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Diabetic neuropathy presents unique research challenges


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Nigel A. Calcutt, PhD
Nigel A. Calcutt, PhD

The 81st Scientific Sessions symposium Resolving Key Controversies in Diabetic Neuropathy featured a panel of researchers who discussed some of the most challenging issues they face while investigating methods to prevent and treat diabetic neuropathies.

The session, which was originally presented Saturday, June 26, can be viewed by registered meeting attendees at through September 29, 2021. If you haven’t registered for the Virtual 81st Scientific Sessions, register today to access all of the valuable meeting content.

Nigel A. Calcutt, PhD, Professor of Pathology at the University of California, San Diego, opened the symposium with a discussion about the challenges of translating success in animal models to success in clinical trials. He noted that a recent Medline search for papers published on “diabetic neuropathy treatment” yielded more than 18,000 results.

“And how many FDA-approved treatments are there for diabetic neuropathy? Zero,” Dr. Calcutt said. “So, there’s clearly been a challenge in translating ideas into drugs. In part, at least to start with, this comes from the differences between the models and humans.”

The stressors that contribute to neuropathy in humans are not just hyperglycemia, he said, but also dyslipidemia as well as a strong association with hypertension.

Fabiana Picconi, MD
Fabiana Picconi, MD

“Exposure to those stressors can go on for years to decades or more, and the presentation of neuropathy is therefore a relatively slow onset over a number of years and a slow progression of many years,” Dr. Calcutt said.

In a mouse or rat model, because the animals live for only weeks or months with extreme hyperglycemia, there is a much shorter duration of exposure and neuropathy presents with rapid onset and progression, he said.

“We have to accept that diabetic rodents are not diabetic humans—they are a model and there is a big ‘if’ in that model—so one has to be very cautious,” Dr. Calcutt said. “You can bolster things by doing as many studies as possible to give you confidence, but making that leap for human trials is at best a semi-educated guess based upon cumulative data in animal models.”

Fabiana Picconi, MD, Unit of Endocrinology, Diabetes, and Metabolism, University of Rome Tor Vergata, Italy, discussed the impact of lipid-lowering statin treatment on the risk for diabetic neuropathies.

Karolina S. Khan, MD, PhD
Karolina S. Khan, MD, PhD

“The proverbial smoking gun providing a robust and definitive association between statins and peripheral neuropathy remains to be established,” she said. “Additional longitudinal studies on the role of cholesterol metabolism in diabetic peripheral neuropathy are required to determine whether there is a critical threshold of serum cholesterol for an impairment of nerve regeneration.”

Although observational associations persist, Dr. Picconi said a scientific statement from the American Heart Association states there is no conclusive evidence for a causal relationship between statin treatment and peripheral neuropathy.

“Most importantly, the potential risks of statins on diabetic peripheral neuropathy is largely outweighed by the substantial clinical effect of statins in cardiovascular disease prevention in diabetes,” she said.

Karolina S. Khan, MD, PhD, Department of Neurosurgery and Neurology, Aarhus University Hospital, Denmark, discussed the effects of diabetic neuropathy on the risk of falls and fractures.

“Fall accidents are the second-leading cause of unintentional injury deaths in the world, and recently it has been suggested that individuals with diabetic neuropathy suffer from an even higher risk of falling and more severe injuries such as fractures,” Dr. Khan said.

Kara R. Mizokami-Stout, MD
Kara R. Mizokami-Stout, MD

Additionally, she said that people with diabetic neuropathy report a higher fear of falling and may suffer from impaired gait and increased postural instability.

“Assessments of postural stability, gait kinematics, functional and psychological tests, amongst others, should be included when designing an effective fall prevention program in order to prevent falling in the diabetic neuropathy population,” she said. “Further investigational studies are needed to describe the underlying mechanisms regarding the direct effects of diabetic neuropathy on skeletal fragility and fractures.”

Kara R. Mizokami-Stout, MD, Assistant Professor of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan, concluded the symposium by analyzing the impact of social and psychological determinants of health on diabetic peripheral and autonomic neuropathy.

While the number of studies exploring the association between social and psychological determinants of health on diabetes self-management, glycemic control, and microvascular outcomes continues to grow, Dr. Mizokami-Stout said studies related specifically to an association with diabetic neuropathy are sparse.

She cited the recent results from a large Scottish study of type 1 diabetes patients that showed individuals who lived in more disadvantaged areas had significantly higher odds of developing diabetic peripheral neuropathy than those living in less deprived areas.

“Early evidence demonstrates patients with diabetes and peripheral and autonomic neuropathy are particularly affected by social and psychological determinants. However, the underlying mechanisms need further exploration,” she said. “Therefore, developing and supporting studies that specifically target social determinants of health should be considered for both peripheral and autonomic neuropathy.”


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