Mol Metab.: auth.: group Thorens

Mol Metab. 2021 Oct 8;101355. doi: 10.1016/j.molmet.2021.101355. Online ahead of print.

Plasma triacylglycerols are biomarkers of ß-cell function in mice and humans

Ana Rodríguez Sánchez-Archidona 1Céline Cruciani-Guglielmacci 2Clara Roujeau 3Leonore Wigger 4Justine Lallement 5Jessica Denom 6Marko Barovic 7Nadim Kassis 8Florence Mehl 9Jurgen Weitz 10Marius Distler 11Christian Klose 12Kai Simons 13Mark Ibberson 14Michele Solimena 15Christophe Magnan 16Bernard Thorens 17


Objectives: To find plasma biomarkers prognostic of type 2 diabetes, which could also inform on pancreatic ß-cell deregulations or defects in the function of insulin target tissues. Such biomarkers could help stratify patients according to the underlying patho-mechanisms and lead to more precise therapeutic approaches.

Methods: We conducted a systems biology approach to characterize the plasma lipidomes of C57Bl/6J, DBA/2J, and BALB/cJ mice under different nutritional conditions as well as their pancreatic islet and liver transcriptomes. We searched for correlations between plasma lipids and tissue gene expression modules.

Results: We identified strong correlations between plasma triacylglycerols (TAGs) and islet gene modules that comprise key regulators of glucose- and lipid-regulated insulin secretion and of the insulin signaling pathway, the two top hits were Gck and Abhd6 for positive and negative correlations, respectively. Correlations were also found between sphingomyelins and islet gene modules that overlapped in part with the gene modules correlated with TAGs. In liver, the gene module most strongly correlated with plasma TAGs was enriched in mRNAs encoding fatty acid and carnitine transporters as well as multiple enzymes of the ß-oxidation pathway. In humans, plasma TAGs also correlated with the expression of several of the same key regulators of insulin secretion and of the insulin signaling pathway identified in mice. This cross-species comparative analysis further led to the identification PITPNC1 as a candidate regulator of glucose-stimulated insulin secretion.

Conclusion: TAGs emerge as biomarkers of a liver-to-ß-cell axis that links hepatic ß-oxidation to ß-cell functional mass and insulin secretion.

Keywords: PITPNC1; Triacylglycerols; plasma biomarkers; systems biology; type 2 diabetes; ß-cell function.