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Omega-3 Fatty Acids and Insulin Sensitivity

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ClinicalTrials.gov Identifier: NCT01686568
Recruitment Status : Completed
First Posted : September 18, 2012
Results First Posted : July 10, 2015
Last Update Posted : March 3, 2017
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

Tracking Information
First Submitted Date  ICMJE September 11, 2012
First Posted Date  ICMJE September 18, 2012
Results First Submitted Date  ICMJE June 16, 2015
Results First Posted Date  ICMJE July 10, 2015
Last Update Posted Date March 3, 2017
Actual Study Start Date  ICMJE December 21, 2012
Actual Primary Completion Date October 30, 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 16, 2015)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 17, 2012)
  • Change from baseline in insulin sensitivity by hyperinsulinemic-euglycemic clamp [ 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.
  • Change from baseline in beta cell function following ingestion of a mixed meal [ Time Frame: baseline, after 6 months of treatment ]
    Following consumption of a mixed meal, insulin secretion and beta cell function will be evaluated from serial measurements of C-peptide, insulin, and glucose.
Change History Complete list of historical versions of study NCT01686568 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: January 18, 2017)
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 17, 2012)
  • Change from baseline in mitochondrial function determined by muscle biopsy [ Time Frame: Baseline, after 6 months of treatment ]
  • Change from baseline in muscle and liver lipid content [ Time Frame: baseline, 6 months ]
    Magnetic resonance spectroscopy will be used to measure lipid content in skeletal muscle and liver.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Omega-3 Fatty Acids and Insulin Sensitivity
Official Title  ICMJE Dietary Omega-3 Fatty Acids as a Therapeutic Strategy in Insulin Resistant Humans
Brief Summary This study is being done to understand the effects of dietary omega-3 fats on insulin sensitivity in adult men and women.
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  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Insulin Resistance
Intervention  ICMJE
  • 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
  • Drug: placebo
Study Arms  ICMJE
  • Experimental: Omega-3
    Patients in this group will receive oral supplementation with EPA+DHA (3.9grams/day) for 6 months.
    Intervention: Drug: Omega-3
  • Placebo Comparator: Placebo
    Patients in this group will be supplemented with placebo capsules containing ethyl oleate.
    Intervention: Drug: placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: June 16, 2015)
31
Original Estimated Enrollment  ICMJE
 (submitted: September 17, 2012)
40
Actual Study Completion Date  ICMJE June 8, 2015
Actual Primary Completion Date October 30, 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01686568
Other Study ID Numbers  ICMJE 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 )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Ian R. Lanza, Mayo Clinic
Study Sponsor  ICMJE Mayo Clinic
Collaborators  ICMJE
  • 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  ICMJE
Principal Investigator: Ian Lanza, PhD Mayo Clinic
PRS Account Mayo Clinic
Verification Date January 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP