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 ßcell 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.