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Review
. 2018 Feb 6;19(2):476.
doi: 10.3390/ijms19020476.

Role of Zinc Homeostasis in the Pathogenesis of Diabetes and Obesity

Ayako Fukunaka  1 , Yoshio Fujitani  2
Affiliations
Review

Role of Zinc Homeostasis in the Pathogenesis of Diabetes and Obesity

Ayako Fukunaka et al. Int J Mol Sci. .

Abstract

Zinc deficiency is a risk factor for obesity and diabetes. However, until recently, the underlying molecular mechanisms remained unclear. The breakthrough discovery that the common polymorphism in zinc transporter SLC30A8/ZnT8 may increase susceptibility to type 2 diabetes provided novel insights into the role of zinc in diabetes. Our group and others showed that altered ZnT8 function may be involved in the pathogenesis of type 2 diabetes, indicating that the precise control of zinc homeostasis is crucial for maintaining health and preventing various diseases, including lifestyle-associated diseases. Recently, the role of the zinc transporter ZIP13 in the regulation of beige adipocyte biogenesis was clarified, which indicated zinc homeostasis regulation as a possible therapeutic target for obesity and metabolic syndrome. Here we review advances in the role of zinc homeostasis in the pathophysiology of diabetes, and propose that inadequate zinc distribution may affect the onset of diabetes and metabolic diseases by regulating various critical biological events.

Keywords: ZIP13; ZnT8; beige adipocyte; diabetes; obesity; pancreatic β cell; therapeutic target; zinc; zinc transporters.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of insulin clearance in WT and ZnT8-KO mice. Zinc co-secreted with insulin suppresses insulin secretion from pancreatic β cells and inhibits hepatic insulin clearance in WT mice (left). In contrast, reduced zinc secretion results in enhanced insulin secretion from β cells in ZnT8-KO mice and hepatic insulin clearance is not suppressed (right). Thus, peripheral insulin levels in ZnT8-KO mice are maintained at lower levels than in WT mice.
Figure 2
Figure 2
Schematic model of the relationship among hIAPP, insulin, and zinc. (A) hIAPP can easily form toxic oligomers that induce apoptosis and amyloidogenesis in β cells in T2DM patients; (B) When the zinc concentration in insulin secretory granules is high, zinc is used to form zinc-insulin-hexamer, and hIAPP can easily form toxic oligomers. On the other hand, when the zinc concentration is low in insulin secretory granules (such as insulin secretory granule in ZnT8-KO mice), insulin exists as monomer or dimer, which preferentially binds to hIAPP monomer and prevents hIAPP from self-associating and aggregating.
Figure 3
Figure 3
Insulin signaling pathway and insulin mimicking function of zinc ions. Insulin binds to the insulin receptor located in the plasma membrane in the peripheral tissues, such as liver and muscle. The insulin-signaling pathway is activated and the glucose transporter GLUT4 is translocated to the plasma membrane. Zinc might inhibit the activity of PTP1B, which activates the insulin-signaling pathway. PI3K, phosphatidylinositol-3-kinase; IRS, insulin receptor substrate; PKD, protein kinase D.
Figure 4
Figure 4
The expression of zinc transporters during white adipocyte differentiation. Preadipocytes are differentiated and trigger DNA replication and reentry into the cell cycle (mitotic clonal expansion, MCE). The expression of several genes related to zinc homeostasis is altered.
Figure 5
Figure 5
Zinc transporter ZIP13 inhibits adipocyte browning. Schematic model of the role of ZIP13 in adipocyte browning.
See this image and copyright information in PMC

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