Non-Enzymatic Glycation of Transferrin and Diabetes Mellitus

Figures & data

Figure 1 The process of Tf binding to a receptor to transport iron. The iron (Fe³⁺⁾ in food is reduced to “Fe²⁺ ”under the action of gastric acid and reducing substances, which is absorbed by intestinal mucosa cells, the absorbed “Fe²⁺ ” is oxidized as “Fe³⁺ by ceruloplasmin, then Fe³⁺ binds to Tf, and the conformation of Tf changes immediately after binding with Fe³⁺, which helps Tf to bind to the Tf receptor (TfR) on the cell membrane surface to form a “TfR-Tf-Fe³⁺” complex. Subsequently, the complex enters the cell through receptor-mediated endocytosis to form an endosome coated with clathrin. In the acidic milieu (pH<5.5) in the endosome, Fe³⁺ dissociates from Tf and is reduced to Fe²⁺ by metalloreductases such as six-transmembrane epithelial antigen of the prostate 3 (STEAP3) followed by transportation into the cytosol by divalent metal transporter 1 (DMT1).Following, the Tf/TfR complex recirculates to the cell surface, separates, and enters into the blood circulation for the next process of iron ion transport.

Abbreviations: Apo-Tf, non-iron bound transferrin; Holo-Tf, diferric transferrin; TfR, Tf receptor; STEAP3, six-transmembrane epithelial antigen of the prostate 3; DMT1, divalent metal transporter 1.

Figure 2 The roles and mechanism of non-enzymatic glycated Tf in diabetes and its complications.

Abbreviations: Tf, transferrin; AGEs, advanced glycated end-products; RAGE, AGEs receptor; TfR, Tf receptor; Pdx-1, pancreaticoduodenal homeobox-1; NTBI, non-Tf-bound iron species; ROS, reactive oxygen species; MAPK/ERK, mitogen-activated protein kinase/extracellular signal-regulated kinase; PI3K/AKT, phosphatidylinositol 3 kinase/protein kinase; JAK2/STAT1, janus kinase/signal transducer and activator of transcription 1; mTORC1-UVRAG, mTOR complex 1-UVRAG-2⁻oxygen free radicals; OH, hydroxyl; TNF-α, tumor necrosis factor-α; IL-6, interleukin-6; TGF-β, transforming growth factor-β; IL-13, interleukin-13;

Figure 3 The non-enzymatic glycation process.