Sci. Aging Knowl. Environ., 22 December 2004
Vol. 2004, Issue 51, p. nf116
[DOI: 10.1126/sageke.2004.51.nf116]

NEWS FOCUS

Once More, With Feeling

Hobbling glycation-detecting protein restores feeling in diabetic mice

R. John Davenport

http://sageke.sciencemag.org/cgi/content/full/2004/51/nf116

Shackling a particular receptor protein could sweeten life for diabetic patients, new results suggest. Blocking the molecule, which normally detects sugar-marred proteins, prevents numbness in diabetic mice. Drugs that cripple the receptor might reduce this common diabetes complication.

Soaring amounts of blood sugar create myriad problems for diabetics, including atherosclerosis, kidney malfunction, and neuropathy, nerve loss that can dull normal pain sensation (see "The Burden of Pain on the Shoulders of Aging"). Some studies suggest that reactions between sugars and proteins foster these ailments. Sugars attach to proteins to form compounds called advanced glycation endproducts (AGEs). In turn, AGEs stick to a cell-surface protein called RAGE, sparking inflammation (see "Provoking RAGE"). Previous findings revealed that the RAGE signal contributes to hampered circulation and crippled kidneys. In new work, Angelika Bierhaus, a molecular biologist at the University of Heidelberg in Germany, and colleagues investigated whether RAGE also triggers neuropathy.

First, the researchers examined nerves from diabetes patients and from unaffected people. Diseased tissue showed elevated quantities of RAGE and one particular AGE, as well as extra NF-{kappa}B, an inflammation-spurring molecule that's activated by RAGE. In addition, these molecules tended to cluster, hinting that they might collaborate.

To test whether they promote neuropathy, the researchers induced diabetes in rodents using a drug that kills insulin-producing pancreatic cells. NF-{kappa}B's gene-activating capacity rose 20-fold in the animals, compared to controls. Quantities of IL-6 also skyrocketed; this molecule, roused by NF-{kappa}B, stokes inflammation. But when the team gave diabetic animals a free-floating form of RAGE that soaks up AGEs and prevents them from initiating the RAGE response, NF-{kappa}B remained quiescent. NF-{kappa}B activity level didn't rise when rodents that lack the RAGE gene became diabetic, although it was higher than in genetically normal animals.

Next, the researchers scrutinized the rodents' pain response. They placed animals on a hot plate and assessed how quickly the mice lifted and licked their paws. Diabetic mice reacted more slowly than normal mice did, suggesting that they'd lost some sensation in their extremities. However, mice with deactivated RAGE flinched as rapidly as did normal animals. Together the results suggest that calming the RAGE pathway helps preserve feeling.

The work "provides a molecular and cellular basis for loss of pain perception in diabetes," says neurobiologist Jeffrey Keller of the University of Kentucky in Lexington. "That's exciting." Because researchers are already exploring the use of RAGE-blocking drugs for atherosclerosis, the discovery might prompt the rapid development of therapies for neuropathy, he says. Biochemist Vincent Monnier of Case Western Reserve University in Cleveland says, "It's wonderful work. Everything is confirming the role of RAGE in mediating diabetes dysfunction." However, he notes that the elevated baseline NF-{kappa}B activity in animals without RAGE might cause harmful immune responses, even though the absence of RAGE apparently quells inflammation spikes that lead to neuropathy in diabetic animals. Bierhaus counters that the heightened NF-{kappa}B activity might be at least partially beneficial; for instance, RAGE-less animals resist infection well, she says. Further studies should help clarify whether suppressing RAGE will make diabetes less of a bitter pill to swallow.


December 22, 2004
  1. A. Bierhaus et al., Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily. J. Clin. Invest. 114, 1741-1751 (2004).[CrossRef][Medline]
Citation: R. J. Davenport, Once More, With Feeling. Sci. Aging Knowl. Environ. 2004 (51), nf116 (2004).








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