Zinc signalling and subcellular distribution: emerging targets in type 2 diabetes

Mocchegiani, Eugenio; Giacconi, Robertina; Malavolta, Marco

doi:10.1016/j.molmed.2008.08.002

Cited by 82 publications

(83 citation statements)

References 102 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The zinc transport activity of ZnT-8 has been positively correlated with insulin-secreting capacity, 11,14 vesicular zinc is crucial for insulin maturation and secretion. 12 A previous study showed that uptake of zinc into secretory vesicles was increased in cells expressing ZnT-8 W325 compared with those expressing R325, as demonstrated using zinquin fluorescent dye. 25 Although we adopted a different zinc transport assay, the in vitro vesicle 65 Zn uptake assay, we obtained the same results as those from the zinc fluorescence-based cell assay.…”

Section: Discussionmentioning

confidence: 91%

See 1 more Smart Citation

A low-risk ZnT-8 allele (W325) for post-transplantation diabetes mellitus is protective against cyclosporin A-induced impairment of insulin secretion

et al. 2010

View full text Add to dashboard Cite

SLC30A8 encodes the b-cell-specific zinc transporter-8 (ZnT-8) expressed in insulin secretory granules. The single-nucleotide polymorphism rs13266634 of SLC30A8 is associated with susceptibility to post-transplantation diabetes mellitus (PTDM). We tested the hypothesis that the polymorphic residue at position 325 of ZnT-8 determines the susceptibility to cyclosporin A (CsA) suppression of insulin secretion. INS (insulinoma)-1E cells expressing the W325 variant showed enhanced glucose-stimulated insulin secretion (GSIS) and were less sensitive to CsA suppression of GSIS. A reduced number of insulin granule fusion events accompanied the decrease in insulin secretion in CsA-treated cells expressing ZnT-8 R325; however, ZnT-8 W325-expressing cells exhibited resistance to the dampening of insulin granule fusion by CsA, and transported zinc ions into secretory vesicles more efficiently. Both tacrolimus and rapamycin caused similar suppression of GSIS in cells expressing ZnT-8 R325. However, cells expressing ZnT-8 W325 were resistant to tacrolimus, but not to rapamycin. The Down's syndrome candidate region-1 (DSCR1), an endogenous calcineurin inhibitor, overexpression and subsequent calcineurin inhibition significantly reduced GSIS in cells expressing the R325 but not the W325 variant, suggesting that differing susceptibility to CsA may be due to different interactions with calcineurin. These data suggest that the ZnT-8 W325 variant is protective against CsA-induced suppression of insulin secretion. Tolerance of ZnT-8 W325 to calcineurin activity may account for its protective effect in PTDM.

show abstract

Section: Discussionmentioning

confidence: 91%

“…12 Accumulation of zinc in b-cell secretory vesicles is instrumental in the formation of a zinc-dependent hexameric insulin complex. On glucose stimulation, vesicles fuse with the plasma membrane and subsequently release zinc ions and insulin into circulation.…”

Section: Introductionmentioning

confidence: 99%

A low-risk ZnT-8 allele (W325) for post-transplantation diabetes mellitus is protective against cyclosporin A-induced impairment of insulin secretion

et al. 2010

View full text Add to dashboard Cite

show abstract

“…We carried out enzymatic digestions of B20-30, in the presence or absence of copper(II), aluminum(III) and zinc(II), metals chosen for their important role in neurodegenerative diseases [24,26,66,67]. Moreover, since copper enters the cell as copper(I) through high-affinity plasma membrane copper transporters or low affinity permeases [68] and IDE is mainly cytosolic [1], it is interesting to analyze the effect of both oxidation states on B (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) processing. Furthermore, as silver belongs to the same group of copper and silver(I) has the same chemistry of copper(I), we have also performed studies using this ion, in order to have a replication of the copper(I) results without any possible invalidation due to copper(I) oxidation problems (although we worked in a reducing environment, copper(I) could be oxidized to copper(II) during the incubation with the enzyme).…”

Section: Mass Spectrometry Studies Of Ide Proteolytic Activity Versusmentioning

confidence: 99%

“…To assess how metal ions affect the IDE enzymatic activity, steady state kinetics on the B (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) peptide in the presence and in the absence of the above mentioned ions were performed. Fig.…”

Section: Effect Of Metal Ions On B(20-30) Processing By Idementioning

confidence: 99%

See 1 more Smart Citation

Metal ions affect insulin-degrading enzyme activity

Grasso

Salomone

Tundo

et al. 2012

Journal of Inorganic Biochemistry

View full text Add to dashboard Cite

Insulin degradation is a finely tuned process that plays a major role in controlling insulin action and most evidence supports IDE (insulin-degrading enzyme) as the primary degradative agent. However, the biomolecular mechanisms involved in the interaction between IDE and its substrates are often obscure, rendering the specific enzyme activity quite difficult to target. On the other hand, biometals, such as copper, aluminum and zinc, have an important role in pathological conditions such as Alzheimer's disease or diabetes mellitus. The metabolic disorders connected with the latter lead to some metallostasis alterations in the human body and many studies point at a high level of interdependence between diabetes and several cations. We have previously reported (Grasso et al., Chem. Eur. J. 17 (2011) 2752-2762) that IDE activity toward Aβ peptides can be modulated by metal ions. Here, we have investigated the effects of different metal ions on the IDE proteolytic activity toward insulin as well as a designed peptide comprising a portion of the insulin B chain (B20-30), which has a very low affinity for metal ions. The results obtained by different experimental techniques clearly show that IDE is irreversibly inhibited by copper(I) but is still able to process its substrates when it is bound to copper(II).

show abstract

Zinc deficiency correlates with severity of diabetic polyneuropathy

et al. 2021

View full text Add to dashboard Cite

Objectives: There are controversies about the role of zinc in the development of both types 1 and 2 diabetes. The aim of this study was to assess serum zinc level in diabetic patients with and without peripheral neuropathy in comparison to healthy controls and to explore the possible relationship between serum zinc level and severity of peripheral neuropathy. Methods: This case control study was conducted on 120 subjects: 40 patients fulfilled the criteria for diagnosis of probable diabetic polyneuropathy (DPN), 40 diabetic patients without polyneuropathy (N-DPN) and 40 healthy controls. DPN patients were submitted to clinical assessment of diabetic neuropathy using neuropathy symptom and change (NSC) scale, Michigan Neuropathy Screening Instrument Physical Assessment (MNSI) scale and electrophysiological assessment using nerve conduction study.Zinc serum level was measured in all subjects included in this study using direct colorimetric test method.Results: Diabetic patients with and without neuropathy were found to have significantly lower mean values of serum zinc than healthy controls (p = .025, .03 respectively). There is a statistically significant negative correlation between zinc serum level and hemoglobin A1C (HA1C) (p ˂ .001), NSC score (p = .001) and MNSI score (p = .003) in DPN group. There were also statistically significant correlations between zinc serum level and nerve conduction study values. Conclusion:Zinc deficiency significantly correlates with the severity of DPN and glycemic control.

show abstract

Zinc signalling and subcellular distribution: emerging targets in type 2 diabetes

Cited by 82 publications

References 102 publications

A low-risk ZnT-8 allele (W325) for post-transplantation diabetes mellitus is protective against cyclosporin A-induced impairment of insulin secretion

A low-risk ZnT-8 allele (W325) for post-transplantation diabetes mellitus is protective against cyclosporin A-induced impairment of insulin secretion

Metal ions affect insulin-degrading enzyme activity

Zinc deficiency correlates with severity of diabetic polyneuropathy

Contact Info

Product

Resources

About