New link between iron deficiency in pancreatic cells and diabetes

Irp2-/- mice were systematically analyzed at the German Mouse Clinic. Besides microcytic anemia and adult onset of neurodegenerative disease, the Irp2 deficient mice developed diabetes. This was not caused by impaired peripheral and hepatic insulin action, but primarily related to impaired ß-cell function. Examination of the insulin secretion demonstrate, that glucose-stimulated secretion was attenuated in the Irp2 knock-out mice and the proinsulin accumulated in the ß-cells. The scientists found out, that loss of Irp2 caused cellular iron deficiency in ß cells by dysregulating the iron-uptake protein transferrin receptor 1 (TfR1) and iron storage protein ferritin. Iron supplementation of Irp2-/- mice normalized insulin and proinsulin content in vivo. Further investigations revealed that the loss of iron in the cells impaired Fe–S cluster biosynthesis, thus reducing the function of Cdkal1, a Fe–S cluster enzyme that catalyzes a critical step in the translation process. As a consequence, proinsulin translation was impaired, reducing insulin content and secretion in Irp2−/− β cells.

These findings point to a previously unidentified link between insulin processing and cellular iron deficiency that may have relevance to type 2 diabetes in humans. Further investigations of the role of iron deficiency in the pathogenesis of diabetes will shed light on this new connection.

Literature:

Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification.

by Santos MCFD, Anderson CP, Neschen S, Zumbrennen-Bullough KB, Romney SJ, Kahle-Stephan M, Rathkolb B, Gailus-Durner V, Fuchs H, Wolf E, Rozman J, de Angelis MH, Cai WM, Rajan M, Hu J, Dedon PC, Leibold EA.

Nat Commun. 2020 Jan 15;11(1):296. doi: 10.1038/s41467-019-14004-5.