Beneficial effects of long-chain n-3 fatty acids on insulin-resistance: basic and clinical aspects

This review aims to provide a comprehensive overview of the available data on the effects of long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) on insulin resistance (IR) associated with non-communicable diseases (NCDs), including obesity and type 2 diabetes. In recent years, inflammation of adipose tissue (AT) has emerged as a pivotal contributor to IR in these NCDs. Basic studies conducted on isolated adipocytes and rodents consistently demonstrate that LC n-3 PUFAs attenuate AT inflammation through multiple mechanisms. Furthermore, rodent studies have shown that even low doses of LC n-3 PUFAs can effectively prevent IR, particularly when induced by a high-fat diet (HFD). However, trials conducted in humans, using primarily hyperinsulinemic clamp methods, have yielded more varied results, with several studies indicating a sensitising effect on liver and, occasionally, muscle (as assessed by plasma glucose utilisation). In patients with polycystic ovary syndrome (PCOS), gestational diabetes, and metabolic dysfunction-associated steatohepatitis (MASLD), LC n-3 PUFAs have been observed to decrease IR, as measured by the Homeostasis Model Assessment-Insulin Resistance (HOMA-IR) score. In contrast, most meta-analyses of studies conducted in patients with type 2 diabetes (T2D) have concluded to the inefficacy of LC n-3 PUFAs in reducing IR. However, several meta-analyses have identified a protective effect of LC n-3 PUFAs against T2D in Asians, with no heterogeneity observed, contrasting the findings in Western populations, where heterogeneity exists. The most recent analysis and the large UK Biobank cohort have concluded to a protective effect of LC n-3 PUFAs. Therefore, it can be proposed that LC n-3 PUFAs should be administered to individuals with NCD-associated IR and at high risk of T2D, in conjunction with a healthy diet, such as the Mediterranean diet.