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

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.

Study Overview

• Status: Suspended
• Conditions: Diabetic Neuropathies
• Intervention / Treatment: Dietary supplement: Fish-oil derived n-3 polyunsaturated fatty acids

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Bettina Mittendorfer, Ph.D.; Phone Number: 314-362-8450; Email: mittend@wustl.edu

Study Locations

• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
    • Saint Louis, Missouri, United States, 63110
      • Washington University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention Group; 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; 4.2 g/d (7 pills with 600 mg each)
Placebo Comparator: Placebo Group; Subjects randomized to placebo will receive 4.2 g/d sunflower oil.	Dietary supplement: Fish-oil derived n-3 polyunsaturated fatty acids; 4.2 g/d (7 pills with 600 mg each)
No Intervention: Control group; 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

Collaborators and Investigators

• Sponsor: University of Missouri-Columbia
• Investigators: Principal Investigator: Bettina Mittendorfer, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): January 14, 2021
• Primary Completion (Estimated): December 12, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: July 9, 2020
• First Submitted That Met QC Criteria: November 22, 2021
• First Posted (Actual): December 6, 2021

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 2, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Neuromuscular Diseases; Peripheral Nervous System Diseases; Diabetic Neuropathies
• Other Study ID Numbers: 2097478

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No