Genetic Mechanisms Linking Zinc to Diabetes and Liver Disease

News

New Research Reveals Genetic Mechanisms Linking Zinc to Diabetes and Liver Disease

Researchers have, for the first time, unveiled the genetic mechanisms by which zinc provides protection against type 2 diabetes and associated conditions like fatty liver disease.

These findings advance our understanding of metabolism and open doors to the development of novel diabetes treatment approaches.

Zinc plays a crucial role in immune function, cell growth and division, DNA synthesis, and metabolism.

Given its significance, our bodies have evolved mechanisms to maintain zinc levels, one of which involves the Solute Carrier Family 39 Member 5 (SLC39A5) gene that encodes a protein belonging to the zinc transporter family, facilitating the transport of zinc into cells.

New Research Reveals Genetic Mechanisms Linking Zinc to Diabetes and Liver Disease

Previous research had hinted at a connection between zinc and improved blood sugar levels in individuals with diabetes, but the “how” remained unclear, prompting researchers to focus on SLC39A5 to explore the mechanisms behind it.

“We know that increasing zinc intake can improve blood sugar control in prediabetes or type 2 diabetes patients, and individuals with mutations in the key zinc transport protein are at a reduced risk of developing diabetes,” said Shek Man Chim, the first author of the study. “However, the mechanisms through which zinc influences systemic blood sugar levels and diabetes risk have remained unclear.”

Researchers conducted a meta-analysis of four studies in Europe and the United States, examining the functional loss mutations of SLC39A5 in over 62,000 diabetes patients and more than 518,000 healthy controls. The results confirmed that carriers of SLC39A5 mutations had elevated circulating zinc levels, which were associated with a reduced risk of diabetes.

Having established this link, researchers knocked out the SLC39A5 gene in mice, rendering them deficient in the zinc transport protein. They found that circulating (blood) zinc levels in the mice increased significantly compared to the control group, with female and male mice experiencing approximately 280% and 227% increases, respectively. Zinc content in tissues also increased significantly, especially in the liver, bones, kidneys, and brain, although zinc content in the pancreas was lower. The elevated zinc levels did not adversely affect the mice’s liver and kidney functions.

After inducing obesity in the gene knockout mice through a high-fat, high-fructose diet, researchers observed a significant reduction in fasting blood sugar levels compared to mice on the same diet in the control group. Loss of SLC39A5 also led to reduced insulin resistance, a hallmark of diabetes in which tissues do not respond to insulin signals designed to facilitate glucose uptake by cells.

Since diabetes often co-occurs with non-alcoholic fatty liver disease (NAFLD), researchers investigated whether knocking out SLC39A5 would also benefit the liver. Indeed, they found that mice lacking the SLC39A5 gene had less fat accumulation in the liver, and markers of liver damage in the blood were also reduced. In obese mice lacking SLC39A5, researchers observed less fat accumulation in the liver and improved insulin sensitivity.

Non-alcoholic fatty liver disease can progress to a more advanced form known as non-alcoholic steatohepatitis (NASH), which involves liver inflammation and tissue scarring (fibrosis). Researchers discovered that removing SLC39A5 in obese mice reduced liver damage markers and fasting blood sugar, thereby improving inflammation and fibrosis.

“Our research provides the first genetic evidence for the protective role of zinc against high blood sugar and unveils the mechanistic basis for this effect,” said corresponding author Harikiran Nistala. “Our findings suggest that blocking SLC39A5 may be a potential avenue for treating type 2 diabetes and other conditions resulting from simple zinc deficiency.”

The study’s paper was published in the “Genetics and Genomics” journal.