The role for iron in the pathogenesis of diabetes is on debate. While the consequences of excess iron in β-cell function and survival are established, the effects of iron deficiency on β-cell function and diabetes risk in humans are not yet fully understood.
In a collaborative effort scientists of the University of Utah and the German Mouse Clinic unraveled a critical role for iron-regulatory protein 2 (Irp2) in the regulation of β cell iron homeostasis and reveal a previously unrecognized role for iron in proinsulin processing and insulin secretion in these cells. The study was published in Nature Communications.
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.
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. Irp2 regulates insulin production through iron-mediated Cdkal1-catalyzed tRNA modification. Nat Co mmun. 2020 Jan 15;11(1):296. doi: 10.1038/s41467-019-14004-5.