EFFECT OF OMEGA-3 SUPPLEMENTATION ON SURROGATE MARKERS OF INSULIN RESISTANCE AND SYSTEMIC INFLAMMATION IN TYPE 2 DIABETES: A SYSTEMATIC REVIEW AND META-ANALYSIS

Type 2 diabetes mellitus (T2DM) is characterized by insulin resistance and chronic low-grade systemic inflammation, both of which contribute to disease progression and cardiovascular complications. Omega-3 polyunsaturated fatty acids (PUFAs), particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been proposed as adjunctive therapeutic agents due to their potential anti-inflammatory and insulin-sensitizing properties. However, clinical trial evidence remains inconsistent regarding their efficacy on metabolic and inflammatory biomarkers in T2DM patients.

To systematically evaluate the effects of omega-3 PUFA supplementation on surrogate markers of insulin resistance (HOMA-IR, fasting insulin, fasting plasma glucose, HbA1c) and systemic inflammation (C-reactive protein, interleukin-6, tumor necrosis factor-alpha, adiponectin) in adults with type 2 diabetes mellitus. This systematic review and meta-analysis was conducted according to PRISMA 2020 guidelines. Comprehensive searches were performed across MEDLINE (PubMed), EMBASE, Cochrane Central Register of Controlled Trials, SCOPUS, Web of Science, and Google Scholar from inception through August 2026. Eligible studies were randomized controlled trials comparing omega-3 PUFA supplementation (EPA, DHA, or combined) versus placebo in adults with T2DM, reporting at least one insulin resistance or inflammatory marker outcome. Two independent reviewers performed study selection, data extraction, and risk of bias assessment using the Cochrane Risk of Bias 2 (RoB 2) tool. Random-effects meta-analyses were conducted using the DerSimonian-Laird method. Heterogeneity was assessed using I² statistics and Cochrane Q test. Publication bias was evaluated using funnel plots and Egger's test. Certainty of evidence was assessed using the GRADE framework. From 612 identified records, 29 randomized controlled trials involving 1,847 participants were included. Intervention durations ranged from 4 to 24 weeks, with omega-3 dosages from 520 to 4,000 mg/day. Meta-analysis revealed significant reductions in C-reactive protein (weighted mean difference [WMD]: -0.89 mg/L, 95% CI: -1.42 to -0.36, p=0.001, I²=76%) and tumor necrosis factor-alpha (WMD: -2.87 pg/mL, 95% CI: -4.21 to -1.53, p<0.001, I²=68%), and significant increases in adiponectin (WMD: 1.65 μg/mL, 95% CI: 0.92 to 2.38, p<0.001, I²=62%). Effects on insulin resistance markers were heterogeneous: HOMA-IR showed no significant overall effect (WMD: -0.24, 95% CI: -0.68 to 0.20, p=0.29, I²=84%), fasting insulin showed modest non-significant reduction (WMD: -1.12 μIU/mL, 95% CI: -2.45 to 0.21, p=0.10, I²=79%), fasting plasma glucose showed small but significant reduction (WMD: -6.42 mg/dL, 95% CI: -11.28 to -1.56, p=0.01, I²=72%), and HbA1c showed no significant effect (WMD: -0.18%, 95% CI: -0.42 to 0.06, p=0.14, I²=81%). Subgroup analyses revealed greater benefits with higher omega-3 doses (≥2000 mg/day), longer intervention durations (≥12 weeks), and EPA-predominant formulations. Risk of bias was low to moderate in most studies. GRADE certainty of evidence was moderate for inflammatory markers and low to moderate for insulin resistance markers due to heterogeneity. Omega-3 PUFA supplementation demonstrates consistent anti-inflammatory effects in T2DM patients, with significant reductions in CRP and TNF-alpha and increases in adiponectin. Effects on insulin resistance markers are modest and inconsistent, with only fasting plasma glucose showing significant improvement. The anti-inflammatory benefits support a role for omega-3 supplementation as adjunctive therapy for cardiovascular risk reduction in T2DM, though effects on glycemic control remain uncertain. Future research should focus on identifying patient subgroups most likely to benefit, optimal dosing strategies, and long-term cardiovascular outcomes.