LPCAT1 Mediates Lysolecithin Dysregulation in Type 2 Diabetes, Contributing to Endothelial Dysfunction and Impaired Glucose Homeostasis

Dysregulation of lysophosphatidylcholines (LPCs) and phosphatidylcholines (PCs) is associated with endothelial dysfunction and impaired tissue repair. However, the organ-specific modulation of lysolecithin remodeling in type 2 diabetes mellitus (T2DM) and its functional consequences remain poorly explored.

Our research aimed to analyze the dynamics of LPC/PC remodeling in a T2DM mice model and to identify a novel therapeutic approach based on the orally bioavailable peptide SP6 derived from Spirulina platensis.

Tissue lipidomics, GLUT expression, and insulin secretion were evaluated using UHPLC-HRMS merocyanine assay, rtPCR, immunoblotting, and immunofluorescence assays. Insulin secretion was spatially characterized in the pancreas using MALDI-MS imaging.

Hyperglycemia induces an LPC/PC imbalance and increases membrane fluidity, impairing VEGF/API5 expression and hindering wound healing and VE-cadherin localization. This occurs through the downregulation of LPCAT1 and a consequent impact on GLUT1 translocation. In vivo analysis of diabetic mice revealed a multi-organ influence on lysolecithin remodeling, with selective modulation of LPC 16:0, 18:0, and 20:4 in plasma, liver, and pancreas. The SP6 peptide was able to counteract T2DM-associated lysolecithin reprogramming in various compartments, at least in part through the modulation of LPCAT1, increased insulin secretion, and glycemic control via enhanced ATP production and GLUT4 expression.

Our results highlight, for the first time, tissue-specific lysolecithin reprogramming in T2DM pathogenesis and identify LPCAT1-mediated lysolecithin remodeling as a mediator of endothelial and metabolic dysfunction. SP6 exerts multi-organ protective effects by modulating lipid metabolism, vascular integrity, and glucose homeostasis. These data support its potential as a novel preventive agent for T2DM and its related complications, opening new perspectives for the development of innovative preventive treatments that can effectively counteract the progression of this chronic disease.