Diabetes: How sugar leads to pain
Many diabetic people suffering from chronic pain, especially in the calves and feet. The mechanism of diabetic nerve disease, scientists have I and Clinical Chemistry at the University Hospital Heidelberg, now enlightened by Professor Dr. Angelika Bierhaus and Professor Dr. Peter P. Nawroth, medical director of Abeilung Internal Medicine: The metabolite methylglyoxal, which in the breakdown of sugars blood arises, binds to pain-conducting nerve cells and makes them hypersensitive. Here there is a threshold for the sensation of pain. For the first time a treatment approach was identified which acts directly on the release of the pain and not to the nervous system: In animals lowered agents intercepted the methylglyoxal, the strong sensation of pain. The scientific studies were supported by the Dietmar Hopp Foundation, St. Leon-Rot; their results have been 13. May 2012 published in the renowned journal "Nature Medicine".
Methylglyoxal increases the irritability of pain-conducting nerve cells
Accompanying diseases of diabetes mellitus such as damage to blood vessels, nerves and kidneys can only be partly explained by an elevated blood sugar level or the duration of the disease. The chronic pain in the legs in particular sometimes occurs before the diabetes is noticed. In award-winning research in recent years, the Heidelberg working group has shown that aggressive metabolites also contribute to this: "Even in patients whose blood sugar levels are well controlled, or even before the onset of the disease, such harmful substances accumulate in the body," explains the first author of the publication , dr Thomas Fleming. Scientists from 16 research institutions worldwide were involved in elucidating the mechanism of diabetic nerve disease (neuropathy).
The metabolic product methylglyoxal (MG) is formed in the blood through the breakdown of the sugar glucose - especially in the case of high blood sugar levels, in diabetics, but also independently of it. Body cells protect themselves from this toxic decomposition product with the help of proteins (glyoxalases), which break down MG. “In many nerve cells, these protective proteins are only weakly active. In diabetics, their activity is further reduced. This makes nerve cells particularly sensitive to methylglyoxal,” explains Fleming. The scientists therefore investigated how exactly MG affects nerve cells that are responsible for pain perception.
To do this, they examined certain proteins in the cell envelope, so-called sodium channels. These proteins regulate the irritability of nerve cells. They discovered: MG binds to a sodium channel (NaV1.8), which only occurs in pain receptors, changes its functionality and thus makes the nerve cell more excitable. They found this change in the nerve tissue of mice that had previously been given MG and in animals suffering from a disease similar to diabetes. The sodium channels were also impaired by MG in nerve cells from diabetic patients with increased sensitivity to pain.
New therapeutic approach promises fewer side effects
Healthy mice that had been injected with methylglyoxal, like mice with diabetes, developed an increased sensitivity to pain, measurable by the increased blood flow to pain-processing areas of the brain. In both groups of test animals, symptoms were alleviated with the help of a new drug that binds to MG and renders it harmless. It was just as effective to increase the activation of the animals' endogenous protective proteins.
“The results show for the first time that methylglyoxal directly causes the increased pain sensation. This makes it a promising starting point for the treatment of this neurological disorder," says Professor Nawroth. So far, there have been no satisfactory therapies for these symptoms: Available drugs affect the nervous system and make you tired, but they only relieve the pain in a third of patients - by up to 30 percent. The hoped-for therapeutic success of the new drug, which has now been patented, is based on a completely new mechanism of action: It targets the methylglyoxal circulating in the blood and thus stops the processes that cause the pain in the first place. "We believe we have found the first truly effective drug for diabetic pain," said the article's senior author.
Literature:
Angelika Bierhaus, Thomas Fleming, Stoyan Stoyanov, Andreas Leffler, Alexandru Babes, Cristian Neacsu, Susanne K Sauer, Mirjam Eberhardt, Martina Schnölzer, Felix Lasischka, Winfried L Neuhuber, Tatjana I Kichko, Ilze Konrade, Ralf Elvert, Walter Mier, Valdis Pirags , Ivan K Lukic, Michael Morcos, Thomas Dehmer, Naila Rabbani, Paul J Thornalley, Diane Edel, Carla Nau, Josephine Forbes, Per M Humpert, Markus Schwaninger, Dan Ziegler, David M Stern, Mark E Cooper, Uwe Haberkorn, Michael Brownlee , Peter W Reeh & Peter P Nawroth. Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nature Medicine (2012). Published online 13 May 2012. doi:10.1038/nm.2750
Source: Heidelberg [UK]
