Skeletal muscle insulin resistance in prediabetes: a lipidomic perspective on diacylglycerols, ceramides, and phospholipids

Lipid metabolism disorders, accompanied by the accumulation of lipids, are believed to contribute to skeletal muscle insulin resistance development. These alterations may attenuate insulin signaling and glucose uptake and utilization. However, the specific roles of individual lipids remain incompletely understood. The study examined the relationship between skeletal muscle lipid composition and insulin resistance in a non-obese prediabetic hereditary hypertriglyceridemic (HHTg) rats. Male HHTg rats aged 4 and 12 months, exhibiting insulin resistance, and dyslipidaemia were used in this study. Skeletal muscle lipidomic profiles were analyzed using tandem mass spectrometry. Compared to age-matched Wistar controls, HHTg rats exhibited increased serum triglycerides, elevated NEFA and impaired glucose tolerance. Impaired muscle insulin sensitivity in HHTg rats was associated with the accumulation of triglycerides and 1,3-diacylglycerols, and most notably with an increase in specific ceramide species (18:0, 22:0, 24:0, 24:1) in both 4- and 12-month-old animals. Elevated mRNA expression of Degs1, a key enzyme in ceramide biosynthesis, may underlie the observed ceramide accumulation. Lipidomic profiling revealed decreases in membrane phospholipids, including phosphatidylethanolamine (PE 41:2), lysophosphatidylcholine (LPC 22:6), and lysophosphatidylethanolamine (LPE 20:0). In HHTg prediabetic model, skeletal muscle insulin resistance develops independently of obesity and prior to diabetes onset, driven by the accumulation of lipotoxic diacylglycerols and ceramides, alongside a reduction in specific phospholipids and lysophospholipids. Impaired fatty acid oxidation and enhanced ceramide biosynthesis contribute to ectopic lipid deposition, with ceramides exerting a more pronounced effect on insulin signaling. Strain-specific alterations in lipid metabolism are more significant than age-related alterations.