A low calorie diet and high intensity exercise can reduce nerve damage in prediabetic mice, according to a Michigan Medicine study. 

Researchers say findings reinforce the potential of lifestyle factors to treat peripheral neuropathy, a prevalent and painful complication of obesity, prediabetes and type 2 diabetes. 

The condition lacks effective medical therapies and affects over 20 million people in the United States.

“While diet and exercise are recommended for improving peripheral neuropathy in prediabetes, obesity and type 2 diabetes, and patients know they are important, there are no detailed guidelines for treatment,” said first author Stéphanie Eid, Ph.D., a research assistant professor of neurology at University of Michigan Medical School. 

“Our findings reveal that specific diet and exercise interventions could be key to reducing nerve damage in obesity and diabetes.”

For the study, investigators in the Michigan Medicine NeuroNetwork for Emerging Therapies assessed the effect of diet and exercise on mice who were fed a high fat diet. 

Those mice not only developed obesity and neuropathy, but their peripheral nerves also became resistant to insulin. Essentially, the mice had diabetes in their nerves. 

The team subjected the mice to a 40% caloric restriction, high intensity interval training or both interventions. 

The interval training, also called HIIT, is a form of exercise that alternates between short bursts of intense activity and periods of lower intensity.

In results published in Diabetes, dietary and exercise interventions successfully reduced the effects of neuropathy in the mice. 

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Caloric restriction, alone or alongside HIIT, reduced metabolic dysfunction associated with a high fat diet, such as impaired glucose metabolism and excessive weight gain. 

“It is clear that diet is superior for improving overall metabolic health, yet both interventions show benefits,” said Eid, who is also the diabetes team leader at the NeuroNetwork for Emerging Therapies.

“By leveraging these strategies, we can empower patients to take control of their health, potentially improving their nerve function and overall well-being.”

The low calorie diet, with or without HIIT, also reduced insulin resistance within the peripheral nerves of mice by activating the AMP-activated protein kinase, or AMPK, a key enzyme that regulates cellular energy balance.

When someone has neuropathy, AMPK activity is reduced, which is associated with lower energy levels and nerve injury. 

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Dietary intervention, alone or coupled with HIIT, boosted AMPK activation in the sciatic nerves of mice. 

In a test tube, AMPK activation reversed insulin resistance in Schwann cells, which form the myelin sheath that cover the nerves.

“Taken together, these results help us understand how peripheral neuropathy develops and the different mechanisms by which diet and exercise improve it,” said senior author Eva Feldman, M.D., Ph.D., James W. Albers Distinguished Professor at U-M, the Russell N. DeJong Professor of Neurology at U-M Medical School and director of the NeuroNetwork for Emerging Therapies at Michigan Medicine.

“Understanding how Schwann cells contribute to nerve insulin resistance and neuropathy progression — and how AMPK activation can reverse this — opens up potential therapeutic options for treating neuropathy. This is especially promising for people who are unwilling or unable to comply with dietary and exercise interventions. We look forward to further exploring this path in our research.”

Additional authors: Bhumsoo Kim, Ph.D., John Hayes, Andrew Carter, Crystal Pacut, Adam Allouch, Emily Koubek, Ph.D., all of University of Michigan, Sarah Elzinga, Ph.D., of Michigan State University, and Amy Rumora, Ph.D., of Columbia University.

Funding/disclosures: Research reported in this publication was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (P30DK020572, K01DK135799, R00DK119366, R01DK130913; R24DK08284). This study was also supported by the National Institute on Aging of the NIH (K99AG071667). This content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. 

Additional support was provided in part by the Robert and Katherine Jacobs Environmental Health Initiative, Sinai Medical Staff Foundation, Edith S. Briskin/SKS Foundation NeuroNetwork Emerging Scholar Fund, Novo Nordisk Foundation, NeuroNetwork for Emerging Therapies, Tauber Family Student Internship Program, Andrea and Lawrence Wolfe Brain Health Initiative, Nathan and Rose Milstein Research Fund and John H. Doran Neuropathy Research Fund.

Paper cited: “High-Intensity Interval Training, Caloric Restriction, or Their Combination Have Beneficial Effects on Metabolically Acquired Peripheral Neuropathy,” Diabetes. DOI: 10.2337/db23-0997

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