Polar lipid derangements in type 2 diabetes mellitus: potential pathological relevance of fatty acyl heterogeneity in sphingolipids

While pathological alterations in plasma neutral lipids with type 2 diabetes mellitus (T2DM) has been relatively well-characterized, only limited information is available on the variations in global polar lipidome (glycerophospholipids and sphingolipids) with the disease. To systematically identify polar lipid aberrations associated with early stage T2DM, we quantitatively profiled and compared changes in more than 300 plasma lipid species from distinct groups of T2DM patients against overtly healthy controls. Sphingolipid classes including ceramides, sphingomyelins, lactosylceramides (LacCer) and ganglioside GM3 (GM3) were significantly elevated in mild T2DM with a concomitant decrease in glucosylceramides (GluCer), suggesting the increased conversion of GluCer to LacCer in mild diabetes. Individual GM3 species were altered in T2DM according to their acyl chain lengths. While long-chain GM3s (fatty acyl carbon ≥18) were significantly increased in T2DM, the opposite was observed for GM3 18:1/16:0. Importantly, long-chain GM3 species were negatively correlated with HOMA2-%β and positively correlated with FBG; and could distinguish between healthy individuals and mildly diabetic patients with similar HOMA2-%β. The current study therefore identifies metabolic alterations in sphingolipid pathways as early events in T2DM pathogenesis, and provides hypothesis-generating new insights relevant for larger scale clinical studies aimed at identification of early molecular markers of T2DM.