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国际糖尿病 >>EASD年会
[EASD2011]第26届Camillo Golgi奖获得者Dr.Bierhaus专访——糖尿病晚期并发症新的生化概念
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专家访谈 基础研究 作者:A.Bierhaus 来源:国际糖尿病 2011/9/21 15:42:00    加入收藏
内容概要:Angelika Bierhaus博士的演讲展示了单独控制血糖不能预防晚期糖尿病并发症的证据。近期临床研究表明,在1型糖尿病中,HbA1c和糖尿病病程仅能解释11%的晚期糖尿病并发症;在2型糖尿病中,更严格的血糖控制似乎不能使患者额外获益,这一“糖尿病悖论”使临床医生和患者感到困惑。HbA1c与硬终点(如死亡或心血管事件)之间的U形曲线提示非酶糖化反应和晚期糖基化终产物(AGE)的积累可能在糖尿病晚期发挥一定作用。AGE与其受体RAGE结合后,通过持续激活转录因子NF-κB而诱发炎症,最终导致晚期糖尿病并发症。在2型糖尿病中,导致活性氧基团(Reactive Oxygen Species,ROS)、活性碳基团(Reactive Carbonyl Species,RCS)和蛋白质糖基化的途径独立于血糖控制而被激活,因此,即便是在血糖控制于接近正常时,活性代谢产物也会积累。Bierhaus总结说:“晚期糖尿病并发症途径的新观点不仅强调高血糖,还强调代谢产物形成过多和代谢产物解毒减少之间的平衡,它不仅有助于解释‘糖尿病悖论’,还将为晚期糖尿病并发症尚未解决的问题提供新的治疗方法。”

     Angelika Bierhaus  德国海德堡海德堡大学医学与临床化学系


 
<International Diabetes>: Dr. Bierhaus, you have introduced a concept of measuring metabolic pain without the necessity of talking to the patient.  Would you please explain that to us?

  《国际糖尿病》:Bierhaus博士,您提出了一个不需要向患者询问就能够评价患者代谢性疼痛的新概念,请您跟我们解释一下。
 
    Dr.Bierhaus:  Whenever glucose is metabolized, not only in healthy people, but even more in diabetic subjects who have increased glucose metabolism, reactive gluco-toxic metabolites are formed.  This is a normal way that glucose is broken down to three bodies and then to smaller molecules you need to gain energy in the mitochondrial respiratory chain.  One of these small molecules is a reactive metabolite called methylglyoxyl.  This methylglyoxyl appears within the organelle and is basically cytotoxic and can induce inflammation.  The body has developed defense mechanisms, like enzymes, that can detoxify this methylglyoxyl.  The most important enzyme is glycosylase-1 and under normal conditions in healthy subjects the methylglyoxyl is immediately detoxified.  In diabetic situations these enzymes that detoxify methylglyoxyl are reduced and do not work properly so that methylglyoxyl accumulates because it can not be detoxified readily by cellular defense mechanisms. Methylglyoxyl is not only cytotoxic but from its chemical structure it is very similar to a substance we all know called capsaicin, which make spicy meals spicy.  All of the spicy things we can eat in Brazil and Mexico have a lot of capsaicin and that it induces pain when we eat it.  Our idea was that methylglyoxyl accumulates in diabetic patients and we know from the structure that it is very similar to a structure that induces pain, this accumulation might contriubute to neuropathic pain.  The next consideration was that if an enzyme that can detoxify this reactive enzyme is reduced, the tissues and organs with low enzymatic activity might be most affected.  We did a survey and found that peripheral nerves have the lowest amount of glycosylase activity, which is further reduced in diabetic patients resulting in greater accumulation of methylglyoxyl.  Our current hypothesis was developed that increased methylglyoxyl could correlate with induced pain. Methylglyoxyl acts as a reactive metabolite by binding to specific amino acids, mainly arginine.  As a complex methylglyoxyl is bound to arginine to a greater extent and is a non-enzymatic ligation where arginine is modified.  The result is that the structure of the effected macromolecule is changed and cannot be detoxified by any enzyme in the body and the modification remains.  In the body there are sodium channels, which mediate signals to the neuron.  These sodium channels work such that they have an inactivation gate that open in situations of danger and pain.  For example, if there is a hotplate and you place your hand on it, the signal must travel from the hotplate to the brain that it is hot.  This works because the inactivation gate of the sodium channel, mainly the sodium channel 1.8, opens, ions enter the neuron inducing action potentials that travel to the dorsal horn of the dorsal ganglion to the brain.  These signals communicate to the brain that the hotplate is hot, the inactivation gate closes, no more sodium enters the neuron, and action potentials cease.  Unfortunately, this sodium activation channel 1.8 has a lot of arginine surrounding the activation gate with one arginine directly in the inside of the inactivation gate.  We studied this and found that if the inactivation gate open, the methylglyoxyl in the plasma and especially high in diabetic patients, also enters the sodium channel because it is very small.  While entering binds to the arginine of the inactivation gate irreversibly.  Then it is very simple with the non-enzymatic modification of the arginine in the inactivation gate prohibiting it from closing, allowing sodium to continuously enter the neuron chronically stimulating action potentials in the absence of pain producing stimuli.  That is what happens in diabetes.  Diabetics often report pain, often in the night or somehow suddenly during the day, with no apparent reason for the pain.  They may have a slight stimulus that is barely noticeable which cause the inactivation gates to open allowing methylglyoxyl, in addition to sodium ions, to enter the inactivation gate binding to the arginine and blocks the inactivation gate in the open position causing a constant pain-inducing stimulus.  The result is that the patients have pain and no one knows why.  We tested this with different approaches biochemically, electrophysiologically and functionally and were also able to follow this pain up in experimental animal because we could follow this pain up with changes in methylglyoxyl concentrations.  As methylglyoxyl changes the inactivation sodium channel 1.8, we could see increased blood flow in the pain percepting areas of the brain in mice.  If we blocked methylglyoxyl binding to the sodium channel we were able to reduce the pain in the brain.  It is a central event and we could show that from the periphery to the pain processing centers of the brain methylglyoxyl could induce pain.  In addition we have started our first clinical studies where we found increased levels of methylglyoxyl and decreased enzymatic activity of the defense mechanism and these hypotheses were confirmed.  Through our double-blind studies we could find patients with pain simply by an increase in methylglyoxyl higher than the threshold of 600 nanomoles/ml in the plasma and by decrease glycosylase activity.  Even if we did not know anything about the patients before we classified all patients correctly by pain based on the increase in methylglyoxyl and the decrease of glycosylase activity.  Since the mechanism of methylglyoxyl induced pain is so simple we are now currently developing a peptide with several arginines, in which in the animal and clinical situation, we can test by injecting low concentration into diabetics whether the peptide could somehow scavenge the methylglyoxyl in the plasma before it can bind to the inactivation sodium channels.  Thereby it would lower pain in diabetics.  If it works in animal models we how not only to decrease pain but to completely eliminate pain for at least three days before having to add more peptide.  If you look at the clinical situation at the moment in that most anti-pain agents have a lot of side effects because they directly affect the central nervous system.  This peptide is simpler and would not affect the central nervous system but just scavenge a reactive metabolite that is to much before it can interact with the nervous system and enter neurons.  Once the reactive metabolite is successfully scavenged it would be removed by the kidneys.  We hope this can be implemented soon and we could get approval for clinical trials because we are very confident that we can help patients.

    Dr.Bierhaus:   葡萄糖代谢过程中,健康人体内的糖毒性代谢产物会增加,糖尿病患者体内糖毒性代谢产物产生量更多。 它们就是葡萄糖分解产生的三种产物,之后转变成更小的分子,为线粒体呼吸链提供能量。 其中的一个小分子是一种反应性的代谢产物,名叫丙酮醛。这种丙酮醛存在于细胞器中,是一种毒性物质,可以诱导炎症反应。机体针对这种物质产生了保护机制,主要是一些具有解毒作用的酶。其中最重要的是转葡糖基酶-1,健康个体正常情况下可以通过这种酶将丙酮醛立即解毒。而在糖尿病个体中,这些酶

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