Circulating lipidome underpins gender differences in the pathogenesis of type 2 diabetes

Metabolic alterations in human lipidome significantly impact various chronic diseases including type 2 diabetes (T2D). However, epidemiology and clinical studies have yet to identify clinically meaningful lipid markers for T2D. Fatty acids (FAs) are the backbone of lipid species. However, conflicting results on the essential FAs including omega 3 and omega 6 in the development of metabolic diseases urge deeper evaluations of diverse clinical cohorts including underrepresented populations. This study investigated the lipidomics profiles of 3,000 individuals from a well-characterized cohort of Asian Indians. Untargeted lipidomic profiles were created using blood samples applying reversed-phase liquid chromatography-accurate mass tandem mass spectrometry. Free FAs and lysophosphatidylcholines (LPCs) were upregulated, while sphingomyelin and phosphatidylcholines were decreased in T2D. We observed a significant increase of essential FAs-FA20:4 (AA), FA20:5 (EPA), and FA22:6 (DHA) in T2D after adjusting for age, gender, and body mass index. However, most ω-3 and ω-6 FAs were reduced by 2 to 6-fold in obesity in both genders. We also observed gender differences in age-associated lipid patterns in which cholesterol sulfate and LPC 22:6 were elevated in all age groups in men, but LPC 22:6 rapidly increased after menopause in women, and sphingomyelins increased in men after 40 years. Machine learning analysis identified long-chain FAs, ether-based LPCs, and clinical risk scores among the most informative features associated with T2D. Our study identified lipidomic markers that could be potential mediators of T2D and obesity. Their patterns may underpin gender differences in the pathogenesis of metabolic and cardiovascular diseases.