SAN DIEGO—New data suggest that a simple diet and exercise program produces cutaneous reinnervation and lessens pain in patients with impaired glucose tolerance neuropathy, a condition that is increasingly referred to as prediabetes.

The results, presented at the 58th Annual Meeting of the American Academy of Neurology, are drawn from an NIH-funded study in which intraepidermal nerve fiber (IENF) density was measured at baseline and again one year later in 32 patients with impaired glucose tolerance neuropathy who followed an individualized regimen that called for a target weight loss of 7% of their body weight, 150 minutes of moderate exercise per week, and quarterly visits to a dietitian.

REVERSING NERVE INJURY

One-year results showed that the IENF density had improved by roughly one third. "Our observations suggest for the first time that it is possible to reverse prediabetic nerve injury," said A. Gordon Smith, MD, Associate Professor of Neurology and Pathology at the University of Utah in Salt Lake City.

Impaired glucose tolerance is very common in the roughly 10% to 15% of persons older than 40 who have peripheral neuropathy, Dr. Smith pointed out. In fact, about 40% of patients with peripheral neuropathy have impaired glucose tolerance versus about 15% of persons without peripheral neuropathy, he noted.

The present study was undertaken to determine whether aggressive treatment of impaired glucose tolerance results in slowed neuropathy progression. Participants in the trial were overweight and had impaired glucose tolerance confirmed by a two-hour oral glucose tolerance test per the American Diabetes Association guidelines. They also had symptomatic peripheral neuropathy and a confirmatory abnormality on nerve conduction testing, quantitative sensory testing, or sweat testing along with the absence of any other problem or laboratory abnormality known to be associated with peripheral neuropathy.

The patients were advised to follow a low-fat diet and exercise program that was patterned after the Diabetes Prevention Program, although slightly less intensive, Dr. Smith said. The Diabetes Prevention Program was the first major clinical trial to demonstrate that intensive lifestyle modification involving a healthy diet and moderate physical activity for 50 minutes a day five days a week could postpone or delay the onset of type 2 diabetes in persons who were overweight and had impaired glucose tolerance. The Diabetes Prevention Program group also reported that the biguanide metformin was associated with a less-pronounced risk reduction during the three-year trial.

In the present trial, the investigators performed 3-mm skin biopsies at the distal leg and proximal thigh, at baseline and after one year. Baseline distal IENF density averaged 0.9 fibers/mm, and proximal IENF density averaged 4.8 fibers/mm. After one year, distal IENF density had improved by an average of 0.3 mm, and proximal IENF density had improved by an average of 1.4 mm. The improvements were significant.

Distal reinnervation was generally not seen in patients with very low distal IENF density. Improvements in weight, cholesterol levels, and two-hour oral glucose tolerance were also recorded at one year.

INTRIGUING IMPROVEMENT

"What’s particularly interesting and somewhat surprising is that patients’ nerve fiber density and skin biopsy improve," Dr. Smith observed. "We know the natural history of impaired glucose tolerance neuropathy is slow progression over time and that it does not spontaneously remit or improve. Therefore, the finding of improvement of nerve fiber density in the skin over one year suggests that something has happened to cause these improvements that’s inconsistent with the natural history, thereby suggesting that the diet and exercise regimen and improved metabolic parameters are at least transiently effective in causing small fiber nerve regeneration."

Results also showed that the change in proximal IENF density correlated with decreased neuropathic pain. "That is, those patients who had the most dramatic cutaneous reinnervation had the most dramatic improvement in pain," he said. "Conversely, if we didn’t observe much reinnervation, there wasn’t much improvement in pain."

This observation is important, he added, because it suggests that the skin biopsy technique, which was very well tolerated, will be an extremely useful progression measure for future treatment studies involving patients with impaired glucose tolerance neuropathy.

BROAD IMPLICATIONS

Beyond suggesting that prediabetic patients may benefit from a diet and exercise program, the data have implications for patients with normal glucose tolerance and neuropathy, Dr. Smith noted. "We advise these patients to diet and exercise with similar goals based on our data as well as other data suggesting that they have a high risk of metabolic syndrome," he said.

Dr. Smith said his group is now planning a study that will randomize patients with impaired glucose tolerance neuropathy to best medical care or to a very aggressive program that manages not only hyperglycemia but also hyperlipidemia and hypertension.

NR

—Jill Stein

Suggested Reading
Gordon Smith A, Robinson Singleton I. Idiopathic neuropathy, prediabetes and the metabolic syndrome. J Neurol Sci. 2006;242:9-14.
Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

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