Unearthed Phenomenon Offers Hope for Diabetic Neuropathy

A phenomenon largely ignored since its discovery 100 years ago appears to be a crucial component of diabetic pain, according to new research from The University of Texas at Dallas’ Center for Advanced Pain Studies (CAPS).

Findings from a new study, published in Nature Communications on May 5, suggest that cell clusters called Nageotte nodules are a strong indicator of nerve cell death in human sensory ganglia. These could prove to be a target for drugs that would protect these nerves or help manage diabetic neuropathy.

“The key finding of our study is really a new view of diabetic neuropathic pain,” said Dr. Ted Price BS’97, Ashbel Smith Professor of neuroscience in the School of Behavioral and Brain Sciences, CAPS director and co-corresponding author of the study. “We believe our data demonstrate that neurodegeneration in the dorsal root ganglion is a critical facet of the disease — which should really force us to think about the disease in a new and urgent way.”

Diabetic neuropathy is one of the most common forms of neuropathic pain and affects about 11 million people — nearly one-third of the 38 million diabetics in the United States, according to the Centers for Disease Control and Prevention. It typically affects the extremities, causing sharp, shooting pain.

“Diabetic neuropathy can be debilitating,” said neuroscience research scientist Stephanie Shiers PhD’19, 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 (U19) from the National Institutes of Health, Shiers and other scientists at CAPS are mapping human dorsal root ganglia and other sensory system tissue to understand human pain mechanisms.

“I found an abundance of these Nageotte nodules in a subset of the 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.”

Nageotte nodules are dead sensory neurons that have decayed, and what remains is a cluster of non-neuronal cells. They were first documented in 1922 in rabbits by the French neuroanatomist Jean Nageotte. In the past 100 years, these nodules have been almost entirely ignored in the research literature, only appearing in about 20 papers, many of which are a half-century old.

“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.”

In this study, Shiers and her colleagues sought to characterize Nageotte nodules at the molecular level. Using histology and spatial sequencing, they demonstrated that Nageotte nodules are abundant in sensory ganglia of those with diabetic neuropathy. They 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.”

“This appears to be a unique pathology — something never described before in humans.”

neuroscience research scientist Stephanie Shiers PhD’19

If that’s the case, the discovery could be an indicator of how to create treatment options.

“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 the rare earlier papers mentioning Nageotte nodules are mostly case studies of single individuals, this study had samples from 90 people. Shiers said her documentation of axons sprouting in this manner is also novel — another aspect of this study that represents new territory.

“This could change our basic understanding of sensory neurons. 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.” Shiers said. “We don’t know if this morphology is pathological or if we have lacked understanding of these cells in humans.”

Researchers can study human dorsal root ganglia from such a large selection of patients due to the work of the Southwest Transplant Alliance, a nonprofit organization that recovers donated organs and tissues for transplantation.

“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. “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 said, “The entire study would never have happened without them. This partnership is the most important thing that enables this work.”

Price said the research has led to new ways of thinking about neuropathy.

“In my view, 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.”

Other UT Dallas-affiliated authors from the Department of Neuroscience include Dr. Gregory Dussor, the James Bartlett Chair in Behavioral and Brain Sciences and department head; Dr. Diana Tavares Ferreira, assistant professor; research scientists Andi Wangzhou MS’15, PhD’21, Dr. Joseph Lesnak and Ishwarya Sankaranarayanan PhD’22; doctoral student and former Green Fellow Khadijah Mazhar BS’17; and research assistant Nwasinachi Ezeji BS’20, MS’22. Additional authors are from the Southwest Transplant Alliance and The University of Adelaide in Australia.

This research was supported by the National Institute of Neurological Disorders and Stroke through grants U19NS130608 and R01NS111929.