Biologically targeted probes for Zn<sup>2+</sup>: a diversity oriented modular “click-S<sub>N</sub>Ar-click” approach

Pancholi, Jessica; Hodson, David J.; Jobe, Kajally; Rutter, Guy A.; Goldup, Stephen M.; Watkinson, Michael

doi:10.1039/c4sc01249f

Cited by 53 publications

(31 citation statements)

References 95 publications

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“…In terms of endocrine organ function, the physiologically relevant output is hormone release. However, large-scale imaging of exocytosis in individual cells is only just becoming possible, although the currently available dyes possess signal-to-noise ratios incompatible with high-speed acquisition at visible light wavelengths [43][44][45][46]. To circumvent these issues, membrane voltage or intracellular Ca 2?…”

Section: Islets As Discrete Secretory Unitsmentioning

confidence: 99%

Beta cell connectivity in pancreatic islets: a type 2 diabetes target?

Rutter

Hodson

2014

Cell. Mol. Life Sci.

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Beta cell connectivity describes the phenomenon whereby the islet context improves insulin secretion by providing a three-dimensional platform for intercellular signaling processes. Thus, the precise flow of information through homotypically interconnected beta cells leads to the large-scale organization of hormone release activities, influencing cell responses to glucose and other secretagogues. Although a phenomenon whose importance has arguably been underappreciated in islet biology until recently, a growing number of studies suggest that such cell-cell communication is a fundamental property of this micro-organ. Hence, connectivity may plausibly be targeted by both environmental and genetic factors in type 2 diabetes mellitus (T2DM) to perturb normal beta cell function and insulin release. Here, we review the mechanisms that contribute to beta cell connectivity, discuss how these may fail during T2DM, and examine approaches to restore insulin secretion by boosting cell communication.

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Section: Islets As Discrete Secretory Unitsmentioning

confidence: 99%

Beta cell connectivity in pancreatic islets: a type 2 diabetes target?

Rutter

Hodson

2014

Cell. Mol. Life Sci.

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“…These probes display a robust fluorescence enhancement on Zn 2+ chelation and have been successfully used to detect insulin secretion in real time with subcellular resolution [94][95][96].…”

Section: Tools For Imaging Zn 2+ Secretion During Insulin Releasementioning

confidence: 99%

Zinc and diabetes

Chabosseau

Rutter

2016

Archives of Biochemistry and Biophysics

148

104

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Zn 2+ ions are essential for the normal processing and storage of insulin and altered pancreatic insulin content is associated with all forms of diabetes mellitus. Work of the past decade has identified variants in the human SLC30A8 gene, encoding the zinc transporter ZnT8 which is expressed highly selectively on the secretory granule of pancreatic islet β and α cells, as affecting the risk of Type 2 Diabetes. Here, we review the regulation and roles of Zn 2+ ions in islet cells, the mechanisms through which SLC30A8 variants might affect glucose homeostasis and diabetes risk, and the novel technologies including recombinant targeted zinc probes and knockout mice which have been developed to explore these questions. Abbreviation ISG: Insulin Secreting Granules; T2D: Type 2 Diabetes; T1D: Type 1 Diabetes; 2 Diabetes mellitus is a common metabolic disease, affecting approximately 9% of the adult population worldwide. It is characterized by high circulating glucose levels over a prolonged period of time which leads to long-term health complications [1]. Type 1 Diabetes (T1D) involves the autoimmune destruction of insulin-secreting β cells while Type 2 Diabetes (T2D) is linked to both a decrease of insulin release and deficient hormone action on targeted organs [2].The links among Zn 2+ , diabetes and insulin were established in the 1930s, a decade after the discovery of the hormone, when a study showed crystallized insulin contains Zn 2+ and that Zn 2+ , along with other metal ions, could reversibly trigger insulin crystallization [3]. Zinc was later demonstrated to prolong insulin action when co-injected with the hormone [4].These early studies, as well as much more recent findings showing association between T2D risk and the inheritance of gene variants encoding a critical β cell Zn 2+ transporter, ZnT8[5] have generated considerable interest in the role of Zn 2+ in diabetes aetiology and as a possible therapeutic target [6]. Zinc and the diabetic patientScott and Fisher were the first to report a direct link between zinc and diabetes in patients.While assessing the insulin content in the pancreas of diabetic patients compared to nondiabetic cadavers, they showed that in the former group zinc content was reduced by 75 % [7].Epidemiological studies also demonstrated that diabetes and whole body zinc status are associated [8][9][10][11]. In T1D and T2D patients, serum zinc levels are significantly decreased [9][10][11], this being associated with an increased zinc urinary loss [8].Zinc may have important anti-oxidant properties, as it acts as a cofactor of the superoxide dismutase enzyme which regulates the detoxification of reactive oxygen species, regulating the expression and protecting against the oxidative stress induced by chronic hyperglycaemia (for review, [12]). Furthermore, zinc inhibits alpha-ketoglutarate-dependent mitochondrial respiration suggesting that Zn 2+ can interfere with mitochondrial antioxidant production and may also stimulate production of reactive oxygen [13].Zinc supplementation h...

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“…to mitochondria with the addition of a thiamine pyrophosphate group (25) . Attachment to the cell surface to allow sampling of extracellular Zn 2+ has also been achieved, and used to measure co-release of Zn 2+ alongside insulin (26,27) . The latter 'click-SnAr-click' strategy was also used to add targeting moieties to other intracellular localisations (e.g.…”

Section: Imaging Free Zn 2+ In Living Cellsmentioning

confidence: 99%

“…The latter 'click-SnAr-click' strategy was also used to add targeting moieties to other intracellular localisations (e.g. mitochondria and lysosomes) (27) . Genetically-encoded zinc sensors use Fӧrster Resonance Energy Transfer as the sensing modality and consist of a donor and acceptor fluorescent protein linked by a zinc-binding peptide sequence (28) .…”

Section: Imaging Free Zn 2+ In Living Cellsmentioning

confidence: 99%

Intracellular zinc in insulin secretion and action: a determinant of diabetes risk?

et al. 2015

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Zinc is an important micronutrient, essential in the diet to avoid a variety of conditions associated with malnutrition such as diarrhoea and alopecia. Lowered circulating levels of zinc are also found in diabetes mellitus, a condition which affects one in twelve of the adult population and whose treatments consume approximately 10 % of healthcare budgets. Zn 2+ ions are essential for a huge range of cellular functions and, in the specialised pancreatic β-cell, for the storage of insulin within the secretory granule. Correspondingly, genetic variants in the SLC30A8 gene, which encodes the diabetes-associated granule-resident Zn 2+ transporter ZnT8, are associated with an altered risk of type 2 diabetes. Here, we focus on (i) recent advances in measuring free zinc concentrations dynamically in subcellular compartments, and (ii) studies dissecting the role of intracellular zinc in the control of glucose homeostasis in vitro and in vivo. We discuss the effects on insulin secretion and action of deleting or overexpressing Slc30a8 highly selectively in the pancreatic β-cell, and the role of zinc in insulin signalling. While modulated by genetic variability, healthy levels of dietary zinc, and hence normal cellular zinc homeostasis, are likely to play an important role in the proper release and action of insulin to maintain glucose homeostasis and lower diabetes risk.

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Biologically targeted probes for Zn²⁺: a diversity oriented modular “click-S_NAr-click” approach

Abstract: We report a high yielding, one-pot method for the synthesis of zinc responsive probes targeted to specific organelles and examine selected sensors in pancreatic islet cells.

Cited by 53 publications

References 95 publications

Beta cell connectivity in pancreatic islets: a type 2 diabetes target?

Beta cell connectivity in pancreatic islets: a type 2 diabetes target?

Zinc and diabetes

Intracellular zinc in insulin secretion and action: a determinant of diabetes risk?

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Biologically targeted probes for Zn2+: a diversity oriented modular “click-SNAr-click” approach

Abstract: We report a high yielding, one-pot method for the synthesis of zinc responsive probes targeted to specific organelles and examine selected sensors in pancreatic islet cells.

Cited by 53 publications

References 95 publications

Beta cell connectivity in pancreatic islets: a type 2 diabetes target?

Beta cell connectivity in pancreatic islets: a type 2 diabetes target?

Zinc and diabetes

Intracellular zinc in insulin secretion and action: a determinant of diabetes risk?

Contact Info

Product

Resources

About

Biologically targeted probes for Zn²⁺: a diversity oriented modular “click-S_NAr-click” approach