Sphingolipid Dysregulation in Type 2 Diabetes and Its Microvascular Complications

Sphingolipids arestructural components of cell membranes and bioactive mediators governing cellular metabolism and intercellular communication. Beyond their classical roles in insulin sensitivity and glucose/lipid homeostasis, ceramide, sphingosine-1-phosphate (S1P), sphingomyelin and glycosphingolipids coordinate through lipid rafts, extracellular vesicles, organelle contact sites and circulating carriers to facilitate signaling among pancreas, liver, adipose tissue, vascular endothelium and kidney. This review summarizes literature on how dietary and endogenous sphingolipids contribute to T2DM and its microvascular complications. Preclinical studies, mainly in cultured cells and rodent models, indicate that overnutrition with excess take of saturated and industrial trans fats promotes ceramide accumulation, which impairs AKT/AMPK signaling, enhancing hepatic gluconeogenesis and β-cell dysfunction, whereas S1P exerts protective metabolic and vascular effects. Whether these mechanisms are similarly dominant in humans remains to be established. Chain-length-specific ceramides generated by distinct ceramide synthases (CerS1–6) determine organelle and intercellular responses in experimental models. In human observational studies, ceramide/S1P ratios and selected sphingolipid species have been associated with metabolic risk, but their diagnostic and risk-stratification value requires clinical validation. We further discuss nutritional patterns, antidiabetic and lipid-lowering agents, and emerging nanomedicine or exosome-based strategies that restore sphingolipid balance. Targeting compartment- and chain-length-specific sphingolipid signaling may provide more precise therapeutic opportunities for T2DM and its complications.