Researchers have discovered for the first time the genetic mechanism by which zinc protects against type 2 diabetes and the fatty liver disease associated with it. These findings advance our understanding of metabolism and open the door to the development of new diabetes treatments. Zinc aids in immune function, cell growth and division, DNA synthesis and metabolism. Given the importance of zinc, our bodies have evolved mechanisms to maintain zinc levels. One such mechanism involves the solute transport family 39 member 5 (SLC39A5) gene, which encodes a protein belonging to the zinc transporter family that transports zinc into cells.
Previous studies have found a link between zinc and improvements in blood sugar levels in diabetics, but "how" the improvement was not entirely clear, prompting the researchers to start with SLC39A5 to explore the mechanisms behind it.
"We know that increasing zinc intake improves glycemic control in people with prediabetes or type 2 diabetes, and that people with mutations in key zinc transporters also have a reduced risk of developing diabetes," said Shek Man Chim, first author of the study. "However, the mechanisms by which zinc affects systemic blood glucose levels and diabetes risk remain unclear."
The researchers conducted a meta-analysis of four studies from Europe and the United States that looked at SLC39A5 loss-of-function mutations in more than 62,000 people with diabetes and more than 518,000 healthy controls. The results confirmed that increased circulating zinc levels in SLC39A5 mutation carriers were associated with a reduced risk of diabetes.
After identifying this link, the researchers knocked out the SLC39A5 gene in mice, leaving them lacking the zinc transporter. They found that the mice had elevated circulating (blood) zinc levels compared with controls, by about 280% in female mice and 227% in male mice. Zinc levels were also significantly elevated in tissues, especially the liver, bones, kidneys, and brain, but were lower in the pancreas. Elevated zinc levels did not negatively affect liver and kidney function in mice.
After inducing obesity in the knockout mice with a high-fat, high-fructose diet, the researchers found that the mice had significantly lower fasting blood glucose compared with control mice fed the same diet. Loss of SLC39A5 also led to a reduction in insulin resistance, a hallmark of diabetes in which tissues fail to respond to insulin signals designed to allow cells to take up glucose.
Because diabetes often co-occurs with non-alcoholic fatty liver disease (NAFLD), the researchers investigated whether knocking out SLC39A5 would also benefit the liver. They found that it was true: Mice without the SLC39A5 gene had less fat accumulation in their livers and fewer markers of liver damage in their blood. In obese mice without SLC39A5, the researchers observed less fat accumulation in the liver and greater insulin sensitivity compared with controls.
Non-alcoholic fatty liver disease can develop into an advanced form called non-alcoholic steatohepatitis (NASH), which causes liver inflammation and tissue scarring (fibrosis). The researchers found that removing SLC39A5 in obese mice reduced markers of liver damage and fasting blood glucose, and improved inflammation and fibrosis.
"Our study provides the first genetic evidence that zinc protects against hyperglycemia and reveals the mechanistic basis of this effect," said corresponding author Harikiran Nistala. "Our observations suggest that blocking SLC39A5 may be a potential avenue for treating type 2 diabetes and other indications where zinc supplementation is simply insufficient."
The research paper was published in the journal Genetics and Genomics.