Investigation of Transport Mechanisms and Regulation of Intracellular Zn2+ in Pancreatic α-Cells

Gyulkhandanyan, Armen V.; Lü, Hongfang; Lee, Simon J. Craddock; Bhattacharjee, Ananya; Wijesekara, Nadeeja; Fox, Jocelyn E. Manning; MacDonald, Patrick E.; Chimienti, Fabrice; Dai, Feihan F.; Wheeler, Michael B.

doi:10.1074/jbc.m707005200

Cited by 99 publications

(91 citation statements)

References 80 publications

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“…ZnT3 (SLC30A3) protein has been reported in the islets, and in the pancreatic β cell line INS-1E but not in a corresponding pancreatic α-cell line, α-TC6 [40][41][42]. While ZnT3 mRNA was reported in purified human β cells in one study [38], levels were zero, or at the limit of detection, in samples from several subjects in another [37].…”

Section: Znt Familymentioning

confidence: 94%

Zinc and diabetes

Chabosseau

Rutter

2016

Archives of Biochemistry and Biophysics

152

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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Section: Znt Familymentioning

confidence: 94%

Zinc and diabetes

Chabosseau

Rutter

2016

Archives of Biochemistry and Biophysics

152

104

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“…Correspondingly, zinc diminished pyruvate-or glucose-induced glucagon secretion from isolated rat α-cells through the reversible activation of K ATP channels and a subsequent decrease in electrical activity (92) . Likewise, studies in the mouse demonstrated an inhibitory effect of Zn 2+ on glucagon secretion (93) . However, in the latter species, this effect of zinc could not be attributed to K ATP channel activation but to uptake of the ion by calcium channels and an alteration in redox state (93) .…”

Section: +mentioning

confidence: 99%

“…Likewise, studies in the mouse demonstrated an inhibitory effect of Zn 2+ on glucagon secretion (93) . However, in the latter species, this effect of zinc could not be attributed to K ATP channel activation but to uptake of the ion by calcium channels and an alteration in redox state (93) . Of note, fasting plasma glucagon levels were normal in global ZnT8 null mice and glucagon secretion from isolated islets was not higher in KO mice than controls.…”

Section: +mentioning

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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“…4, become dissociated and release both atoms of Zn 2C . Recent studies have claimed that zinc atoms can also work as modulators of the a-cell function (Gyulkhandanyan et al 2008), although their role remains controversial. On one hand, it has been found that Zn 2C activates K ATP channels and decreases glucagon release in isolated rat a-cells (Ishihara et al 2003, Franklin et al 2005.…”

Section: Regulation Of Glucagon Secretion By Fatty Acids and Amino Acidsmentioning

confidence: 99%

Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes

Quesada¹,

Tudurí²,

Ripoll³

et al. 2008

Journal of Endocrinology

337

330

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The secretion of glucagon by pancreatic a-cells plays a critical role in the regulation of glycaemia. This hormone counteracts hypoglycaemia and opposes insulin actions by stimulating hepatic glucose synthesis and mobilization, thereby increasing blood glucose concentrations. During the last decade, knowledge of a-cell physiology has greatly improved, especially concerning molecular and cellular mechanisms. In this review, we have addressed recent findings on a-cell physiology and the regulation of ion channels, electrical activity, calcium signals and glucagon release. Our focus in this review has been the multiple control levels that modulate glucagon secretion from glucose and nutrients to paracrine and neural inputs. Additionally, we have described the glucagon actions on glycaemia and energy metabolism, and discussed their involvement in the pathophysiology of diabetes. Finally, some of the present approaches for diabetes therapy related to a-cell function are also discussed in this review. A better understanding of the a-cell physiology is necessary for an integral comprehension of the regulation of glucose homeostasis and the development of diabetes.

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Investigation of Transport Mechanisms and Regulation of Intracellular Zn2+ in Pancreatic α-Cells

Cited by 99 publications

References 80 publications

Zinc and diabetes

Zinc and diabetes

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

Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes

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