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Omega-3 Fatty Acids and Insulin Sensitivity

This study has been completed.
Sponsor:
Collaborators:
National Center for Advancing Translational Science (NCATS)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Building Interdisciplinary Research Careers in Women's Health
Information provided by (Responsible Party):
Ian R. Lanza, Mayo Clinic
ClinicalTrials.gov Identifier:
NCT01686568
First received: September 11, 2012
Last updated: January 18, 2017
Last verified: January 2017
  Purpose
This study is being done to understand the effects of dietary omega-3 fats on insulin sensitivity in adult men and women.

Condition Intervention Phase
Insulin Resistance Drug: Omega-3 Drug: placebo Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Care Provider, Investigator, Outcomes Assessor
Primary Purpose: Treatment
Official Title: Dietary Omega-3 Fatty Acids as a Therapeutic Strategy in Insulin Resistant Humans

Resource links provided by NLM:


Further study details as provided by Ian R. Lanza, Mayo Clinic:

Primary Outcome Measures:
  • Insulin Sensitivity by Hyperinsulinemic-euglycemic Clamp at Baseline and 6 Month Follow up [ Time Frame: Baseline, after 6 months of treatment ]
    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.


Secondary Outcome Measures:
  • Beta Cell Function From Insulin Secretion Following Ingestion of a Mixed Meal at Baseline and 6 Month Follow up [ Time Frame: baseline, after 6 months of treatment ]
    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.

  • Mitochondrial Function Determined by Muscle Biopsy at Baseline and 6 Month Follow up [ Time Frame: Baseline, after 6 months of treatment ]
    Measurements of oxygen consumption in isolated mitochondria will be performed using a polarographic oxygen electrode.

  • Insulin Concentration Needed to Suppress Palmitate Appearance Rates (IC50(Palmitate)f) [ Time Frame: approximately after 6 months of treatment ]
    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).

  • Senescent Cells [ Time Frame: approximately after 6 months of treatment ]
    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.

  • Immunohistochemistry Assessments of Macrophage Burden [ Time Frame: approximately after 6 months of treatment ]
    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).

  • Macrophage Crown-like Structures [ Time Frame: approximately after 6 months of treatment ]
    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.


Enrollment: 31
Actual Study Start Date: December 21, 2012
Study Completion Date: June 8, 2015
Primary Completion Date: October 30, 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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:
  • Essential fatty acids
  • Omega-3 fatty acids
  • Omega-3 polyunsaturated fatty acids
  • PUFAs
  • Lovaza
Placebo Comparator: Placebo
Patients in this group will be supplemented with placebo capsules containing ethyl oleate.
Drug: placebo

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).

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01686568

Locations
United States, Minnesota
Mayo Clinic in Rochester
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
National Center for Advancing Translational Science (NCATS)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Building Interdisciplinary Research Careers in Women's Health
Investigators
Principal Investigator: Ian Lanza, PhD Mayo Clinic
  More Information

Publications:
Responsible Party: Ian R. Lanza, Assistant Professor of Medicine, Mayo Clinic
ClinicalTrials.gov Identifier: NCT01686568     History of Changes
Other Study ID Numbers: 12-004590
KL2TR000136 ( U.S. NIH Grant/Contract )
U24DK100469 ( U.S. NIH Grant/Contract )
DK50456 ( Other Grant/Funding Number: Minnesota Obesity Center )
DK40484 ( Other Grant/Funding Number: Minnesota Obesity Center )
5T32DK007352 ( U.S. NIH Grant/Contract )
5UL1TR000135 ( U.S. NIH Grant/Contract )
Study First Received: September 11, 2012
Results First Received: June 16, 2015
Last Updated: January 18, 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases

ClinicalTrials.gov processed this record on August 16, 2017