The purpose of this clinical trial is to find out whether one type of fish oil works better than another at improving metabolic health in people who are at high risk of developing type 2 diabetes.

Some metabolic problems-such as difficulty controlling blood sugar, unhealthy particles that transport cholesterol in the blood, and poor fat tissue function-can increase the risk of type 2 diabetes. This study aims to determine whether different types of fish oil can:

1. Improve how well the body produces insulin and responds to it,
2. Improve the quality of the particles that carry "bad" cholesterol in the blood, and 3) Improve the health and function of participants' fat tissue.

To answer these questions, researchers will compare the effects of two types of fish oil: EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid). These will be compared with corn oil, which is used as a placebo and does not contain EPA or DHA.

When included in this study, participants will:

A) Take softgel capsules containing EPA, DHA, or placebo (corn oil) every day for 12 weeks, B) Keep a daily log to record when they take their study softgels, and C) Visit the research unit six times, including one and a half days before and after the intervention, to complete specialized metabolic tests that are mostly only available in research settings.

Background and Rationale:

According to the International Diabetes Federation, about 590 million adults worldwide-or 1 in 9 adults-were living with diabetes in 2025, most of whom had type 2 diabetes (T2D). An additional 230 million adults (about 4 in 10) are unaware that they have diabetes and therefore remain undiagnosed. Diabetes substantially increases the risk of illness and death and has an impact comparable to aging approximately 15 years, making it a leading cause of disability and mortality worldwide.

Type 2 diabetes develops gradually as multiple risk factors accumulate over time, including unhealthy lifestyle habits and aging. These factors reduce the body's ability to produce insulin and/or respond effectively to insulin, a hormone that regulates blood sugar levels. As a result, blood sugar levels progressively rise and may eventually lead to a diagnosis of T2D.

Importantly, type 2 diabetes is preventable.

In people with T2D, elevated blood levels of apolipoprotein B (apoB) increase the risk of cardiovascular disease (apoB is a measure of the number of particles that carry "bad" cholesterol known as low density lipoproteins (LDL)). Traditionally, high apoB levels were considered a consequence of T2D. However, research from the principal investigator's laboratory has shown that high apoB levels may also contribute to the development of T2D.

This appears to occur because LDL particles can promote inflammation and impair the normal function of fat tissue. Poorly functioning fat tissue is associated with multiple metabolic abnormalities that increase the risk of both T2D and cardiovascular disease. Large population based studies confirmed that elevated blood apoB levels can predict the development of T2D many years before diagnosis.

Recent findings from the research team also indicate that 12 week supplementation with marine derived omega 3 fatty acids, EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid), can improve several risk factors for T2D, particularly in individuals with higher blood apoB levels. However, these data suggest that EPA and DHA may not provide identical benefits in reducing these risk factors.

Study Objective:

The overall aim of this study is to compare the effects of EPA versus DHA on major risk factors for T2D in adults with overweight or obesity and elevated blood apoB levels.

Study Design and Procedures:

After eligibility is confirmed, participants will visit the research institute (IRCM) for two baseline visits scheduled one week apart. During these visits, investigators will used specialized metabolic testing to:

1. Assess how participants' bodies process glucose and produce insulin using blood samples, and
2. Examine how participants' fat tissue responds to their own LDL using a small fat tissue biopsy.

Participants will then be randomly assigned to follow one of three interventions for 12 weeks: EPA, DHA or corn oil (placebo). At the end of the 12 week intervention, participants will return to the research institute to undergo the same assessments performed at baseline.

Data Analysis:

At the conclusion of the study, results from participants in each intervention group (EPA, DHA, and placebo) will be averaged and compared. This will allow researchers to determine the effects of EPA and DHA on key risk factors for T2D and to evaluate whether one omega 3 fatty acid is more effective than the other.

Inclusion Criteria:

Males and post-menopausal females:

• With a body mass index (BMI >25-40 kg/m2)
• Having confirmed menopausal status (FSH ≥ 30 U/l)
• Non-smokers (tobacco) or have quitted for over a year
• Low-moderate alcohol consumption: <7 alcoholic servings/ week
• Plasma apoB ≥1.05 g/L

Exclusion Criteria:

• Elevated risk of cardiovascular disease (≥ 20% of calculated Framingham Risk Score)
• Prior history of cardiovascular events (e.g. stroke, transient ischemic attack, myocardial infarction, angina, heart failure, arrhythmias, flutter, atrial …)
• Systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg
• Diabetes or HbA1c ≥ 6.5%
• Reactive hypoglycaemia
• Prior history of cancer within the last 3 years or if lymph nodes were removed
• Thyroid disease - untreated or unstable Synthroid dose
• Severe renal dysfunction - eGFR < 30 mL/min/1.73 m²
• Hepatic dysfunction - AST/ALT > 3 times normal limit
• Anemia - Hb < 120 g/L in females and < 130 in males
• Bleeding disorders
• Blood coagulation problems (i.e. bleeding predisposition)
• Malabsorptive disease or surgeries (e.g. bariatric surgeries)
• Autoimmune and chronic inflammatory disease (i.e. celiac, inflammatory bowel, Graves, multiple sclerosis, psoriasis, rheumatoid arthritis, and lupus).
• Chronic diarrhea
• Cholecystectomy (e.g. removal of gall bladder)
• Sleep apnea
• Seizures
• Known history of difficulties accessing a vein
• Known history of vagal shock or loss of consciousness during blood withdrawal
• Concomitant medications (systemic corticosteroids; hypertension medication; anti-psychotic medications - psycho-active medication that promote weight gain; anticoagulant or anti-aggregates treatment (e.g. aspirin, NSAIDs, warfarin, coumadin..); systemic adrenergic agonists; weight-loss medication (e.g. GLP-1 agonists); lipid lowering medication (e.g. statins, anti-PCSK9); )
• Allergy to seafood/fish or corn oil
• Allergy to bovine gelatine or glycerine (softgel components)
• Allergy to Xylocaine (anesthesia used during fat tissue biopsy)
• Anticipated surgery or blood transfusion
• Known substance abuse
• Very high physical activity (> 5 hours of aerobic exercise per week)
• Already taking more than 1 gm of EPA and/or DHA supplementation per day
• Lack of compliance to the study requirements (i.e. not being fasting)
• Cancellation of the same scheduled testing visit more than once
• Lack of time to participate in the full length of the study (18-22 weeks)
• Other conditions deemed inappropriate by the study physician (e.g. difficulties in understanding/communicating in French or English)

Frozen plasma and white adipose tissue samples (when available in sufficient quantity) may be shared with other investigators for analysis. However, all statistical analyses incorporating the complete participant data will be conducted exclusively by the IRCM research team, in accordance with the Information and Consent Form signed by the participants