Omega-3 Fatty Acids and Insulin Sensitivity

Dietary Omega-3 Fatty Acids as a Therapeutic Strategy in Insulin Resistant Humans

This study is being done to understand the effects of dietary omega-3 fats on insulin sensitivity in adult men and women.

Study Overview

• Status: Completed
• Conditions: Insulin Resistance
• Intervention / Treatment: Drug: placebo; Drug: Omega-3

Detailed Description

Dietary omega-3 polyunsaturated fatty acids (n-3 PUFA), which include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish oil, prevent insulin resistance in rodents, but data in humans is ambiguous. No existing studies have systematically evaluated the influence of n-3 PUFAs on insulin sensitivity and beta cell function in insulin resistant, non-diabetic humans. The Investigators hypothesize that 6 months of oral supplementation of purified EPA/DHA (3.9g/day) will significantly improve hepatic and peripheral insulin sensitivity and beta cell responsiveness in insulin-resistant, non-diabetic individuals. Based on recent work in mice, the investigators also hypothesize that EPA/DHA will increase the content and function of mitochondria in skeletal muscle, measured using a combination of in vivo and in vitro methods. Overall, the investigators hypothesize that EPA+DHA supplementation will improve hepatic and peripheral insulin sensitivity in insulin resistant humans, and this improvement will be associated with mitochondrial biogenesis and attenuated lipid accumulation in skeletal muscle and liver.

A sub-study was added in which participants receiving dietary omega-3 fatty acids or placebo supplements underwent abdominal subcutaneous adipose tissue biopsies to measure the content of total, pro- (M1) and anti- (M2) inflammatory macrophages (immunohistochemistry), crown-like structures (immunohistochemistry), and senescent cells (β-galactosidase staining), as well as a two-step euglycemic, pancreatic clamp with a stable-isotope labeled precursor ((U-13C)palmitate) infusion to determine the insulin concentration needed to suppress palmitate flux by 50% (IC50(palmitate)f).

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Age 18-65 years
2. Insulin resistant (Homeostasis Model Assessment (HOMA) Insulin Resistance (IR) ≥2.6)

Exclusion criteria:

1. Current use of omega-3 nutritional supplements
2. Fasting plasma glucose ≥126 mg/dL
3. Active coronary artery disease
4. Participation in structured exercise (>2 times per week for 30 minutes or longer)
5. Smoking
6. Medications known to affect muscle metabolism (e.g., beta blockers, corticosteroids, tricyclic-antidepressants, benzodiazepines, opiates, barbiturates, anticoagulants)
7. Renal failure (serum creatinine > 1.5mg/dl)
8. Chronic active liver disease (AST>144 IU/L and alanine transaminase (ALT)>165 IU/L)
9. Anti-coagulant therapy (warfarin/heparin)
10. International normalized ratio (INR) >3
11. Use of systemic glucocorticoids
12. Chronic use of NSAIDS or aspirin
13. Pregnancy or breastfeeding
14. Alcohol consumption greater than 2 glasses/day
15. Hypothyroidism
16. Fish or shellfish allergy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Omega-3; Patients in this group will receive oral supplementation with EPA+DHA (3.9grams/day) for 6 months.	Drug: Omega-3; Patients in this group will receive oral supplementation with EPA+DHA (3.9grams/day) for 6 months.; Other Names: Lovaza; Omega-3 polyunsaturated fatty acids; Omega-3 fatty acids; Essential fatty acids; PUFAs
PLACEBO_COMPARATOR: Placebo; Patients in this group will be supplemented with placebo capsules containing ethyl oleate.	Drug: placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Insulin Sensitivity by Hyperinsulinemic-euglycemic Clamp at Baseline and 6 Month Follow up	A 2-stage insulin clamp will be performed with titration of dextrose to maintain euglycemia. D2 glucose will be infused to evaluate hepatic glucose production at baseline and in response to insulin. Hyperinsulinemic-euglycemic clamp technique: The plasma insulin concentration is acutely raised and maintained by a continuous infusion of insulin. Meanwhile, the plasma glucose concentration is held constant at basal levels by a variable glucose infusion. When the steady-state is achieved, the glucose infusion rate (GIR) equals glucose uptake by all the tissues in the body and is therefore a measure of tissue insulin sensitivity.	Baseline, after 6 months of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Beta Cell Function From Insulin Secretion Following Ingestion of a Mixed Meal at Baseline and 6 Month Follow up	Following consumption of a mixed meal, beta cell function will be evaluated from serial measurements of C-peptide. C-peptide was measured using a two-side immunometric assay using electrochemiluminescence detection.	baseline, after 6 months of treatment
Mitochondrial Function Determined by Muscle Biopsy at Baseline and 6 Month Follow up	Measurements of oxygen consumption in isolated mitochondria will be performed using a polarographic oxygen electrode.	Baseline, after 6 months of treatment
Insulin Concentration Needed to Suppress Palmitate Appearance Rates (IC50(Palmitate)f)	Sensitivity of adipose tissue lipolysis to insulin suppression, was calculated as the insulin concentration needed to suppress palmitate appearance rates (ie, flux) by 50% (IC50(palmitate)f).	approximately after 6 months of treatment
Senescent Cells	Tissue burden of senescent cells, which was measured by staining for senescence-associated B-galactosidase activity and expressed as the number per 100 nucleated positive cells.	approximately after 6 months of treatment
Immunohistochemistry Assessments of Macrophage Burden	One week after the pancreatic clamp study, participants were provided a standardized meal before an overnight fast. The next morning an abdominal adipose tissue biopsy was collected, and the samples were analyzed for adipocyte size. Immunohistochemistry was used to assess macrophage burden (total (CD68), M1 (CD14) and M2 (CD206) macrophages per 100 adipocytes).	approximately after 6 months of treatment
Macrophage Crown-like Structures	Macrophages surrounding dying or dead adipocytes form crown-like structures (CLSs). One week after the pancreatic clamp study, participants were provided a standardized meal before an overnight fast. The next morning an abdominal adipose tissue biopsy was collected, and the samples were analyzed for adipocyte size. Immunohistochemistry was used to assess the number of crown-like structures per 10 images.	approximately after 6 months of treatment

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Center for Advancing Translational Sciences (NCATS); Building Interdisciplinary Research Careers in Women's Health
• Investigators: Principal Investigator: Ian Lanza, PhD, Mayo Clinic

Publications and helpful links

General Publications

• Lalia AZ, Johnson ML, Jensen MD, Hames KC, Port JD, Lanza IR. Effects of Dietary n-3 Fatty Acids on Hepatic and Peripheral Insulin Sensitivity in Insulin-Resistant Humans. Diabetes Care. 2015 Jul;38(7):1228-37. doi: 10.2337/dc14-3101. Epub 2015 Apr 7.
• Hames KC, Morgan-Bathke M, Harteneck DA, Zhou L, Port JD, Lanza IR, Jensen MD. Very-long-chain omega-3 fatty acid supplements and adipose tissue functions: a randomized controlled trial. Am J Clin Nutr. 2017 Jun;105(6):1552-1558. doi: 10.3945/ajcn.116.148114. Epub 2017 Apr 19.

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 21, 2012
• Primary Completion (ACTUAL): October 30, 2014
• Study Completion (ACTUAL): June 8, 2015

Study Registration Dates

• First Submitted: September 11, 2012
• First Submitted That Met QC Criteria: September 17, 2012
• First Posted (ESTIMATE): September 18, 2012

Study Record Updates

• Last Update Posted (ACTUAL): March 3, 2017
• Last Update Submitted That Met QC Criteria: January 18, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperinsulinism; Insulin Resistance
• Other Study ID Numbers: 12-004590; KL2TR000136 (NIH); U24DK100469 (NIH); DK50456 (OTHER_GRANT: Minnesota Obesity Center); DK40484 (OTHER_GRANT: Minnesota Obesity Center); 5T32DK007352 (NIH); 5UL1TR000135 (NIH)

Drug and device information, study documents

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