Lysophosphotidylinositols (LysoPIs) are upregulated following human ß-cell loss and act to potentiate insulin release.

In this study, we identified new lipid species associated with the loss of pancreatic ß-cells triggering diabetes. We performed lipidomics measurements on serum from prediabetic mice lacking ß-cell prohibititin-2 (ß-Phb2−/−, a model of monogenic diabetes), in patients without previous history of diabetes but scheduled for pancreaticoduodenectomy resulting in the acute reduction of their ß-cell mass (about 50%), and in patients with type 2 diabetes. We found higher lysophosphatidylinositols (LysoPIs) as the main circulating lipid species altered in prediabetic mice. The changes were confirmed in the patients with acute reduction of their ß-cell mass and in type 2 diabetes. Increased LysoPIs significantly correlated with HbA1c (reflecting glycemic control), fasting glycemia, and disposition index; without correlation with insulin resistance or obesity in type 2 diabetic humans. INS-1E ß-cells as well as pancreatic islets isolated from non-diabetic mice and human donors exposed to exogenous LysoPIs showed potentiated glucose-stimulated and basal insulin secretion. Finally, addition of exogenous LysoPIs partially rescued impaired glucose-stimulated insulin secretion in islets from mice and humans in the diabetic state. Overall, LysoPIs appear as lipid species being upregulated in the prediabetic stage associated with the loss of ß-cells and supporting the secretory function of the remaining ß-cells.