Importance of Early Intervention

At present, researchers believe that pathogenesis of peripheral neuropathy in patients with prediabetes may involve microvascular abnormalities, dyslipidemia and metabolic syndrome. As a way of monitoring patients with these conditions for peripheral neuropathy, Singleton urges endocrinologists to measure intraepidermal nerve fiber density (IENFD).

“The number of nerve fibers matters,” said Singleton. “Thin nerve fibers seem more vulnerable to injury in prediabetes.”

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Early intervention with lifestyle changes involving diet and exercise may be vital to preventing the severity of nerve damage, he said.

In another study published in 2006 in Diabetes Care, Singleton and his colleagues found that diet and exercise counseling can result in cutaneous reinnervation and improved pain in patients with prediabetes.3 

The study involved 32 patients with prediabetes. The researchers performed 3-mm skin biopsies with measurement of IENFD at the distal leg and proximal thigh at baseline and after 1 year.

Results showed improvements in distal IENFD and proximal IENFD over the 12-month study period. The researchers also found that the change in proximal IENFD correlated with decreased neuropathic pain and a change in sural sensory amplitude.

Available Therapies

“Unfortunately, to date, there are no available treatments to reverse the damage of nerve fibers associated with diabetic neuropathy once established. Intensive treatment of glucose in patients with type 1 diabetes and other risk factors in patients with type 2 diabetes may prevent the development of these complications,” Rodica Busui, MD, PhD, professor of internal medicine, endocrinology, metabolism and diabetes, and co-director of the Neuropathy Center at the University of Michigan in Ann Arbor, said.

Currently, in most cases, clinicians may only treat the symptoms of neuropathy, such as pain, and prescribe alone or in combination gabapentin, pregabalin, fluoxetine and amitriptyline as first-line therapy. 

“Even though in U.S. there are only three agents approved by the FDA to treat neuropathic pain in diabetes, which include pregabalin, duloxetine and tapentadol, which is a narcotic, there are other agents that we know work as well and have a high effectiveness in treating neuropathic pain,” Busui told Endocrinology Advisor. 

“Several guidelines offer additional levels of evidence regarding the efficacy of various other agents such as tricyclic antidepressants, gabapentin and more, but clinicians should consider the presence of comorbidities and possible drug interactions when selecting specific agents.”

She noted that none of these agents have any effect on the nerve fiber damage, however, and they are only used to manage the pain. 

“We don’t have agents that address the mechanism of the disease. We are treating other risk factors. There is evidence to date suggesting that exercise and diet are able to prevent and reverse nerve damage. There are several clinical trials that have looked at diet and exercise and show improvement in both symptoms and more objective measures. Some small studies have shown that the damage can be prevented and ever reversed in prediabetics,” Busui said.

Martin Myers, MD, who is a diabetes specialist and a professor of internal medicine at the University of Michigan, agrees with Busui. He said there is a vital need to diagnose peripheral neuropathy in patients with prediabetes earlier in the course of the disease. 

Additionally, Myers said lifestyle interventions might lead to significant improvements in neuropathic pain.

“Prediabetes is getting to be a bigger and bigger problem and, as a consequence, there are more people with this pain syndrome,” Myers said in an interview with Endocrinology Advisor. “The treatment is the same for diabetics and prediabetics. None of the treatments are going to give them their feeling back. They are going to treat the pain from neuropathy.”

However, in the future, that may change. He said advances in the understanding of what happens to nerve fibers in patients with prediabetes may lead to new treatments that can slow the cascade of events that culminate in peripheral neuropathy in both people with diabetes and those with prediabetes.


  1. Diabetes Latest: More than 29 million adults have diabetes; 1 in 4 doesn’t know. Centers for Disease Control and Prevention website. June 17, 2014. Accessed June 2015.
  2. Lee C et al. Diabetes Care. 2015;38(5):793-800.
  3. Smith GA et al. Diabetes Care. 2006;29(6):1294-1299.