How a Tiny Protein Could Change Type 2 Diabetes Treatment

Discover how a tiny protein in the mitochondrial genome could revolutionize type 2 diabetes treatment with precision medicine insights.

Scientists have uncovered a previously unknown microprotein encoded within the human mitochondrial genome that could play a key role in the development of type 2 diabetes (1^✔ ✔Trusted Source
MENTSH: A novel mitochondrial microprotein linked to a SNP associated with type 2 diabetes

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The study, published in the journal Theranostics, reveals that the newly discovered molecule—named MENTSH (MDP Encoded in the ND-Two Subunit of Humans)—helps regulate the body’s metabolism and insulin response. Researchers believe the finding could eventually lead to targeted therapies for diabetes and obesity, particularly among people with specific genetic variants.

Unlike most genetic studies that focus on DNA stored inside the cell nucleus, this research explored the much smaller mitochondrial genome, which resides inside mitochondria—the tiny structures responsible for producing energy in every cell.

“This discovery not only represents a potential novel therapeutic for diabetes and obesity, but it also unravels a new cause of diabetes in Hispanics, who are known to be disproportionately affected by these conditions,” said Pinchas Cohen, senior author of the study and dean of the USC Leonard Davis School of Gerontology.

Looking Beyond Traditional Genetics

For decades, scientists have searched for genes linked to obesity and type 2 diabetes by examining the nuclear genome. However, the mitochondrial genome has received far less attention despite its essential role in energy production and metabolism.

Recent research has shown that mitochondria produce several tiny proteins known as microproteins, which influence numerous biological functions.

The USC team has now added another important member to this growing family.

The researchers analyzed health records and genetic data from more than 15,000 adults in a mitochondrial genome-wide association study. Their investigation identified a specific single-nucleotide polymorphism (SNP) strongly associated with type 2 diabetes. This genetic variation lies within the gene responsible for producing the newly identified MENTSH microprotein.

Genetic Variant Linked to Higher Diabetes Risk

The study found that the genetic variant effectively switches off production of the MENTSH protein by disrupting its “start codon”—the genetic signal that tells cells where protein production should begin.

Interestingly, this variant occurs most frequently among populations indigenous to the Americas and is present in approximately 20% of Mexican and Mexican American individuals.

Researchers say the finding could help explain why certain populations experience disproportionately higher rates of type 2 diabetes and obesity. Because the variant can be detected through genetic screening, it may eventually help identify people at greater risk of developing metabolic disease before symptoms appear.

From Genetic Discovery to Potential Therapy

After identifying the microprotein, scientists confirmed that MENTSH is biologically active using cell culture experiments and advanced mass spectrometry.

They then tested both the naturally occurring protein and laboratory-engineered versions in mouse models of obesity and diabetes.

The results were encouraging. Mice treated with MENTSH showed improved insulin signaling, while modified versions of the protein significantly reduced weight gain despite being fed high-fat diets.

Rather than producing a broad effect throughout the body, MENTSH appeared to act differently depending on the tissue. In skeletal muscle, it activated AKT, a critical signaling pathway that helps cells respond to insulin and absorb glucose more efficiently.

In fat tissue, however, it reduced AKT activity—a combination researchers say promotes healthier metabolism. “What’s exciting is that this molecule appears to act differently in muscle versus fat, which is exactly the kind of targeted effect you’d want in a metabolic therapy,” said Kelvin Yen, the study’s first author and research associate professor at the USC Leonard Davis School of Gerontology.

Precision Medicine for Diabetes

The findings point toward a future where diabetes treatment could become far more personalized. Instead of relying solely on standard medications, doctors may one day screen patients for the MENTSH-related genetic variant and tailor therapies based on their mitochondrial genetics.

This approach, known as precision medicine, aims to match treatments with an individual’s unique genetic profile, potentially improving effectiveness while reducing unnecessary side effects.

Researchers believe MENTSH-based therapies could be especially beneficial for people carrying the newly identified genetic variant. “For the first time, we’ve connected a mitochondrial microprotein to diabetes risk in a specific population, which opens the door to treatments tailored to the people who need them most,” said co-author Jerome Rotter, professor at the Lundquist Institute for Biomedical Innovation.

A New Direction for Metabolic Disease Research

Beyond diabetes, the discovery highlights the importance of exploring the mitochondrial genome for hidden proteins that may influence a wide range of metabolic disorders. Scientists say many more undiscovered microproteins could exist within mitochondrial DNA, each playing previously unknown roles in human health. The research also demonstrates that mitochondrial genetics may contribute to disease risk in ways scientists have only recently begun to understand.

Human Trials Still Needed

Although the results are promising, researchers caution that the work remains at the preclinical stage.

The beneficial effects of MENTSH have so far been demonstrated only in laboratory experiments and animal models. Extensive safety testing and clinical trials will be required before any MENTSH-based therapy can be evaluated in people.

If future studies confirm the findings, the tiny protein could become an entirely new therapeutic target for both type 2 diabetes and obesity, offering a treatment that improves insulin function while supporting healthier metabolism.

The discovery not only expands scientists’ understanding of metabolic disease but also reinforces the growing promise of precision medicine—where even the smallest hidden proteins may hold the key to treating some of the world’s fastest-growing chronic health conditions.

Reference:

1. MENTSH: A novel mitochondrial microprotein linked to a SNP associated with type 2 diabetes – (https://www.thno.org/v16p8180.htm)

Source-Medindia