As the global prevalence of type 2 diabetes continues to rise, fueled in part by diets high in fat and fructose, a significant health complication is becoming more common: peripheral neuropathy. This condition, which results from nerve damage often in the hands and feet, affects roughly half of those with type 2 diabetes. Symptoms include weakness, loss of sensation, and, in many cases, excruciating pain. A groundbreaking study from Boston Children’s Hospital sheds new light on the early stages of this disease and presents potential strategies to slow or prevent its progression.
Researchers, led by Dr. Clifford Woolf, director of the F.M. Kirby Neurobiology Center at Boston Children’s Hospital, discovered that months before nerve damage becomes apparent, immune cells flood peripheral nerves in an apparent attempt to protect them. This novel finding, published in Nature, may offer new avenues for preventing neuropathy or at least mitigating its effects.
Immune Cells Play a Protective Role
The study, led by graduate student Sara Hakim, PhD, utilized a mouse model of diabetes induced by a high-fat, high-fructose diet. Within 8 to 12 weeks, the mice exhibited the key features of type 2 diabetes, and by six months, nerve degeneration began, signaling the onset of neuropathy.
“We were able to track the disease progression over time and observe the body’s early efforts to combat nerve damage,” says Hakim, now with Vertex Pharmaceuticals. “Diabetic neuropathy typically takes years or even decades to develop in humans, so our model provided valuable insights into the early, protective responses.”
The team’s analysis revealed that, contrary to previous belief, immune cells called macrophages did not exacerbate nerve damage. Instead, the researchers found that these cells initially infiltrated the nerves, releasing signaling molecules known as chemokines. These macrophages attracted other immune cells, which began to enter the nerves 12 weeks after the mice were put on the diet—right around the time sensory symptoms emerged, but before any actual nerve degeneration took place.
Surprising Findings on Macrophages
The study’s findings challenged the long-held assumption that macrophages were a detrimental force in diabetic neuropathy. When the researchers blocked macrophage infiltration, they observed that the progression of neuropathy actually worsened.
“The macrophages were protective—they slowed the onset of neuropathy and reduced its severity,” says Dr. Woolf. This surprising discovery opens the door to new potential treatments aimed at enhancing this immune response to prevent nerve damage in diabetic patients.
Exploring Protective Strategies
The next step for Dr. Woolf’s team is to explore how these infiltrating macrophages protect against neuropathy and whether their actions can be sustained or enhanced. One possibility is to accelerate macrophage recruitment to the nerves, while another approach could involve mimicking the protective molecules they release, such as galectin 3.
By profiling the immune cells and identifying the genes they express, the team has pinpointed several signaling molecules that could play a protective role. “We are now working to determine which of these molecules are most active and could be leveraged for therapeutic purposes,” says Dr. Woolf.
This research also reinforces the idea that pain and nerve damage in diabetes are not solely a result of neuronal dysfunction. Instead, they stem from complex interactions between the nervous system and the immune system. Last year, the Woolf Lab discovered thousands of molecular interactions between pain-sensing neurons and various types of immune cells, further highlighting the critical role the immune system plays in pain and nerve health.
Moving Forward
With this new understanding of immune cells’ role in preventing neuropathy, researchers are optimistic that future therapies could focus on enhancing the immune response to delay or prevent nerve damage in individuals with type 2 diabetes. Additionally, identifying biomarkers to predict those at risk for developing neuropathy could be a crucial step in early intervention.
As research continues, these findings offer hope for better management and potentially even prevention of one of the most debilitating complications of type 2 diabetes.
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