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

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posted on 2023-10-20, 17:38 authored by Cecilia Jiménez-Sánchez, Flore Sinturel, Teresa Mezza, Ursula Loizides-Mangold, Jonathan Paz Montoya, Lingzi Li, Gianfranco Di Giuseppe, Giuseppe Quero, Idris Guessous, François Jornayvaz, Patrick Schrauwen, Dirk Jan Stenvers, Sergio Alfieri, Andrea Giaccari, Ekaterine Berishvili, Philippe Compagnon, Domenico Bosco, Howard Riezman, Charna Dibner, Pierre Maechler

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.

Funding

This work was supported by Swiss National Science Foundation grants 310030_184708/1 (to C.D.) and 310030_192486 (to P.M.), the Vontobel Foundation, the Novartis Consumer Health Foundation, EFSD/Novo Nordisk Programme for Diabetes Research in Europe, the Olga Mayenfisch Foundation, Fondation pour l'innovation sur le cancer et la biologie, Ligue Pulmonaire Genevoise, Swiss Cancer League KFS-5266-02-2021-R, Velux Foundation, Leenaards Foundation, Swiss Life Foundation, the ISREC Foundation, and the Gertrude von Meissner Foundation (CD); by the Bo & Kerstin Hjelt Diabetes Foundation and Fundación Alfonso Martín Escudero (C.J.S.); by Swiss Life Foundation and Young Independent Investigator Grant SGED/SSED (FS); by grants from the Università Cattolica del Sacro Cuore (Fondi Ateneo Fondi Ateneo Linea D.1, anno 2020, and Fondi Ateneo Linea D.1, anno 2021,); and by the Italian Ministry of Education, University and Research (MIUR, GR-2018-12365577 to T.M.).

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