Zinc Levels Linked to Type 2 Diabetes and Fatty Liver Disease Risk

Researchers have discovered a mechanistic link between zinc levels in humans and the risk of developing type 2 diabetes and fatty liver disease. This research, published in eLife, sheds light on zinc's role in metabolism, offering insights into potential therapeutic targets.

Zinc is known to play a significant role in insulin production and glucose metabolism. However, the precise mechanisms linking zinc to blood glucose control and diabetes risk have remained unclear. To investigate, researchers from Regeneron analyzed genetic data from a large population of participants and identified a rare mutation that reduces the function of a zinc transporter protein called SLC39A5. This mutation was associated with increased zinc levels and a reduced risk of type 2 diabetes.

Further analysis, involving over 62,000 diabetes cases and more than 518,000 healthy controls, confirmed that individuals with the SLC39A5 mutation had elevated zinc levels and a decreased risk of diabetes.

To explore the function of SLC39A5, the team genetically engineered mice lacking this zinc transporter protein. These mice showed elevated zinc levels and improved glucose control, reduced insulin resistance, and less fat accumulation in the liver when fed a high-fat, high-fructose diet compared to control mice.

Non-alcoholic fatty liver disease (NAFLD) often accompanies diabetes. Mice lacking SLC39A5 had less fat buildup in the liver and improved insulin sensitivity, suggesting a protective effect against NAFLD.

To assess whether SLC39A5 loss could protect against the progression of NAFLD to non-alcoholic steatohepatitis (NASH), a more severe liver inflammation, mice were exposed to a high-fat, high-cholesterol diet. Mice lacking SLC39A5 displayed reduced liver damage, lower fasting blood glucose, and improvements in liver inflammation and fibrosis compared to the control group.

However, some differences were noted between male and female mice, prompting further exploration. Additionally, researchers plan to investigate SLC39A5's role in pancreatic cell function and glucose tolerance.

This study highlights genetic evidence of zinc's protective role against high blood sugar and uncovers the mechanisms behind this effect. Blocking SLC39A5 could be a potential therapeutic approach for type 2 diabetes and other conditions where zinc supplementation alone may not be sufficient.