Molecular Mechanisms of Lipid‐Modifying Enzymes in Cellular Adaptation and Systemic Glucose Homeostasis

Lipid-modifying enzymes dynamically regulate membrane architecture, signaling compartmentalization, and inter-organ metabolic communication, thereby influencing systemic glucose homeostasis. Advances in lipidomics and structural enzymology reveal how enzymatic remodeling of phospholipids, sphingolipids, and acyl chains governs insulin receptor organization, PI3K-AKT signaling, and GLUT4 trafficking. Dysregulated lipid flux mediated by factors such as FABP4, ceramides, and diacylglycerols disrupts membrane microdomains, impairs β-cell function, and promotes hepatic gluconeogenesis and skeletal muscle insulin resistance. Conversely, omega-3 polyunsaturated fatty acids enhance membrane fluidity and anti-inflammatory signaling. Integrating lipid enzymology with metabolic physiology establishes a unified mechanistic framework linking membrane remodeling to insulin responsiveness and diabetes pathogenesis.