Background
Type 2 diabetes (T2D) has become one of the leading chronic diseases worldwide in terms of both incidence and mortality. According to the International Diabetes Federation (IDF), approximately 537 million adults were living with diabetes globally in 2021, with more than 90% of cases being T2D. In addition, the latest data from the U.S. National Health and Nutrition Examination Survey (NHANES) showed that in 2020, about 38.6% of American adults were in a prediabetic state, facing a high risk of progressing to T2D and developing related complications.
Although numerous studies have confirmed that dietary factors play a crucial role in the onset and progression of T2D, the preventive effects of marine n-3 polyunsaturated fatty acids, such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), on T2D risk among people with prediabetes remain highly controversial. In particular, whether these fatty acids regulate blood glucose levels through skeletal muscle, and the underlying mechanisms involved, are still unclear.
Research Progress
The study first analyzed data from the UK Biobank and found that habitual fish oil supplementation was associated with a 9% reduction in the risk of developing type 2 diabetes (T2D) among individuals with prediabetes. This protective effect was modified by variants at GLUT4. To further investigate the underlying mechanisms, the team conducted a long-term dietary intervention with DHA or EPA (1% w/w in the diet) in db/db mice, subsequently they performed a nontargeted metabolomics analysis of skeletal muscles by ultrahigh-performance liquid chromatography (UHPLC)-Q-Orbitrap-high-resolution mass spectrometry (HRMS) analysis. Results showed that EPA intervention significantly reduced the concentration of pyruvic acid in the skeletal muscle of female mice, DHA intervention increased that in male mice and both increased the content of lactic acid. In addition, DHA and EPA significantly altered branched-chain amino acids (BCAAs), creatine, and glucose metabolism-related metabolites. Further research revealed that DHA and EPA enhance glucose metabolism under insulin stimulation in skeletal muscle by upregulating the expression of pyruvate dehydrogenase (PDH) and glycogen synthase (GS), while suppressing PDK4 expression, thereby promoting glucose oxidation and glycogen synthesis.
Regarding the mechanism of GLUT4 translocation, EPA comprehensively promotes GLUT4 membrane translocation by significantly activating AKT phosphorylation, upregulating GLUT4 expression, and enhancing both mRNA and protein levels of key vesicle trafficking factors including Rab GTPases (rab4/5/8a/13/14) and t-SNAREs (SNAP23/syntaxin4). In contrast, DHA primarily functions through selective upregulation of rab5/8a and syntaxin4 expression. Notably, EPA showed a better ability than DHA in rescuing hyperglycemic phenotype by regulating t-SNAREs and Rab GTPases in the GLUT4 vesicle trafficking process.
Future Prospects
This study is the first to confirm, in a large-scale prospective cohort, that fish oil supplementation can reduce the risk of developing type 2 diabetes (T2D) in individuals with prediabetes. It systematically reveals that DHA and EPA improve glucose homeostasis in prediabetic individuals by enhancing aerobic glucose metabolism, glycogen synthesis, and GLUT4 vesicle translocation in skeletal muscle, thereby lowering the risk of T2D onset. Notably, EPA demonstrated a superior hypoglycemic effect compared to DHA. These findings provide a precision nutrition-based preventive strategy for prediabetes intervention and offer theoretical support and new directions for developing T2D prevention and treatment approaches targeting GLUT4 translocation.
The complete study is accessible via DOI: 10.34133/research.0683