Targeting the Zinc Transporter ZIP7 in the Treatment of Insulin Resistance and Type 2 Diabetes

Abstract

Type 2 diabetes mellitus (T2DM) is a disease associated with dysfunctional metabolic processes that lead to abnormally high levels of blood glucose. Preceding the development of T2DM is insulin resistance (IR), a disorder associated with suppressed or delayed responses to insulin. The effects of this response are predominately mediated through aberrant cell signalling processes and compromised glucose uptake into peripheral tissue including adipose, liver and skeletal muscle. Moreover, a major factor considered to be the cause of IR is endoplasmic reticulum (ER) stress. This subcellular organelle plays a pivotal role in protein folding and processes that increase ER stress, leads to maladaptive responses that result in cell death. Recently, zinc and the proteins that transport this metal ion have been implicated in the ER stress response. Specifically, the ER-specific zinc transporter ZIP7, coined the "gate-keeper" of zinc release from the ER into the cytosol, was shown to be essential for maintaining ER homeostasis in intestinal epithelium and myeloid leukaemia cells. Moreover, ZIP7 controls essential cell signalling pathways similar to insulin and activates glucose uptake in skeletal muscle. Accordingly, ZIP7 may be essential for the control of ER localized zinc and mechanisms that disrupt this process may lead to ER-stress and contribute to IR. Accordingly, understanding the mechanisms of ZIP7 action in the context of IR may provide opportunities to develop novel therapeutic options to target this transporter in the treatment of IR and subsequent T2DM.

Keywords: ZIP7; endoplasmic reticulum stress; insulin resistance; type 2 diabetes; zinc; zinc transporters.

Figure 1

Phylogenetic relationships of the human ZnT and ZIP proteins (SLC30A & SLC39A family of zinc transporters). Protein sequences were attained by converting human SLC39A and SLC30A mRNA into amino acids sequences and aligned by Geneious alignment using global alignment. The dendrogram was generated from Geneious tree builder utilizing the Jack-knife method. Molecular phylogenetic analysis as generated by the genetic distance model “Jukes-Cantor”, the re-sampling method used Jack-knife with 229,871 random seeds. (A) Phylogenetic relationships of SLC39A family (ZIP), (B) Phylogenetic relationships of SLC30A family (ZnT).

Figure 2

Schematic diagram of ZIP7 and its role in regulating pathways involved in glucose mobilization, ER stress, IR and T2DM.