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Completed

NCT Number: NCT01686568

Omega-3 Fatty Acids and Insulin Sensitivity

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

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Key information

Conditions

Insulin Resistance Glucose Metabolism Disorders Hyperinsulinism Metabolic Diseases Nutritional and Metabolic Diseases

Age range

18 year–65 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

Mayo Clinic in Rochester

Rochester, Minnesota, 55905, United States

About this study

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).

Who can participate

Healthy volunteers accepted: Yes

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

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

Exclusion criteria

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

Treatment and study plan

Omega-3

Drug

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

Drug

Primary outcomes

  1. 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 outcomes

  1. 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.

  2. 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.

  3. 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).

  4. 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.

  5. 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).

  6. 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.

Sponsors and collaborators

Lead sponsor

Mayo Clinic

Other

Collaborators

  • Building Interdisciplinary Research Careers in Women's Health
  • National Center for Advancing Translational Sciences (NCATS)
  • National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Registry information

Official study title

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

Important dates

Study start
2012
Primary completion
2014
Study completion
2015
First posted
Sep 18, 2012
Registry last updated
Mar 3, 2017

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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