会议预告

行业新闻

Cell Metabolism:胰高血糖素途径或是糖尿病的治疗新靶点

血糖之所以能够保持正常水平不仅是因为降糖激素-胰岛素的存在,一种名为胰高血糖素的升糖激素也起了作用。

几十年来,人们采用针对胰岛素的方法来治疗2型糖尿病,但一项新的研究表明,针对胰高血糖素的升糖作用来进行治疗或许是一种更好的办法。

这项研究结果发表于《Cell Metabolism》在线版。

"我们发现的是一种可减少胰高血糖素对血糖影响的方法,并且无胰高血糖素抑制机体的副作用,"内科学教授兼内科研究副主任、解剖与细胞生物学(生理学与细胞生物物理学)教授、医学博士Ira Tabas说,他与Lale Ozcan博士一起主持了该研究。

虽然胰高血糖素与胰岛素同时被发现,但与后者相比,有关胰高血糖素的研究一直停滞不前,而且糖尿病的治疗几乎都是以胰岛素为目标。

在过去十年中,肠促胰素(一类2型糖尿病新药)的成功重新引发了胰高血糖素研究的兴趣。人们对肠促胰素的了解是从肠促胰素能够刺激胰岛素分泌开始的。然而,最新研究表明,其临床成功绝大部分可归功于肠促胰素对胰高血糖素分泌的影响。

对肠促胰岛素的再认识引起人们重新寻找其他能够对抗胰高血糖素的药物的兴趣,包括在肝脏内阻断胰高血糖素作用的化合物(胰高血糖素在肝脏内可促进葡萄糖的释放)。胰高血糖素具有多重作用,最近的初步临床试验表明,它可使胆固醇升高并导致肝脏中脂肪蓄积。

这项新研究表明,在不影响胰高血糖素其它作用的情况下,可干扰其对血糖的作用,这为更安全地应用抗胰高血糖素途径治疗糖尿病带来了希望。

Tabas博士和Ozcan博士发现,一旦胰高血糖素与其受体结合,只有在一种名为CaMKII的酶被激活之后,葡萄糖才能得以完全释放。 CaMKII被激活时会促使一种名为FoxO1的蛋白质进入细胞核内,该蛋白质可在细胞核内启动葡萄糖释放所需的基因。同时,某种相关通路也会促使一种FoxO1辅助蛋白进入细胞核内。

该研究发表在《Nature》在线版(Tabas博士是该论文的共同作者)。

"即使2型糖尿病患者病情得到很好的控制,其胰高血糖素的作用依然过剩,因此阻断CaMKII可能是降低血糖的一种新方法," Tabas说。

当研究人员阻断了肥胖、糖尿病小鼠的CaMKII时,发现其血糖下降,而且没有出现副作用。相反,胆固醇水平有所下降、胰岛素敏感性得到改善,肝内脂肪减少。

"到目前为止,很难在不影响胰高血糖素其它功能的情况下阻断其对血糖的影响,"Tabas说,"但我认为CaMKII有可能是一个突破点。"

Tabas博士目前正致力于开发一种CaMKII抑制剂来治疗2型糖尿病。

原文:

ScienceDaily (Apr. 12, 2012) - Maintaining the right level of sugar in the blood is the responsibility not only of insulin, which removes glucose, but also of a hormone called glucagon, which adds glucose. For decades, treatments for type II diabetes have taken aim at insulin, but a new study suggests that a better approach may be to target glucagon's sweetening effect.

The findings were published April 12 in the online edition of Cell Metabolism.

"What we've found is a way to reduce glucagon's influence on blood sugar without the side effects of global glucagon repression," said Ira Tabas, MD, PhD, Richard J. Stock Professor and Vice Chair of Research in the Department of Medicine and professor of Anatomy & Cell Biology (in Physiology and Cellular Biophysics), who led the study with Lale Ozcan, PhD, associate research scientist.

Though glucagon was discovered at the same time as insulin, research on it has languished compared with that of its cousin, and treatments have almost exclusively targeted the latter.

In the last decade, the success of incretins, a new class of drugs for type II diabetes, has sparked a renaissance in glucagon research. When they were first introduced, incretins were known to stimulate insulin secretion. But recent studies show that a significant part of their clinical success can be attributed to previously unsuspected inhibiting effects on glucagon secretion.

The experience with incretin has led to a renewed search for other drugs that act against glucagon, including compounds that block glucagon in the liver, where it acts to free glucose. Drugs that block the glucagon receptor in the liver have been tested, but glucagon has multiple roles, and recent early clinical trials show that it can raise cholesterol and lead to fat accumulation in the liver.

The new study shows how glucagon's effect on glucose could be disrupted without disturbing glucagon's other duties, raising prospects for a safer anti-glucagon diabetes treatment.

Drs. Tabas and Ozcan found that once glucagon binds to its receptor, glucose is fully released only after an enzyme called CaMKII is activated. When activated, CaMKII sends a protein called FoxO1 into the cell nucleus, where it turns on the genes needed for glucose secretion. A related pathway, working in parallel to this one, sends a FoxO1 helper protein into the cell nucleus, as reported in a paper on which Dr. Tabas is a co-author, published online on April 8 in Nature.

"Even when their disease is well controlled, most patients with type II diabetes have excess glucagon action, so blocking CaMKII could potentially be a new way to lower blood sugar and better treat the disease," said Dr. Tabas.

When the researchers blocked CaMKII in obese, diabetic mice, the animals' blood sugar went down, with no negative side effects. Instead, cholesterol declined, insulin sensitivity improved, and the liver became less fatty.

"Until now, it has been difficult to block glucagon's effect on blood sugar without interfering with glucagon's other functions," said Dr. Tabas, "but we think CaMKII is different."

Dr. Tabas is now working on the possibility of developing a CaMKII inhibitor to treat diabetes.

血糖之所以能够保持正常水平不仅是因为降糖激素-胰岛素的存在,一种名为胰高血糖素的升糖激素也起了作用。

几十年来,人们采用针对胰岛素的方法来治疗2型糖尿病,但一项新的研究表明,针对胰高血糖素的升糖作用来进行治疗或许是一种更好的办法。

这项研究结果发表于《Cell Metabolism》在线版。

"我们发现的是一种可减少胰高血糖素对血糖影响的方法,并且无胰高血糖素抑制机体的副作用,"内科学教授兼内科研究副主任、解剖与细胞生物学(生理学与细胞生物物理学)教授、医学博士Ira Tabas说,他与Lale Ozcan博士一起主持了该研究。

虽然胰高血糖素与胰岛素同时被发现,但与后者相比,有关胰高血糖素的研究一直停滞不前,而且糖尿病的治疗几乎都是以胰岛素为目标。

在过去十年中,肠促胰素(一类2型糖尿病新药)的成功重新引发了胰高血糖素研究的兴趣。人们对肠促胰素的了解是从肠促胰素能够刺激胰岛素分泌开始的。然而,最新研究表明,其临床成功绝大部分可归功于肠促胰素对胰高血糖素分泌的影响。

对肠促胰岛素的再认识引起人们重新寻找其他能够对抗胰高血糖素的药物的兴趣,包括在肝脏内阻断胰高血糖素作用的化合物(胰高血糖素在肝脏内可促进葡萄糖的释放)。胰高血糖素具有多重作用,最近的初步临床试验表明,它可使胆固醇升高并导致肝脏中脂肪蓄积。

这项新研究表明,在不影响胰高血糖素其它作用的情况下,可干扰其对血糖的作用,这为更安全地应用抗胰高血糖素途径治疗糖尿病带来了希望。

Tabas博士和Ozcan博士发现,一旦胰高血糖素与其受体结合,只有在一种名为CaMKII的酶被激活之后,葡萄糖才能得以完全释放。 CaMKII被激活时会促使一种名为FoxO1的蛋白质进入细胞核内,该蛋白质可在细胞核内启动葡萄糖释放所需的基因。同时,某种相关通路也会促使一种FoxO1辅助蛋白进入细胞核内。

该研究发表在《Nature》在线版(Tabas博士是该论文的共同作者)。

"即使2型糖尿病患者病情得到很好的控制,其胰高血糖素的作用依然过剩,因此阻断CaMKII可能是降低血糖的一种新方法," Tabas说。

当研究人员阻断了肥胖、糖尿病小鼠的CaMKII时,发现其血糖下降,而且没有出现副作用。相反,胆固醇水平有所下降、胰岛素敏感性得到改善,肝内脂肪减少。

"到目前为止,很难在不影响胰高血糖素其它功能的情况下阻断其对血糖的影响,"Tabas说,"但我认为CaMKII有可能是一个突破点。"

Tabas博士目前正致力于开发一种CaMKII抑制剂来治疗2型糖尿病。

原文:

ScienceDaily (Apr. 12, 2012) - Maintaining the right level of sugar in the blood is the responsibility not only of insulin, which removes glucose, but also of a hormone called glucagon, which adds glucose. For decades, treatments for type II diabetes have taken aim at insulin, but a new study suggests that a better approach may be to target glucagon's sweetening effect.

The findings were published April 12 in the online edition of Cell Metabolism.

"What we've found is a way to reduce glucagon's influence on blood sugar without the side effects of global glucagon repression," said Ira Tabas, MD, PhD, Richard J. Stock Professor and Vice Chair of Research in the Department of Medicine and professor of Anatomy & Cell Biology (in Physiology and Cellular Biophysics), who led the study with Lale Ozcan, PhD, associate research scientist.

Though glucagon was discovered at the same time as insulin, research on it has languished compared with that of its cousin, and treatments have almost exclusively targeted the latter.

In the last decade, the success of incretins, a new class of drugs for type II diabetes, has sparked a renaissance in glucagon research. When they were first introduced, incretins were known to stimulate insulin secretion. But recent studies show that a significant part of their clinical success can be attributed to previously unsuspected inhibiting effects on glucagon secretion.

The experience with incretin has led to a renewed search for other drugs that act against glucagon, including compounds that block glucagon in the liver, where it acts to free glucose. Drugs that block the glucagon receptor in the liver have been tested, but glucagon has multiple roles, and recent early clinical trials show that it can raise cholesterol and lead to fat accumulation in the liver.

The new study shows how glucagon's effect on glucose could be disrupted without disturbing glucagon's other duties, raising prospects for a safer anti-glucagon diabetes treatment.

Drs. Tabas and Ozcan found that once glucagon binds to its receptor, glucose is fully released only after an enzyme called CaMKII is activated. When activated, CaMKII sends a protein called FoxO1 into the cell nucleus, where it turns on the genes needed for glucose secretion. A related pathway, working in parallel to this one, sends a FoxO1 helper protein into the cell nucleus, as reported in a paper on which Dr. Tabas is a co-author, published online on April 8 in Nature.

"Even when their disease is well controlled, most patients with type II diabetes have excess glucagon action, so blocking CaMKII could potentially be a new way to lower blood sugar and better treat the disease," said Dr. Tabas.

When the researchers blocked CaMKII in obese, diabetic mice, the animals' blood sugar went down, with no negative side effects. Instead, cholesterol declined, insulin sensitivity improved, and the liver became less fatty.

"Until now, it has been difficult to block glucagon's effect on blood sugar without interfering with glucagon's other functions," said Dr. Tabas, "but we think CaMKII is different."

Dr. Tabas is now working on the possibility of developing a CaMKII inhibitor to treat diabetes.

全文检索小助手:

如果您有“基础胰岛素相关文献全文”的检索需求,敬请联系help.basalinsulin@gmail.com,我们将为您搜索并发送到您的邮箱内! 请在“全文求助”邮件内尽量详细说明“标题、作者、杂志及卷期、PMID、全文链接”等内容,以便我们更精准地进行搜索!

求助全文

最新评论 暂无评论

不能超过250字,需审核,请自觉遵守互联网相关政策法规