Zinc and insulin in pancreatic beta-cells

Abstract

Zinc (Zn2+) is an essential element crucial for growth and development, and also plays a role in cell signaling for cellular processes like cell division and apoptosis. In the mammalian pancreas, Zn2+ is essential for the correct processing, storage, secretion, and action of insulin in beta (β)-cells. Insulin is stored inside secretory vesicles or granules, where two Zn2+ ions coordinate six insulin monomers to form the hexameric-structure on which maturated insulin crystals are based. The total Zn2+ content of the mammalian pancreas is among the highest in the body, and Zn2+ concentration reach millimolar levels in the interior of the dense-core granule. Changes in Zn2+ levels in the pancreas have been found to be associated with diabetes. Hence, the relationship between co-stored Zn2+ and insulin undoubtedly is critical to normal β-cell function. The advances in the field of Zn2+ biology over the last decade have facilitated our understanding of Zn2+ trafficking, its intracellular distribution and its storage. When exocytosis of insulin occurs, insulin granules fuse with the β-cell plasma membrane and release their contents, i.e., insulin as well as substantial amount of free Zn2+, into the extracellular space and the local circulation. Studies increasingly indicate that secreted Zn2+ has autocrine or paracrine signaling in β-cells or the neighboring cells. This review discusses the Zn2+ homeostasis in β-cells with emphasis on the potential signaling role of Zn2+ to islet biology.

Zinc and diabetes

“…In the presence of zinc, concentrated in the maturating vesicles via its transport by the zinc transporter ZnT8 [23] (see below), the dimers aggregate to form a hexamer around two Zn 2+ ions. The hexamerization process reduces insulin solubility and triggers its crystallisation, increasing the storage capacity of the insulin secreting vesicles [24,25]. Concomitantly, pH is decreased in the maturating granules via a proton pump (<pH 6) as insulin hexamers are unstable at neutral pH.…”

“…When insulin is secreted into the extracellular medium during exocytosis, hexamers are rapidly converted into active monomers as the pH increases. This process thus also liberates significant concentrations of Zn 2+ into the circulation, potentially with actions independent to those of insulin [25,26]. 4 …”

“…Four isoforms have been described, the most widely expressed isoforms in mammals being MT1 and MT2. Among the metals they associate with, MTs bind Zn 2+ with high affinity but can also function as Zn 2+ donors to other Zn 2+ binding proteins [25,47,48]. …”

Correlation of trace elements (serum zinc and copper) in type 2 diabetic patients with and without complications

“…Six insulin monomers require two Zn ++ ions to form the hexameric-structure on which maturated insulin crystals are based. 12 Some previous studies indicated that the lower serum zinc in diabetics may be due to diabetes related hyperzincuria and impaired gastrointestinal absorption of zinc. 13 In addition to the findings that zinc levels are often low in diabetic, it is also felt that zinc (along with other micronutrients) may participate as an integral component of antioxidant enzymes.…”

Variations of Hair Trace Element Contents in Diabetic Females

“…Zn is essential for the processing, storage, secretion, and action of insulin in beta (β)-cells where six insulin molecules coordinate with two Zn ions to produce a hexameric-structure based molecule for insulin crystals [20].…”