Class Act: AGE-RAGE: What we know about the pathophysiology of diabetic neuropathy.

December 26, 2008

neuropathy.jpgCommentary by Regina Mysliwiec, NYU Medical Student

Faculty Peer Reviewed

G.L. is a 62 year-old African-American male with a six year history of Type 2 Diabetes with variable glucose control and a progressive one year history of burning pain in a unilateral T10 distribution. The pain began at his right abdomen, then spread first to his umbilicus and finally ventrodorsally to his spine. His most recent HgbA1c is 8.0.

One does not have to be a medical student in New York City for very long to find a patient with tingling and numbness that started in the toes, spread up both legs, and is sometimes accompanied by sharp or burning pain. Distal symmetric polyneuropathy is common in diabetes, and diabetes is common in NYC. The patient described above may be an example of the less common diabetic thoracic radiculopathy. What he has in common with his stocking-and-gloved counterparts is poor glucose control. Several long-term clinical trials focusing on the effects of glycemic control have illustrated the correlation between hyperglycemia and what are now commonly known as the microvascular complications of diabetes – including neuropathy. We know that nerve damage happens. What remains somewhat unclear is how it is accomplished.

There appear to be three main mechanisms of nerve damage in diabetics. First, excess glucose causes endothelial injury. Second, there are changes in activation of various cellular pathways that alter cell function without immediately causing cell death. And third, AGE meets RAGE; time and the accumulation of altered molecules wreak additional havoc on patients’ tissues. Endothelial damage is evidenced by the increased presence of thrombomodulin, a marker of microangiopathy in animal models of diabetes. It is assumed that microangiopathy caused by glucose will have sequelae similar to microangiopathy of various other causes: impaired blood flow to nerves, tissue hypoxia, and oxidative stress. In the ‘90s, there was evidence suggesting that inflammatory responses in microvasculature of neurons led to additional ischemic damage to nerves.

Serum glucose does not affect only blood vessels. The more sugar there is in the blood, the longer it spends degrading without being used or filtered and the more it finds its way into tissues. Fructosamines and sorbitol produced by this degradation of sugar interfere with the protein kinase C and the Na/K ATPase of nerve cells. This injury alone is enough to reduce nerve function, but it does not occur alone. Degraded sugar molecules bind to N-terminal and lysyl side chain aspects of protein, nucleotide, and lipid molecules; this is glycosylation that occurs without the involvement of an enzyme. It is called glycation and it renders the molecules in question more stable than their original, non-glycated states.

Being more stable, glycated end products last longer. They are difficult to clear from the body. They accumulate. They deposit themselves on molecules with long lifespans, such as myelin. They are recognized by special cell receptors – receptors for advanced glycated end products, or RAGE – that, when activated by AGEs, trigger various cellular processes involving TNF-α, VEGF, nitric oxide, and other potentially damaging mediators. In molecular studies, AGEs have been found within the perineurium, endothelial cells, and basement membranes of both myelinated and unmyelinated nerve fibers of diabetic patients with neuropathic symptoms.

OK, this is where our knowledge of the mechanism of diabetic neuropathy gets a little fuzzy. Studies show many possible points of injury. AGEs have been shown to modify neurofilament and tubulin. These changes may impair axonal transport, leading to atrophy of the nerve fibers. This could explain the fibrillation (nerve degeneration) found in EMG studies of human patients with diabetic neuropathy. In vitro, AGE accumulation has also caused neuronal and Schwann cell death – processes that, if occurring in vivo, would certainly lead to the demyelination and atrophy of nerve fibers. These processes, and others yet undiscovered, stand between us and a full understanding of the pathophysiology of diabetic neuropathy. They stand between the clinician and the diabetic neuropaths who may not understand why the medicine we ask them to take will treat their pain, but not stop the process that is causing it.

I asked myself what I knew about this physiology for a reason: I wanted to know what could be done about G.L.’s T10 strip of burning, hypersensitive skin. The major clinical implication of finally elucidating a pathophysiological process is development of new therapies. Considering how difficult it is to treat diabetic neuropathy, a successful approach would be welcome. We use antidepressants, anticonvulsants, and other drugs which, by unknown mechanisms, may or may not bring relief*. It has been demonstrated that better glucose control reduces the amount of glycation damage in diabetic nerves. However, there is no evidence that reducing or stopping glycation can reverse the symptoms caused by hyperglycemic damage, such as the sensory loss that remains a painful diabetic neuropathy resolves. Therefore it cannot yet be said that drugs targeting the molecules and mechanisms responsible for glycation will have a beneficial clinical effect. An example of this is aldose reductase inhibitors, which have been shown to reduce the levels of AGEs in diabetic patients (thereby reducing damage) without affecting symptoms believed to be caused by those AGEs. For now, this may mean that G.L.’s pain and hyperesthesia will be treated symptomatically with gabapentin until they eventually give way to anesthesia. But I hope that, for future diabetics, AGE and RAGE don’t have the final word.

*Please also refer to Bedside Rounds: How Do You Diagnose and Treat Diabetic Neuropathy, by Judith Brenner, MD

Commentary by Robert Staudinger MD, Associate Professor, NYU Department of Neurology

Diabetic neuropathy is the most common complication of diabetes, affecting 50% of patients. Diabetes can cause a variety of neuropathies. Most common and well known to all clinicians is a distal symmetric, slowly progressive painful neuropathy. Perhaps less know to the internist is the disabling diabetic radiculoplexopathy (“diabetic amyotrophy”), usually seen in patients with weight loss who develop subacute progressive leg weakness and pain, followed by spontaneous improvement. Diabetic radiculopathy is not limited to the lumbar area, but may also, rarely, involve thoracic segments and then present with abdominal pain. In contrast to cervical or lumbar radiculopathy, a thoracic radiculopathy is often not recognized and a patient may undergo extensive testing including invasive procedures, before the correct diagnosis is made.

The treatment of diabetic neuropathic pain is symptomatic and remains limited. Regina Mysliwiec nicely summarizes our still incomplete understanding of the pathophysiology of diabetic neuropathies. She describes the recent exciting co-localization of AGE and RAGE in diabetic peripheral nerves. Agents that inhibit the ACE-RAGE oxidative stress system could have therapeutic implications in vascular complications in diabetes


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