Montminy, head of Salk's Clayton Foundation Laboratories for Peptide Biology.
The need for new drugs is accelerating, says Montminy, as almost 26 million Americans have type II diabetes, and an estimated 79 million people are at risk of developing the condition. Diabetes is the sixth leading cause of death in the United States, and treatment costs are estimated at $116 billion annually.
In order to develop new and effective treatments for diabetes, researchers need to understand the complex and delicate biology behind human metabolism as well as the disorders that develop when this finely tuned system is out of balance, Montminy says.
During the day, humans burn glucose, derived from the food we eat. This is the fuel that supplies the muscles and other parts of the body expending energy. At night, when we sleep, we revert to stored fat as a source of very dependable but slowly released energy. But certain parts of the body, most notably the brain, require glucose as a source of energy, even when we fast.
Pancreatic islet cells control both sides of this energy equation. Located in the pancreas, they produce glucagon, a hormone released during fasting, to tell the liver to make glucose for use by the brain. This process is reversed when we feed, and when the pancreatic islets release insulin, which tells the liver to stop making glucose.
Thus glucagon and insulin are part of a feedback system designed to keep blood glucose at a stable level.
Montminy's lab has for years focused on the central switches that control glucose production in the liver and others that control glucose sensing and insulin production in the pancreas. Among his key findings is that glucagon -- -- the fasting hormone -- -- turns on a genetic switch (CRTC2) that ramps up production of glucose in the blood. In turn, when insulin is increased in the blood, activity of CRTC2 is inhibited, and the liver produces less glucose.
"But in insulin-resistant type II diabetic individuals, the CRTC2 switch is turned on too strongly because the insulin signal is not getting through," Montminy says. "As a result, the liver produces too much glucose and the level of glucose in the blood stream is too high. Over a period of 10 to 20 years, the abnormal elevation of glucose leads to chronic complications including heart disease, blindness and kidney failure."
The new findings in the Nature study identify a relay system that explains how glucagon activates the CRTC2 switch during fasting, and how that system is compromised during diabetes.
The scientists say this relay system involves a molecular receptor (IP3) on the outside of liver cells that they call a "molecular spigot." Glucagon opens the IP3 spigot during fasting, allowing an increase in calcium, a common signaling molecule in the cell. This stimulates a molecular gas pedal, of sorts, known as calcineurin, which revs up CRTC2, activating genes that allow the liver to drive the metabolic engine by producing more glucose.
This is important, Montminy says, because the team also discovered that activity of the IP3 receptor and calcineurin in the liver are increased in diabetic insulin resistance, resulting in more blood sugar.
The findings therefore suggest that agents that can selectively damp down activity of the IP3 spigot and the calcineurin accelerator might help to shut down the CRTC2 switch and to lower blood sugar in type II diabetic patients, he says. That is precisely what happened when the researchers used these compounds on liver cells.
"We obviously have a lot of work to do to find out whether such a strategy might work in humans," he says.
The research team includes investigators from Salk Institute, Columbia University, University of California San Diego and University of Ottawa. In addition to Montminy, the coauthors on the paper are Yiguo Wang, Gang Li, Jason Goode, Jose Paz, Kunfu Ouyang, Robert Screaton, Wolfgang Fischer, Ju Chen and Ira Tabas.
The study was funded by grants from the National Institutes of Health, the Kieckhefer Foundation, the Clayton Foundation for Medical Research and the Leona M. and Harry B. Helmsley Charitable Trust.
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