The Effect of Omega-3 Fatty Acids on Insulin Resistance

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TL;DR

This narrative review examines the molecular mechanisms by which omega-3 polyunsaturated fatty acids (PUFAs) may improve insulin resistance, focusing on mitochondrial dysfunction, endoplasmic reticulum stress, and inflammatory pathways. Evidence from animal and human studies suggests omega-3 PUFAs can enhance mitochondrial biogenesis, reduce ER stress, and lower inflammation, potentially improving insulin sensitivity. The clinical significance lies in the potential for dietary omega-3 supplementation to serve as an adjunctive strategy for preventing or managing type 2 diabetes and related metabolic disorders.

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**Background:** Insulin resistance (IR) is a reduced responsiveness of peripheral tissues to insulin, often preceding type 2 diabetes mellitus (T2DM). T2DM increases risks for retinopathy, renal impairment, cardiovascular events, and lower limb amputation. Obesity and inadequate physical activity are leading causes of the global rise in T2DM. Omega-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) from fish and alpha-linolenic acid (ALA) from plant sources, have anti-inflammatory properties and may influence insulin sensitivity. This review explores the molecular and cellular mechanisms by which omega-3 PUFAs affect IR, focusing on mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and inflammatory pathways.

**Methods:** This is a narrative review. The authors conducted a literature search using Google Scholar, Science Direct, PubMed, and ResearchGate. Keywords included insulin resistance, polyunsaturated fatty acids, omega-3 fatty acids, diabetes mellitus, endoplasmic reticulum stress, mitochondrial dysfunction, reactive oxygen species, fish oil, and inflammatory pathways. Papers published before 2000 or in languages other than English were excluded. The suitability of articles was assessed, duplicates removed, and ambiguities resolved through discussion.

**Key Results:** The review summarizes evidence from multiple studies: - In animal models, a high-fat diet supplemented with fish oil (3.4% kcal from n-3 PUFAs) for 10 weeks increased expression of mitochondrial biogenesis factors NRF1 and PGC1α in skeletal muscle. - A diet high in fat (200 g fat/kg) including menhaden oil increased mitochondrial carnitine palmitoyl transferase 1 (CPT-1) in skeletal muscle and heart of rats. - EPA (200 μmol/L for 24 h) activated AMPK in primary cultured rat fat cells, and high fat-fed rats supplemented with 10% v/w omega-3 PUFA (fish oil) for six weeks showed increased CPT-1 expression and fatty acid oxidation. - Obese mice fed a high-fat diet rich in fish oil (60% calories from fat for 12 weeks) had improved glucose tolerance and insulin sensitivity, linked to reduced adipose tissue dysfunction and inhibition of ER stress. - Omega-3 PUFAs may influence the NLRP3 inflammasome, which detects cellular homeostasis disturbances such as ER stress and redox shifts. - A table of 18 randomized controlled trials (RCTs) published in the last 5 years (indexed in PubMed) is presented. Key findings include: - Djoussé et al. (2022): Omega-3 supplementation (1 g/day) reduced recurrent heart failure hospitalization in Black subjects with T2DM (HR 0.69, 95% CI 0.50–0.95). - ASCEND Study (2018): No significant difference in major vascular events between omega-3 and placebo in diabetic patients (rate ratio 0.97, 95% CI 0.87–1.08, p=0.55). - Raygan et al. (2019): Flaxseed oil (1000 mg/day) and fish oil (1000 mg/day) for 12 weeks significantly decreased insulin levels (p=0.04) in diabetic patients with coronary heart disease. - Jamilian et al. (2020): Omega-3 from flaxseed oil (2×1000 mg/day) for 6 weeks in women with gestational diabetes decreased fasting plasma glucose (p=0.001), insulin (p=0.001), HOMA-IR (p=0.001), and increased insulin sensitivity (p=0.005). - Abbott et al. (2020): DHA-enriched fish oil (2 g/day) for 12 weeks decreased HOMA-IR by −0.40 units and fasting insulin by −1.62 IU/L in abdominally obese individuals. - Liu et al. (2022): Perilla oil (3 g/day) reduced fasting blood glucose, while fish oil (3 g/day) reduced triglycerides in T2DM patients. - Burhop et al. (2022): Calanus oil (LC n-3 PUFAs) improved fasting insulin, HOMA-IR, and hepatic insulin resistance index in obese subjects after 12 weeks. - Omega-3 PUFAs also affect nonalcoholic fatty liver disease (NAFLD) by reducing hepatic de novo lipogenesis and increasing fatty acid oxidation, mediated by transcription factors such as PPARs.

**Clinical Implications:** The review suggests that omega-3 PUFAs may improve insulin resistance through multiple mechanisms, including enhancing mitochondrial function, reducing ER stress, and modulating inflammatory pathways. However, RCT results are mixed, with some showing benefits (e.g., improved insulin sensitivity, reduced fasting glucose) and others showing no effect on major cardiovascular outcomes. The authors note that further research is needed to fully understand the mechanisms and to determine optimal dosing, sources, and patient populations that may benefit. Dietary recommendations from the American Diabetes Association and UK guidelines encourage consumption of oily fish and Mediterranean-style diets rich in omega-3 PUFAs without necessarily recommending supplementation. The review highlights the potential for omega-3 PUFAs as an adjunctive therapy in managing insulin resistance and T2DM, but emphasizes that current evidence does not support universal supplementation for cardiovascular prevention in diabetes.