The following abstract is written by: Resham Raj Poudel, Yuvaraj Bhusal1, Biswaraj Tharu2, Nisha Kusum Kafle
Abstract
Zinc (Zn) affects glucose metabolism through insulin regulation and has potential implication in diabetes. Zn deficiency has not been proven in diabetes; however, observations of hyperzincuria, hypozincemia, and Zn malabsorption in diabetes indicate additional requirements for Zn. Mutation in Zn transporter 8 – a key protein in insulin secretion – has been associated with Type 2 diabetes. Zn supplementation in prediabetics and diabetics has been supported to improve plasma glucose, hemoglobin A1c (HbA1c), and lipids and potentially improve insulin sensitivity, reduce oxidative stress, and protect from renal damage.
Keywords: Diabetes, hyperzincuria, hypozincemia, insulin, zinc
1. Introduction
ZINC PHYSIOLOGY
Zn is a vital mineral involved in numerous aspects of cellular metabolism. It is widely distributed in variety of food including oyster, red meat, poultry, beans, nuts, and whole grains.[3] Zn is an essential component of more than 300 catalytic enzymes in our body.[4,5] It plays a role in DNA synthesis, protein synthesis, cell division, immune function, and wound healing.[6,7] It supports normal growth and development[8] and is also required for proper sense of taste and smell.[9] The Zn content in pancreatic β‑cells is among the highest of the body and it appears to be an important metal for insulin‑secreting cells.[10] A daily intake of Zn is required to maintain a steady state because the body has no specialized system to store it.[11]Zn intake or absorption, increased loss of Zn from the body, or increased requirements for Zn.[14] Zn deficiency has not been very well documented in diabetes; however, it is suggested that there may be additional requirements for Zn. Different studies have found decreased physiological
measurements of Zn status in diabetics.
THE ROLE OF ZINC IN INSULIN REGULATION
expression of hexokinase‑2 and inhibits the negative regulators of Akt. These have significant roles in increasing expression of glucose transport type 4 and metabolism while decreasing cellular apoptosis, hyperglycemia, and excess glucose in kidney tissues.[20]
There are three classes of protein which control the concentration of Zn in the cytoplasm. Metallothioneins, Zn transporters (ZnTs) encoded by solute linked carrier 30 (SLC30) and Zrt, Irt‑like proteins (ZIPs) encoded by SLC39 genes.[21]
Metallothioneins control Zn availability in β‑cells. When Zn is needed for formation of Zn proteins, the metallothioneins release Zn. If there is excess Zn, it forms metallothionein.[22] ZnTs function to reduce cytoplasmic Zn concentration by transporting them to intracellular vesicles or extracellular spaces.[23,24] There are nine forms of ZnTs named from ZnT1‑8 and ZnT10.[25]ZnT8, encoded by SLC30A8 belongs to cation diffusion facilitator family.[10] It delivers Zn into the granules for insulin maturation and secretion[24] as shown in Figure 1.[26] Studies have shown that ZnT8 overexpression leads to increased glucose‑stimulated insulin secretion, especially for high glucose challenge and protection from Zn depletion‑induced cell death.[23] Similarly, ZnT8 knockdown is associated with increased intracellular insulin with reduced insulin secretion and increased apoptosis of β‑cells, as well as increased hepatic insulin clearance and low peripheral blood insulin. Zn decreases hepatic insulin clearance by inhibiting clathrin‑dependentinsulin endocytosis.[27,28]
It is well established that ZnT8 is a key protein for the regulation of insulin secretion from the pancreatic β‑cells, and its mutation has been associated with Type 2 diabetes mellitus (T2DM).[29] Roles of other ZnTs have been identified such as ZnT3 knockdown has been also associated with decreased insulin secretion as well as apoptosis of β‑cells.[23,27]
Similarly, ZnT7 overexpression results in increased insulin synthesis while ZnT7 knockdown results in low glucose uptake and increased lipogenesis in adipocytes.[30] Zn chelation inhibits ZnT8 and insulin expression, leading to diabetes as well as apoptosis of β‑cells.[31] ZIPs increasecytoplasmic Zn concentrations, especially during low glucose exposure.[22,23] ZIP6 also facilitates the protective effect of glucagon‑like peptide 1 on β‑cell survival.[32]