Heat Shock Therapy to Improve Mitochondrial Function in Neuropathy

Heat Shock Therapy to Improve Mitochondrial Function in Neuropathy

Sensory dysfunction as a result of peripheral nerve damage is a significant problem that leads to reduced quality of life for patients. The prevalence of sensory dysfunction in peripheral neuropathy associates with epidemic increases in prediabetes and diabetes, but also is relevant to chemotherapy treatments and genetic disorders. Clinical approaches to treat peripheral neuropathy and to stimulate axon growth in settings of peripheral axon loss are limited. Although new drugs will hopefully be forthcoming, the most promising approaches likely involve behavioral and lifestyle interventions. Mitochondrial dysfunction is emerging as a key cellular contribution to peripheral axon health and peripheral neuropathy. Mitochondrial deficiencies contribute to neuropathy and include impaired mitochondrial problems with trafficking, mitophagy, fission, and biogenesis. All of these are thought to lead to a bioenergetic crisis, ending in distal axonal degeneration, sensory dysfunction and pain. Heat shock proteins play a critically important role in cellular homeostasis and increasing heat shock protein functions within cells leads to a range of positive improvements, particularly in mitochondria. In addition, new evidence suggests that increasing heat shock protein responses in peripheral nerves has powerful, positive impacts on sensory function and neuropathy.

Our interdisciplinary team will investigate the role of mitochondrial dysfunction in peripheral neuropathy and translate these approaches to improve treatment for patients with peripheral neuropathy. The investigators hypothesize that novel heat treatment interventions that improve mitochondrial function will improve metabolic symptoms and peripheral nerve mitochondria, leading to improvements in sensory function, via heat shock protein induction. The investigators will employ immersion heat treatment to elevate heat shock protein responses that induce positive changes in peripheral nerve mitochondria. One aspect is to confirm the efficacy, safety, and potential for heat treatment to improve sensory dysfunction in human patients with prediabetes. The goal of this proposal is 1) to test the breadth of heat treatment on various forms of neuropathy, 2) identify mechanisms in which heat treatment improves mitochondrial function, and 3) test the efficacy, safety, and potential for heat treatment to improve sensory dysfunction in human patients with prediabetes.

Inclusion criteria:

1. both males and females,
2. ages 45-75,
3. have suspected or diagnosed prediabetes with or without neuropathy (to be confirmed at pre-intervention evaluation).

Exclusion criteria:

1. skin conditions, circulatory insufficiency, or open wounds in the leg that would interfere with healing from a biopsy;
2. stroke or other significant nervous system pathology;
3. lidocaine allergy;
4. anticipated difficulty with blood clotting due to disorder or use of a blood thinner such as Coumadin, Xarelto, or Eliquis;
5. use of any medication used to treat abnormal blood glucose such as Metformin;
6. body weight > 350 lbs.;
7. history of anemia or vitamin b12 deficiency;
8. clinical anemia (hematocrit <32 for women, <36 for men);
9. abnormal SPEP result;
10. history of cancer or chemotherapy treatment;
11. current or recent use (within the last 6 months) of artificial fingernails / nail enhancements that would interfere with quantitative sensory testing;
12. no special classes of subjects such as fetuses, neonates, pregnant women, prisoners, institutionalized individuals, non-English speaking individuals, or other who may be considered vulnerable populations will be included in this study.

Withdrawal/Termination criteria: Prediabetes will be determined using the American Diabetes Association (ADA) Diabetes Management Guidelines. The subject will meet the criteria for a diagnosis of pre-diabetes if the subject has one or more positive test(s) for either A1c (5.7-6.4%), fasting glucose (100-125 mg/dl), or 2-hr oral glucose tolerance test (140-199 mg/dl). If at pre-intervention evaluation, the subject does not meet the criteria for prediabetes (lower than the above-mentioned range), meets the ADA criteria for diabetes (higher than the above-mentioned range), the subject will be considered a screen fail and will not progress to skin biopsy or intervention.