Zinc (Zn) is a chemical element, which is an essential macronutrient for basic cell activities such as cell growth, cell differentiation and survival. It is found in high concentration in the red blood cells as an essential part of the enzyme, carbonic anhydrase, which promotes many reactions relating to carbon dioxide metabolism. In the pancreas, Zn aid in the production, secretion and storage of insulin.
The cellular functions of zinc can be found in the regulation, activation and expression of biological molecules such as transcription factors, enzymes, adapters, channels and growth factors, along with their receptors. When Zn is deficient or excessively absorbed, it disrupts Zn homeostasis and growth, morphogenesis and immune response, as well as neurosensory and endocrine functions.
Biological functions of Zinc
- Zinc is required for the functions of many proteins, including enzymes and transcription factors.
- It acts as a neuromodulator in synaptic transmissions.
- Zinc behaves as a signal transducer to regulate cellular functions in which Zn transporters are involved.
- Zinc is pivotal for mammalian oogenesis.
- In plants and rats, Zn is essential for growth and development.
- Zinc influences insulin production and secretion, and thereby influences blood glucose transport into cells and reduces hyperglycemia.
- In diabetic patients, Zn supplementation lowers oxidative stress.
Zinc transporters are transmembrane proteins that control the movement of zinc across cellular membrane, distribution and storage. They belong to two major gene families, namely, The ZnT proteins (Solute-linked carrier 30, SLC30) and the ZIP ( Zrt/Irt-linked solute-linked carrier 39, SLC39).
The ZIP proteins transport Zn into the cell through the plasma membrane or out of the subcellular organelles when cytosolic zinc is low or depleted. In mammals, there are fourteen members o the ZIP family. They have eight predicted transmembrane domains (TMDs) with an extracytosolic N- and C- terminals. Between TMD3 and TMD4, a long histidine-rich loop region is located.
ZIP family is expressed in a wide range of tissues and cells, and their proteins are located at distinct cellular compartments.
Unlike ZIP, ZnT proteins transport Zn out of the cell through the plasma membrane or into the subcellular organelles when Zn cytosolic concentrations are high. They have a topology of six predicted transmembrane domains and a histidine-rich loop region between TMD4 and TMD5 with their N- and C- terminals located on the cytosolic side of the membrane. They are also expressed in a wide range of tissues and cells, and have distinct subcellular locations.
Zinc, Zn transporters, and Cell signaling
The process of cell signaling is complex and the role of Zn and Zinc transporters in cellular signaling is less defined.
Zinc mimics the actions of hormones, growth factors, and cytokines. It is actually taking precedence as a leading cell signaling molecule analogous to Calcium.
Modes of Zinc (Zn) signaling
There are two modes of Zn signaling, which are “early zinc signaling” (EZS) and “later Zinc signaling” (LZS).
Early Zinc Signaling: EZS involves a rapid change in intracellular levels of free Zn that occurs in minutes due to an extracellular stimulus that is transcription dependent. This rapid change in the intracellular free Zn is called “Zinc wave” and is dependent on both Calcium and MEK signaling.
Late Zinc Signaling: LZS is also triggered by an extracellular signal and involves transcription-dependent changes in expression of proteins involved in Zn homeostasis, such as storage proteins or transporters.
Role of Zinc (Zn) in Insulin Regulation
Zinc plays an integral role in the processing, storage and secretion of insulin by the pancreas, which subsequently increases glucose absorption. Whenever the plasma level of Zinc becomes low, it adversely affects the ability of the beta islet cells to produce and secrete insulin. By increasing the secretion of insulin, Zn promotes the phosphorylation of Akt (Also known as protein kinase B) and Glycogen synthase kinase 3B (GSK3B), which increase glucose uptake and reduces hyperglycemia.
Zinc deficiency and malabsorption has been linked to diabetes mellitus. This shows that Zn enhances insulin secretion and glucose uptake, thereby decreasing hyperglycemia, cellular apoptosis and excess glucose in kidney.
Zinc (Zn) Supplementation in Decreases Oxidative Stress
Hyperglycemia increases oxidative stress in diabetes mellitus. By decreasing blood glucose level, Zn reduces oxidative stress and protects the cells from oxidative injury. When combined with Chromium, Zn decreases thiobarbituric acid reactive substances’ (TBARS) levels. Zinc supplementation also increases glutathione levels, whereas lipid peroxidation is decreased.