[Dec. 29, 2023: JJ Shavit, The Brighter Side of News]
Academics and experts have acclaimed this investigation as a pivotal one that considerably enhances our grasp over zinc's involvement in metabolism. (CREDIT: Creative Commons)
In a groundbreaking study, a major link has been discovered between zinc levels in the human body and the risk factors for type 2 diabetes and non-alcoholic fatty liver disease.
Published in the scientific journal eLife, the study has significantly elevated science's comprehension of zinc's essential role in metabolic processes.
Deep Dive into the Study
Academics and experts have lauded this investigation as pivotal to our grasp over zinc's involvement in metabolic processes. The research team has employed cutting-edge genetic analysis techniques on a large cohort of human participants.
The outcome? A potential therapeutic target for non-alcoholic fatty liver disease and type 2 diabetes. Such a revelation holds interest for those engrossed in both metabolism research and trace element biology.
Zinc's significance in the world of insulin production and glucose metabolism isn't a new revelation. Shek Man Chim, the lead author and Principal Scientist at Regeneron Pharmaceuticals, Inc., New York, US, shed light on this, stating, “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 a reduced risk of diabetes.”
The enigma, however, revolved around the precise mechanism through which zinc influenced systemic blood glucose levels and diabetes susceptibility.
Unraveling the Protective Role of Zinc
Chim, alongside his team, delved deep into the protective attributes of zinc against diabetes. Through rigorous testing of loss-of-function mutations from genetic sequence data sourced from an extensive group of European ancestry participants involved in the Regeneron Genetics Center-Geisinger Health System DiscovEHR study, the researchers made a breakthrough. They pinpointed a rare mutation causing a loss of function in a crucial zinc transporter protein termed SLC39A5. This mutation was directly linked to heightened circulating zinc levels.
Loss of the Zinc transporter SLC39A5 protects from obesity-driven hyperglycemia and liver pathology. (CREDIT: eLife)
To cement their findings, the team orchestrated a meta-analysis, studying over 580,000 participants from four multi-ethnic European and US studies. The conclusions were unequivocal: elevated circulating zinc levels, attributed to the SLC39A5 loss-of-function mutation, were inversely proportional to diabetes risk.
This realization prompted further exploration. Genetically modified mice, devoid of the SLC39A5 transporter protein, were analyzed. The results? Elevated levels of zinc in blood and tissue samples. These modified mice, when subjected to obesity-inducing diets, demonstrated a remarkable reduction in fasting glucose levels in comparison to their control counterparts. Moreover, the absence of SLC39A5 resulted in minimized insulin resistance, a notorious marker for diabetes.
Loss of Slc39a5 results in elevated circulating and hepatic zinc levels in mice. Serum zinc (A) and hepatic zinc (B) in Slc39a5+/+, Slc39a5-/- and Slc39a5+/- mice at 40 weeks of age, n=16-18. **P < 0.01, ***P < 0.001, two-way ANOVA with post hoc Tukey’s test. (CREDIT: eLife)
The Link to Non-Alcoholic Fatty Liver Disease
With diabetes and non-alcoholic fatty liver disease frequently presenting concurrently, the team sought to identify if SLC39A5's absence also shielded the liver. Their speculations were confirmed. Mice lacking SLC39A5 showed reduced fat accumulation in both the liver and crucial blood markers signifying liver damage. The benefits of a lack of SLC39A5 weren't limited to just that. When subjected to liver-damaging diets, these mice also exhibited lower fat buildup in the liver and enhanced insulin sensitivity.
Additionally, the research team ventured further. They investigated the potential of SLC39A5's absence in halting the progression of non-alcoholic fatty liver disease to a more dangerous condition, non-alcoholic steatohepatitis (NASH). This severe liver inflammation often culminates in irreversible scarring or fibrosis. The results were again positive. Mice devoid of SLC39A5 displayed decreased markers of liver damage, reduced fasting blood glucose, and improvements in liver inflammation and fibrosis.
Loss of Slc39a5 improves liver function and steatosis in leptin-receptor deficient female mice and in female mice challenged with high fat high fructose diet (HFFD). (CREDIT: eLife)
Public reviewers did express certain reservations. Notably, differences in metabolic consequences of SLC39A5 inactivation between male and female mice were ambiguous, necessitating additional investigation.
A Potential Game-Changer
Senior author Harikiran Nistala, the current Head of Functional Genomics at Alkermes Inc, Waltham, US, summarized the study's implications.
Loss of Slc39a5 improves hepatic inflammation and fibrosis in female mice challenged with diet-induced NASH. (CREDIT: eLife)
“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,” Nistala remarked. "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."
As the world grapples with rising cases of diabetes and associated metabolic diseases, this research might just be the beacon of hope many have been seeking.
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