Omega-3 Fatty Acids and Insulin Sensitivity

Phase 3

Completed

Conditions: Insulin Resistance

Interventions: Drug: Omega-3
Drug: placebo

Registration Number: NCT01686568

Lead Sponsor: Mayo Clinic

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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 31

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Omega-3	Omega-3	Patients in this group will receive oral supplementation with EPA+DHA (3.9grams/day) for 6 months.
Placebo	placebo	Patients in this group will be supplemented with placebo capsules containing ethyl oleate.

Primary Outcome Measures

Name	Time	Method
Insulin Sensitivity by Hyperinsulinemic-euglycemic Clamp at Baseline and 6 Month Follow up	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

Name	Time	Method
Beta Cell Function From Insulin Secretion Following Ingestion of a Mixed Meal at Baseline and 6 Month Follow up	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	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)	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	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	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	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.