n-3 Polyunsaturated Fatty Acids to Prevent and Treat Diabetic Neuropathy

Study Overview
=================
Brief Summary
-----------------
Sensorimotor neuropathy (SMN) and cardiovascular autonomic neuropathy (CAN) are the most common complications of type 2 diabetes (T2D). SMN affects  30% of people with T2D and CAN  20%. SMN causes pain, impairs and limits physical activity, and increases the risk for physical disability, complications (such as foot ulcerations), and premature mortality. Moreover, both motor and sensory nerve function are important regulators of muscle function; impaired myofiber innervation causes myofiber loss, muscle fat infiltration, and increases the risk of age-associated sarcopenia and falls. CAN often goes unrecognized because it presents with non-specific symptoms, such as resting tachycardia and fixed heart rate, exercise intolerance, and orthostatic hypotension. However, CAN is a serious problem because it increases the risk for cardiovascular events and mortality several-fold. Both SMN and CAN have long been considered a consequence of T2D, but it is now becoming clear that they precede the diagnosis of T2D and are already detectable in people with prediabetes, especially those with impaired glucose tolerance. Treatments for both SMN and CAN focus on symptom management because there are no effective therapeutics that target the underlying neuropathy. The results from studies conducted in animal models suggest fish oil-derived n-3 polyunsaturated fatty acids (n-3 PUFA) may have therapeutic effects for people with SMN and CAN. The purpose of this proposal is to conduct a randomized controlled trial to test the hypothesis that dietary supplementation with fish oil-derived n-3 PUFA improves sensorimotor and cardiovascular autonomic functions in people with impaired glucose tolerance. Forty 55-80 year old men and women with impaired glucose tolerance (plasma glucose 2 h after a 75 g glucose challenge ≥140 mg/dl) and evidence of SMN (assessed as epidermal nerve fiber density) will be randomized to either receive fish oil-derived n-3 PUFA (4.2 g per day; n=20) or placebo (n=20) for six months. Sensorimotor and cardiovascular autonomic function will be evaluated after three and 6 months of the interventions.

Official Title
-----------------
n-3 Polyunsaturated Fatty Acids to Prevent and Treat Diabetic Neuropathy

Conditions
-----------------
Diabetic Neuropathies

Intervention / Treatment
-----------------
* Dietary Supplement: Fish-oil derived n-3 polyunsaturated fatty acids


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: age: ≥55 and ≤80 years BMI: ≥25.0 and ≤39.9 kg/m2; normal plasma glucose (fasting plasma glucose <100 mg/dl and plasma glucose 2 h after a 75 g glucose challenge <140 mg/dl) for the control group and impaired fasting plasma glucose (≥100 mg/dl) or impaired glucose tolerance (plasma glucose 2 h after a 75 g glucose challenge ≥140 mg/dl) or both for the intervention groups Exclusion Criteria: age: <55 and >80 years BMI: <25.0 and >39.9 kg/m2 fasting plasma glucose ≥100 mg/dl or plasma glucose 2 h after a 75 g glucose challenge ≥140 mg/dl for the control group and normal plasma glucose (fasting plasma glucose <100 mg/dl, plasma glucose at 2 h after 75 g glucose ingestion <140 mg/dl) for the intervention groups treatment for T2D, except for metformin regular structured high-intensity exercise >150 min total per week significant neurological or other organ system dysfunction (e.g., progressive neuromuscular disease, unstable angina, vasculitis, certain cardiopulmonary diseases, cancer that has been in remission for <5 years, dementia, allergies to the dietary supplement) or significant ambulatory impairments (e.g., limb amputations, being wheelchair-bound) use of certain medications that are incompatible with the study procedures (e.g., certain anticoagulants) or could confound the study outcomes (e.g., anabolic steroids, metronidazole, etc) alcohol use disorder as defined by the NIAAA or use of controlled substances or smoking >20 cigarettes per week regular consumption of fish oil supplements or >2 servings of fatty fish per week x) prisoners, and persons who are unable to grant voluntary informed consent.

Ages Eligible for Study
-----------------
Minimum Age: 55 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention Group<br>Subjects randomized to n-3 PUFA will receive a total of 4.2 g/d of fish oil. | Dietary Supplement: Fish-oil derived n-3 polyunsaturated fatty acids<br>* 4.2 g/d (7 pills with 600 mg each)<br>|
| Placebo Comparator: Placebo Group<br>Subjects randomized to placebo will receive 4.2 g/d sunflower oil. | Dietary Supplement: Fish-oil derived n-3 polyunsaturated fatty acids<br>* 4.2 g/d (7 pills with 600 mg each)<br>|
| No Intervention: Control group<br>Subjects assigned to the control group will be tested once | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensorimotor function | Nerve conduction velocity | Change from baseline to 6 months | 
| Cardiovascular autonomic function | Heart rate variability | Change from baseline to 6 months | 
| Muscle endurance | Decline in torque during repeat muscle contraction | Change from baseline to 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glucose tolerance | Glucose tolerance (plasma glucose concentration during a 75 gram glucose tolerance test) | Change from baseline to 6 months | 
| Insulin sensitivity | Oral insulin sensitivity index | Change from baseline to 6 months | 
| Beta cell function | Insulin secretion rate | Change from baseline to 6 months | 
| Plasma triglyceride concentration | Plasma triglyceride concentration | Change from baseline to 6 months | 
| Muscle strength | Muscle strength | Change from baseline to 6 months | 
| Physical performance | Physical performance test | Change from baseline to 6 months |