New Genetic Discovery Could Support Precision Diabetes Care

Type 2 diabetes and obesity are among the fastest-growing threats to human health, yet many genetic contributors remain unclear. Most investigations focus on nuclear DNA, while the smaller mitochondrial genome is increasingly recognized for encoding microproteins with broad biological effects. Pinpointing population-specific drivers could support more precise risk assessment and targeted interventions.

A new study now shows that a previously unknown microprotein is linked to type 2 diabetes and may point toward precision treatment. Researchers at the University of Southern California identified a mitochondrial-derived microprotein named MENTSH (MDP Encoded in the ND-Two Subunit of Humans). 

In a mitochondrial genome-wide interaction study using health and genetic data from more than 15,000 adults, the team found a single-nucleotide polymorphism (SNP) associated with type 2 diabetes.  The variant sits within the MENTSH gene and disables its start codon. It occurs most frequently in populations indigenous to the Americas and in 20% of Mexican and Mexican American individuals, suggesting a genetic contributor to metabolic disease in a disproportionately affected population.

The team confirmed that MENTSH is biologically active in cell culture and detected it directly using mass spectrometry. They then administered MENTSH and engineered analogs in mouse models of diabetes and obesity. In these preclinical studies, MENTSH improved insulin signaling, while its analogs potently blocked weight gain in mice fed a high-fat diet. Analyses indicated a tissue-specific mechanism: MENTSH activated AKT signaling in muscle while reducing AKT signaling in fat, a pattern consistent with improved metabolic health.

According to the authors, the findings identify a new biological contributor to metabolic dysfunction and suggest that MENTSH-based approaches could support precision strategies for individuals who carry the SNP. They note that the variant can be readily screened and may serve as a test for diabetes risk. The study was published in Theranostics and involved collaborators including the Lundquist Institute for Biomedical Innovation. The authors emphasize that the work remains preclinical and that additional safety and efficacy studies will be required before evaluation in humans.

“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, a professor at the Lundquist Institute for Biomedical Innovation.

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

Related Links
Lundquist Institute for Biomedical Innovation
University of Southern California