For the first time, researchers have identified the genetic mechanism underlying the protective role zinc has for type 2 diabetes and the fatty liver disease associated with the condition. The findings advance our understanding of metabolism and open the door to developing a novel diabetes treatment.
Zinc helps with immune function, cell growth and division, DNA synthesis, and metabolism. Given its importance, our bodies have evolved mechanisms to maintain zinc levels. One such mechanism involves the Solute Carrier Family 39, Member 5 (SLC39A5) gene, which encodes a protein belonging to the family of zinc transporters that transport zinc into cells.
Previous studies have found a link between zinc and improved blood glucose levels in diabetics, but the ‘how’ was not fully understood, prompting researchers to explore the mechanism underpinning it, starting with SLC39A5.
“We know that increasing zinc intake improves blood glucose control in people with prediabetes or type 2 diabetes, and people with a mutation in a key zinc transporter protein have reduced risk of diabetes,” said Shek Man Chim, the study’s lead author. “However, the mechanism for how zinc influences systemic blood glucose levels and diabetes risk remains unclear.”
The researchers performed a meta-analysis of four European and US studies looking at loss-of-function mutations in SLC39A5 among more than 62,000 diabetics and more than 518,000 healthy controls. This confirmed that circulating zinc levels in carriers of the SLC39A5 mutation were elevated and associated with a decreased risk of diabetes.
Having identified this link, the researchers knocked out the SLC39A5 gene in mice so that they lacked the zinc transporter protein. They found that the mice had elevated circulating (blood) zinc levels, observing an increase of around 280% in female mice and around 227% in males compared to controls. Levels were significantly higher in the tissues, too, especially the liver, bone, kidneys, and brain, but lower in the pancreas. The elevated zinc levels did not negatively affect kidney or liver function in the mice.
After challenging the knockout mice with a high-fat, high-fructose diet to induce obesity, the researchers saw a significant reduction in fasting glucose compared to control mice fed the same diet. Loss of SLC39A5 also resulted in reduced insulin resistance, a hallmark of diabetes where tissues fail to respond to insulin signals designed to get glucose to be taken up by the cells.
Because diabetes often coincides with non-alcoholic fatty liver disease (NAFLD), the researchers examined whether knocking out SLC39A5 benefits the liver, too. They found that it did: mice without the gene had less build-up of fat in the liver and fewer blood markers of liver damage. In obese mice without SLC39A5, the researchers observed less fat accumulation in the liver and improved insulin sensitivity compared to controls.
NAFLD can progress to 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 led to reduced liver damage markers and fasting blood glucose and improved inflammation and fibrosis.
“Our study provides for the first time genetic evidence demonstrating the protective role of zinc against high blood sugar and unravels the mechanistic basis underlying this effect,” said Harikiran Nistala, a corresponding author. “Our observations suggest that blocking SLC39A5 could be a potential therapeutic avenue for type 2 diabetes and other indications where zinc supplementation alone is inadequate.”
The study was published in the journal Genetics and Genomics.