Type 2 diabetes (T2D) affects >8% of Americans, half of whom develop diabetic peripheral neuropathy (DPN). DPN is a major cause for disability due to sensory loss, pain, gait instability, falls, foot ulcers and amputations. There are no effective disease altering therapies for DPN in T2D. Even intensive glycemic control, which is of proven benefit in T1D, is only marginally effective in reducing DPN risk in T2D. The Utah Diabetic Neuropathy Study (UDNS) aimed to facilitate therapeutic development for DPN by evaluating skin biopsy with assessment of intraepidermal nerve fiber density (IENFD) as a biomarker. Results indicate that early DPN is characterized by progressive loss of small fiber function, reflected in declining IENFD, cold thermal sensation and sudomotor function. IENFD correlates with patient symptoms, notably pain severity, and physical examination scores. Early IENFD decline predicts future risk of incident DPN. Among 84 T2D participants randomized to intensive exercise or general counseling, the former experienced a significant improvement in IENFD compared to no change in the control group. These results add to other preliminary data indicating that successful exercise results in improvement in peripheral nerve regenerative capacity. Unfortunately, intensive exercise is of limited long-term efficacy due to poor compliance and the behavioral pattern of compensatory increase in caloric intact and sedentary behavior. We hypothesize that an intervention integrating moderate supervised exercise with actigraphy based strategies to reduce sedentary behavior will result in sustainable metabolic improvement and that this novel strategy will slow the rate of IENFD decline and improve neuropathy specific quality of life in patients with DPN due to T2D. We hypothesize the intervention will improve insulin sensitivity and reduce oxidative stress and inflammation, resulting in enhanced peripheral nerve regenerative capacity. The Activity for Diabetic Polyneuropathy - ADAPT Study will randomize 140 T2D patients with mild to moderate DPN to either generic annual counseling or an integrated program of moderate supervised exercise and actigraphy based anti-sedentariness counseling. IENFD at the distal thigh and the Norfolk Quality of Life - Diabetic Neuropathy (NQOL-DN) will serve as primary endpoint measures. The study will be judged positive if there is a treatment response in both endpoints. The goal is to determine if this novel approach to increasing home activity and reduced sedentary time is an effective therapy for DPN. A second objective is to better evaluate the clinical meaning of change in IENFD. Skin biopsies will be used to explore the intervention's impact on epidermal regeneration and inflammation. Skin, serum and DNA will be banked for future mechanistic studies. There is an urgent need for better early DPN biomarkers. Our data indicate IENFD is reproducible and responsive, and that it correlates with clinically meaningful features of DPN in a cross sectional fashion, but the patient focused meaning of its decline is unknown. The results of the ADAPT Study will be of immediate significance. If the intervention were successful, a greater clinical focus on strategies to reduced sedentary behavior at home would be justifiable and a randomized trial to demonstrate effectiveness in a clinical setting would be appropriate. Demonstration of a minimally clinically meaningful change in IENFD would greatly facilitate early phase proof of concept trials for DPN, thus supporting therapeutic development for this common and disabling diabetic complication.
Type 2 diabetes (T2D) affects over 8% of Americans, and half will develop peripheral neuropathy, a progressive injury to the very longest nerves of the body. Our previous research has found that neuropathy can be detected early in its course and followed by examining nerves that reach to the skin using a small punch biopsy. These cutaneous nerves can be injured by high blood glucose, obesity and high triglycerides, but have the potential to regrow in response to treatments that improve these metabolic conditions. The proposed study will randomize participants with diabetic peripheral neuropathy to receive either standard care, or supervised exercise and counseling to increase physical activity for a period of 18 months.
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| Kluding, Patricia M; Singleton, J Robinson; Pasnoor, Mamatha et al. (2017) Activity for Diabetic Polyneuropathy (ADAPT): Study Design and Protocol for a 2-Site Randomized Controlled Trial. Phys Ther 97:20-31 |
| Singleton, J Robinson; Marcus, Robin L; Lessard, Margaret K et al. (2015) Supervised exercise improves cutaneous reinnervation capacity in metabolic syndrome patients. Ann Neurol 77:146-53 |
| Kinard, Krista I; Smith, A Gordon; Singleton, J Robinson et al. (2015) Chronic migraine is associated with reduced corneal nerve fiber density and symptoms of dry eye. Headache 55:543-9 |
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| Tavakoli, Mitra; Ferdousi, Maryam; Petropoulos, Ioannis N et al. (2015) Normative values for corneal nerve morphology assessed using corneal confocal microscopy: a multinational normative data set. Diabetes Care 38:838-43 |
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| Smith, A Gordon; Singleton, J Robinson (2013) Obesity and hyperlipidemia are risk factors for early diabetic neuropathy. J Diabetes Complications 27:436-42 |
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