Zinc stimulates glucose oxidation and glycemic control by modulating the insulin signaling pathway in human and mouse skeletal muscle cell lines

Abstract

Zinc is a metal ion that is an essential cell signaling molecule. Highlighting this, zinc is an insulin mimetic, activating cellular pathways that regulate cellular homeostasis and physiological responses. Previous studies have linked dysfunctional zinc signaling with several disease states including cancer, obesity, cardiovascular disease and type 2 diabetes. The present study evaluated the insulin-like effects of zinc on cell signaling molecules including tyrosine, PRSA40, Akt, ERK1/2, SHP-2, GSK-3β and p38, and glucose oxidation in human and mouse skeletal muscle cells. Insulin and zinc independently led to the phosphorylation of these proteins over a 60-minute time course in both mouse and human skeletal muscle cells. Similarly, utilizing a protein array we identified that zinc could active the phosphorylation of p38, ERK1/2 and GSK-3B in human and ERK1/2 and GSK-3B in mouse skeletal muscle cells. Glucose oxidation assays were performed on skeletal muscle cells treated with insulin, zinc, or a combination of both and resulted in a significant induction of glucose consumption in mouse (p<0.01) and human (p<0.05) skeletal muscle cells when treated with zinc alone. Insulin, as expected, increased glucose oxidation in mouse (p<0.001) and human (0.001) skeletal muscle cells, however the combination of zinc and insulin did not augment glucose consumption in these cells. Zinc acts as an insulin mimetic, activating key molecules implicated in cell signaling to maintain glucose homeostasis in mouse and human skeletal muscle cells. Zinc is an important metal ion implicated in several biological processes. The role of zinc as an insulin memetic in activating key signaling molecules involved in glucose homeostasis could provide opportunities to utilize this ion therapeutically in treating disorders associated with dysfunctional zinc signaling.

Synthesis, characterization, antidiabetic and antioxidative evaluation of a novel Zn(II)-gallic acid complex with multi-facet activity

“…[10,42,43] In human and mouse skeletal muscle cells, Zn(II) modulated insulin signalling, which resulted in enhanced glucose oxidation and glycaemic control. [14] These reports are consistent with the observed dose-dependent modulatory effect (EC 50 = 208 µM) of Zn(II) acetate on glucose uptake in L6 myotubes, which further significantly (P ˂ 0.05) increased the activity of gallic acid by several folds (EC 50 = 9.17 µM; Ψ > 100 PA ) upon complexation ( Figure 6a and Table 2). The glucose activity of the complex outperformed (Ψ > 22.7 ZA ) that of Zn(II) acetate, suggesting that the two gallic acid moieties acquired by the complex (Figure 1b) may also influence or contribute to the improved bioactivity of the complex.…”

“…[10,11] Zn(II) stimulates both lipogenesis and glucose transport in adipocytes. [12,13] In human and mouse skeletal muscle cells, Zn (II) modulated insulin signalling, which resulted in enhanced glucose oxidation and glycaemic control [14] and thus could be a potential target for the development of a therapeutic agent for diabetes.…”

The Zinc Transporter Zip7 Is Downregulated in Skeletal Muscle of Insulin-Resistant Cells and in Mice Fed a High-Fat Diet

“…Whole cell protein lysates were prepared in RIPA Lysis buffer in the presence of protease and protein phosphatase inhibitors (Thermo Fisher) as previously described [17]. Briefly, whole cell lysates were vortexed every 10 min for 1 h on ice and centrifuged at 15,000 rpm for 5 min.…”

Zinc(II) complexes in diabetes management: Plant‐derived phenolics as understudied promising ligands

“…Zn(II) treatment stimulates glucose transport in isolated rat adipocytes by modulating the activation of post‐insulin receptor kinases, as well as increasing lipogenesis, glycolysis and glucose oxidation (Ezaki, 1989; Shisheva et al, 1992). The possible modulatory effect of Zn(II) on glycogen synthesis was confirmed in mouse and human skeletal muscle cells, when Zn(II) treatment stimulated the activation/phosphorylation of glycogen synthase kinase (Norouzi et al, 2018). Consequently, numerous types of ligands such as antidiabetic drugs, supplements and naturally occurring and synthetic organic ligands have been complexed with Zn(II) to improve the bioactive properties of the ligands and develop potent multi‐facet antidiabetic nutraceutical.…”

“…Zn(II) treatment stimulates glucose transport in isolated rat adipocytes by modulating the activation of post-insulin receptor kinases, as well as increasing lipogenesis, glycolysis and glucose oxidation (Ezaki, 1989;Shisheva et al, 1992). The possible modulatory effect of Zn(II) on glycogen synthesis was confirmed in mouse and human skeletal muscle cells, when Zn(II) treatment stimulated the activation/ phosphorylation of glycogen synthase kinase (Norouzi et al, 2018). In a previous study (Motloung et al, 2020), Zn(II) was chemically combined with gallic acid in a 1:2 mole ratio, respectively, to form a Zn(II)-gallic acid complex.…”