Effects of Zinc on the Insulin Receptor and Insulin Signal Transduction Pathway
Tang, Xiao-Han
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Permalink
https://hdl.handle.net/2142/83542
Description
Title
Effects of Zinc on the Insulin Receptor and Insulin Signal Transduction Pathway
Author(s)
Tang, Xiao-Han
Issue Date
2002
Doctoral Committee Chair(s)
Neil F. Shay
Department of Study
Animal Sciences
Discipline
Animal Sciences
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Keyword(s)
Health Sciences, Nutrition
Language
eng
Abstract
Zinc is reported to have insulin-like effects. However, the mechanism of these effects still remains unclear. In the present work, the ability of a divalent cation zinc, to modify binding characteristics of the human insulin and type 1 IGF receptors and the insulin intracellular signaling pathway was investigated. First, on the receptor binding, zinc decreased insulin binding to its receptor via decreasing the affinities for both the high and low affinity sites, without affecting the number of binding sites, and this effect was cell type specific. In contrast to insulin binding, zinc increased IGF-I binding to the type 1 IGF receptor due to an increase in receptor affinity without effects on the number of binding sites. In addition, zinc modulated the binding of IGF-I to its receptor indirectly through regulating the binding of IGF-I to IGFBPs. Zinc decreased the binding of the IGFBPs secreted by some cells and IGFBP-5 to IGF-I via a decrease in the binding affinity. The study about the stimulation of glucose transport by zinc revealed that zinc affected the insulin intracellular signaling pathway. Zinc enhanced glucose transport in the presence and absence of insulin in 3T3-L1-preadipocytes and -adipocytes. The effect of zinc plus insulin was more than either insulin or zinc alone. Cytochalasin D, an actin network disrupter, attenuated the increase of glucose transport induced by zinc or insulin. The PI 3-kinase inhibitor, wortmannin decreased basal glucose transport and blocked zinc-stimulated glucose transport. H7, an inhibitor of PKC, did not reduce basal glucose transport but decreased zinc-induced glucose transport in a dose-dependent manner. Zinc increased Tyr phosphorylation of the insulin receptor beta subunit, however, the effect was not as great as that of insulin. Not like insulin, zinc did not increased tyrosine phosphorylation of IRS-1 and -2, and the association of the p85 subunit of PI 3-kinase and IRS-1. Zinc significantly increased a marker of Akt activation, serine 473 phosphorylation of Akt, which was totally blocked by wortmannin. It appears that zinc induces an increase in glucose transport into cells and potentiates insulin-induced glucose transport into cells, likely acting through the insulin signaling pathway.
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