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Review
. 2023 Oct 15:477:116694.
doi: 10.1016/j.taap.2023.116694. Epub 2023 Sep 20.

Diabetic cardiomyopathy - Zinc preventive and therapeutic potentials by its anti-oxidative stress and sensitizing insulin signaling pathways

Lu Cai  1 , Yi Tan  2 , Sara Watson  3 , Kupper Wintergerst  3
Affiliations
Review

Diabetic cardiomyopathy - Zinc preventive and therapeutic potentials by its anti-oxidative stress and sensitizing insulin signaling pathways

Lu Cai et al. Toxicol Appl Pharmacol. .

Abstract

Oxidative stress and insulin resistance are two key mechanisms for the development of diabetic cardiomyopathy (DCM, cardiac remodeling and dysfunction). In this review, we discussed how zinc and metallothionein (MT) protect the heart from type 1 or type 2 diabetes (T1D or T2D) through its anti-oxidative function and insulin-mediated PI3K/Akt signaling activation. Both T1D and T2D-induced DCM, shown by cardiac structural remodeling and dysfunction, in wild-type mice, but not in cardiomyocyte-specific overexpressing MT mice. In contrast, mice with global MT gene deletion were more susceptible to the development of DCM. When we used zinc to treat mice with either T1D or T2D, cardiac remodeling and dysfunction were significantly prevented along with increased cardiac MT expression. To support the role of zinc homeostasis in insulin signaling pathways, treatment of diabetic mice with zinc showed the preservation of phosphorylation levels of insulin-mediated glucose metabolism-related Akt2 and GSK-3β and even rescued cardiac pathogenesis induced by global deletion of Akt2 gene in a MT-dependent manner. These results suggest the protection by zinc from DCM is through both the induction of MT and sensitization of insulin signaling. Combined our own and other works, this review comprehensively summarized the roles of zinc homeostasis in the development and progression of DCM and its therapeutic implications. At the end, we provided pre-clinical and clinical evidence for the preventive and therapeutic potential of zinc supplementation through its anti-oxidative stress and sensitizing insulin signaling actions. Understanding the intricate connections between zinc and DCM provides insights for the future interventional approaches.

Keywords: Cardiac dysfunction; Diabetic cardiomyopathy; Diabetic heart; Heart failure; Trace metals; Zinc.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing fiscal interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1.
Fig. 1.
Subcellular localization of Zn transporters and MTs. Localization and potential functions of Zn transporters from the Slc39/ZIP (blue) and Slc30/ZnT (red) families, metallothionein (MT), and metal response element (MRE)-binding transcription factor 1 (MTF1) within the cell. Arrows show the predicted direction of Zn mobilization. The figure was made based on the authors’ previous works.
Fig. 2.
Fig. 2.
Illustration of Zn-MT amino acid sequence and metal (zinc) binding sites of human MT la, which was made based on online materials (https://sites.williams.edu/bigchem/topics/metal-iron-storage-and-transport/metallothioneins/). MTs two key feature are summarized based on its metal binding and high contents of cysteine.
Fig. 3.
Fig. 3.
Schematic illustration of the major findings of the authors’ works (Huang et al., 2021) and assumed mechanisms by which the minimal glucose metabolism is compensated by up-regulated Akt1 in the heart of Akt2-KO mice (left panel) and the normal glucose metabolism is preserved by overexpressed cardiac MT in the heart of Akt2-KO mice (right panel). Red arrow indicates the compensative changes due to the lack of Akt2 (red cross)-mediated glucose metabolism in the heart of Akt2-KO mice. Blue lines indicate the changes related to glucose metabolism and preserved by overexpressed cardiac MT in the heart of MT-TG/Akt2-KO mice. Dashed line presents the possible pathways. IR, insulin receptor.
Fig. 4.
Fig. 4.
The proposed mechanisms how Zn and Zn-MT prevent the development of DCM. First diabetes directly or indirectly via increased angiotensin II (Ang II) activates NOX pathway to general extra ROS/RNS to induce and oxidative or nitrosative stress, inflammation and cell death that in turn stimulates cellular and cardiac remodeling and dysfunction, i.e.: the development of DCM. Zn and Zn-MT inhibits NOX-mediated superoxide and associated downstream pathogenesis and also preserve Akt-dependent glucose metabolism to reduce oxidative stress and inflammation as well as the consequent cell and cardiac remodeling and dysfunction. The proposed mechanisms are based on the findings from of the studies by the authors.
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