Role of zinc in insulin biosynthesis

Emdin, Stefan O.; Dodson, Guy; Cutfield, J. M.; Cutfield, Susan M.

doi:10.1007/bf00275265

Cited by 239 publications

(118 citation statements)

References 32 publications

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“…For example, during biosynthesis and storage in the pancreatic ␤-cell proinsulin assembles into dimers, which in the presence of Zn 2ϩ or other divalent metal ions further assemble into hexamers. Thirdly, the Ca 2ϩ ion might enhance the solubility of progastrin, as has been reported previously for the binding of Zn 2ϩ ions to proinsulin (32). Fourthly, the Ca 2ϩ ion might redirect the processing of progastrin by preventing cleavage at some dibasic sites, in the same way that phosphorylation of Ser 75 prevents cleavage of the Arg 73 -Ser 74 bond (33).…”

Section: Discussionmentioning

confidence: 67%

Biologically Active Recombinant Human Progastrin6–80Contains a Tightly Bound Calcium Ion

Baldwin

Hollande

Yang

et al. 2001

Journal of Biological Chemistry

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Evidence is accumulating that gastrin precursors may act as growth factors for the colonic mucosa in vivo. The aims of this study were to prepare recombinant human progastrin 6 -80 and to investigate its structure and biological activities in vitro. Human progastrin 6 -80 was expressed in Escherichia coli as a glutathione S-transferase fusion protein. After thrombin cleavage progastrin 6 -80 was purified by reverse phase high pressure liquid chromatography and characterized by radioimmunoassay, amino acid sequencing, and mass spectrometry. Assays for metal ions by atomic emission spectroscopy revealed the presence of a single tightly bound calcium ion. Progastrin 6 -80 at concentrations in the pM to nM range stimulated proliferation of the conditionally transformed mouse colon cell line YAMC. The observations that progastrin 6 -80 did not bind to either the cholecystokinin (CCK)-A or the gastrin/CCK-B receptor expressed in COS cells and that antagonists selective for either receptor did not reverse the proliferative effects of progastrin 6 -80 suggested that progastrin 6 -80 stimulated proliferation independently of either the CCK-A or the gastrin/CCK-B receptor. We conclude that recombinant human progastrin 6 -80 is biologically active and contains a single calcium ion. With the exception of the well known zinc-dependent polymerization of insulin and proinsulin, this is the first report of selective, high affinity binding of metal ions to a prohormone.

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Section: Discussionmentioning

confidence: 67%

Biologically Active Recombinant Human Progastrin6–80Contains a Tightly Bound Calcium Ion

Baldwin

Hollande

Yang

et al. 2001

Journal of Biological Chemistry

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“…It is not known whether such potential misfolding leads to toxic aggregates, protofilament-like assemblies, or mature fibrils. Pancreatic islets are ordinarily protected from insulin misfolding and fibrillation by the formation of stable Zninsulin hexamers and their storage as microcrystals in the secretory granules of ␤ cells (2,75). Such protection is not available to proinsulin in the ER wherein the concentration of zinc ions is very low.…”

Section: Discussionmentioning

confidence: 99%

Proinsulin Is Refractory to Protein Fibrillation

Huang

Dong

Phillips

et al. 2005

Journal of Biological Chemistry

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Insulin is susceptible to fibrillation, a misfolding process leading to well ordered cross-␤ assembly. Protection from fibrillation in ␤ cells is provided by sequestration of the susceptible monomer within zinc hexamers. We demonstrate that proinsulin is refractory to fibrillation under conditions that promote the rapid fibrillation of zinc-free insulin. Proinsulin fibrils, as probed by Raman microscopy, are nonetheless similar in structure to insulin fibrils. The connecting peptide, although not well ordered in native proinsulin, participates in a fibril-specific ␤-sheet. Native insulin and proinsulin exhibit similar free energies of unfolding as inferred from guanidine denaturation studies: relative amyloidogenicities are thus not correlated with global stability. Strikingly, the susceptibility of proinsulin to fibrillation is increased by scission of the connecting peptide at single sites. We thus propose that the connecting peptide constrains a large scale conformational change in the misfolded protein. A tethering mechanism is proposed based on a model of an insulin protofilament derived from electron-microscopic image reconstruction. The proposed relationship between cross-␤ assembly and protein topology is supported by studies of single-chain analogs (mini-proinsulin and insulin-like growth factor I) in which foreshortened connecting peptides further retard fibrillation. In addition to its classic function to facilitate disulfide pairing, the connecting peptide may protect ␤ cells from toxic protein misfolding in the endoplasmic reticulum.

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“…Alteration of zinc homeostasis seems to be also associated with type 2 diabetes (T2D) in humans (Simon & Taylor 2001, Taylor 2005. The highest levels of zinc in the organism are found in b cells where it plays an essential role in insulin crystallization (Emdin et al 1980). Co-secreted zinc has also paracrine effects in pancreatic islets.…”

Section: Introductionmentioning

confidence: 99%

Regulation and functional effects of ZNT8 in human pancreatic islets

Lefebvre

Vandewalle²,

Balavoine³

et al. 2012

Journal of Endocrinology

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Zinc ions are essential for the formation of insulin crystals in pancreatic b cells, thereby contributing to packaging efficiency of stored insulin. Zinc fluxes are regulated through the SLC30A (zinc transporter, ZNT) family. Here, we investigated the effect of metabolic stress associated with the prediabetic state (zinc depletion, glucotoxicity, and lipotoxicity) on ZNT expression and human pancreatic islet function. Both zinc depletion and lipotoxicity (but not glucotoxicity) downregulated ZNT8 (SLC30A8) expression and altered the glucose-stimulated insulin secretion index (GSIS). ZNT8 overexpression in human islets protected them from the decrease in GSIS induced by tetrakis-(2-pyridylmethyl) ethylenediamine and palmitate but not from cell death. In addition, zinc supplementation decreased palmitate-induced human islet cell death without restoring GSIS. Altogether, we showed that ZNT8 expression responds to variation in zinc and lipid levels in human b cells, with repercussions on insulin secretion. Prospects for increasing ZNT8 expression and/or activity may prove beneficial in type 2 diabetes in humans.

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Role of zinc in insulin biosynthesis

Cited by 239 publications

References 32 publications

Biologically Active Recombinant Human Progastrin6–80Contains a Tightly Bound Calcium Ion

Biologically Active Recombinant Human Progastrin6–80Contains a Tightly Bound Calcium Ion

Proinsulin Is Refractory to Protein Fibrillation

Regulation and functional effects of ZNT8 in human pancreatic islets

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