A little-known structure in human nerve tissue—first documented more than 100 years ago and largely ignored ever since—has resurfaced as a surprising lead in the search for better treatments for one of the most common complications of diabetes: diabetic neuropathy.

Researchers at the University of Texas at Dallas’ Center for Advanced Pain Studies say these overlooked clusters, called Nageotte nodules, are closely associated with neurodegeneration in the sensory nervous system. 

Their discoveries could help explain why diabetes causes chronic pain for millions and point toward new ways to protect nerves and prevent damage. The nodules themselves may offer a new target for drugs to slow nerve degeneration or help manage pain, according to the university.

Published in Nature Communications, the study focuses on the dorsal root ganglion, a nerve center affected in diabetic neuropathy. The condition affects more than 11 million Americans. The research was supported by grants from the National Institute of Neurological Disorders and Stroke.

“The key finding of our study is really a new view of diabetic neuropathic pain,” said Ted Price, a professor of neuroscience at UT Dallas and co-corresponding author of the study.

Price and the team believe their data show that neurodegeneration in the dorsal root ganglion is a “critical facet” of the disease. That, he says, “should really force us to think about the disease in a new and urgent way.”

Ted Price, UT Dallas Ashbel Smith Professor of neuroscience in the School of Behavioral and Brain Sciences. [Photo: UT Dallas]

A widespread problem

The university said diabetic neuropathy typically affects the extremities, causing sharp, shooting pain. It’s one of the most common forms of neuropathic pain—and one of the most difficult to manage.

Diabetic neuropathy is one of the most common forms of neuropathic pain—and one of the most difficult to manage.

“Diabetic neuropathy can be debilitating,” said neuroscience research scientist Stephanie Shiers, a co-corresponding author. “Treatment options are not great, and if the underlying diabetes is not managed, people may require amputation due to damage to the peripheral nerves to the point of loss of sensation.”

With support from a Research Program Cooperative Agreement grant from the National Institutes of Health, CAPS researchers are mapping human dorsal root ganglia and other sensory system tissue to better understand human pain mechanisms, the university said.

‘Virtually nobody in the pain field had heard of them’

Shiers said she found an abundance of Nageotte nodules in a subset of dorsal root ganglia recovered from organ donors.

“When I looked up the medical history on these samples, they were all from individuals with diabetes,” she said. “These nodules were more prevalent in people with diabetes and even more so in those with diabetic neuropathy. Organ donors die from a range of conditions, so discovering these abnormalities in a large subset of the tissue with a similar medical history was a big break.”

The nodules were first documented in 1922 in rabbits by French neuroanatomist Jean Nageotte.

Originally observed in rabbits by French neuroanatomist Jean Nageotte, the nodules are believed to be remnants of dead sensory neurons surrounded by non-neuronal cells.

In the scientific literature of the past century, they’ve appeared in only about 20 studies, many published more than 50 years ago, according to the university.

“They appear to be a sign of degeneration where hyperglycemia reduces neuron viability,” Shiers said. “Little has been documented about these structures’ molecular composition. Virtually nobody in the pain field had heard of them, and we knew almost nothing about their involvement in pain and neurodegeneration.”

Inside the nodules: A new kind of nerve cell activity

In the CAPS study, researchers used histology and spatial sequencing to show that Nageotte nodules are abundant in the sensory ganglia of people with diabetic neuropathy. The university said the nodules are mainly composed of satellite glia and non-myelinating Schwann cells.

“Intertwined with the nodule is a bundle of axons: fibers of sensory neurons that look like little neuromas. The axons there appear to sprout from sensory neurons; they are pain-sensing fibers,” Shiers said. “This appears to be a unique pathology—something never described before in humans.”

That uniqueness, the university said, could represent a promising new direction for treatment.

“Spontaneous activity in these fibers may be what’s behind diabetic neuropathy,” Shiers said. “We also had several donors with other types of neuropathic conditions that weren’t diabetes-related, and their DRGs also had an abundance of Nageotte nodules.”

While prior studies were mostly limited to individual case reports, the new research included tissue samples from 90 donors. Shiers said her documentation of axons sprouting in this pattern is also novel.

“This could change our basic understanding of sensory neurons,” she said. “Sensory neurons are not supposed to sprout fibers from their cell bodies; they have a unique shape that we call pseudounipolar, but these diabetic sensory neurons do not look pseudounipolar—they look multipolar.”

Organ donation opens new doors for research

The university credited the Southwest Transplant Alliance—a nonprofit that recovers donated organs and tissues for transplantation—with making the research possible.

“The ability to give life to others through research is incredibly important to our donation community,” Southwest Transplant Alliance President and CEO Brad Adams said in a statement. “Knowing that your loved one’s gift led to incredible medical discoveries and advances such as this brings hope and healing to all who have lost a loved one.”

Price credited the role the alliance played in the research.

“The entire study would never have happened without them. This partnership is the most important thing that enables this work,” Price said, adding that the research has led to new ways of thinking about neuropathy.

“One of the most important insights we gained from this work is thinking about treating diabetic neuropathic pain differently. I think what we need to focus on now is neuroprotection at early stages of disease so that these Nageotte nodules do not form in the first place,” Price said.

The university said other UT Dallas-affiliated authors include Dr. Gregory Dussor, Dr. Diana Tavares Ferreira, research scientists Andi Wangzhou, Dr. Joseph Lesnak, and Ishwarya Sankaranarayanan; doctoral student and former Green Fellow Khadijah Mazhar; and research assistant Nwasinachi Ezeji. Additional authors are affiliated with the Southwest Transplant Alliance and The University of Adelaide in Australia.

Quincy Preston contributed to this report.

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