Rare pathogenic mitochondrial DNA variants provide a human model to study mechanisms of insulin resistance. Findings presented at the European Association for the Study of Diabetes Congress 2025 evaluated 15 carriers of the m.3243A>G mutation compared with matched healthy controls. 

Participants underwent hyperinsulinemic-euglycemic clamps, femoral arteriovenous glucose balance, oral glucose tolerance tests, and skeletal muscle biopsies for detailed mitochondrial and metabolic analyses.
Results demonstrated a 45% reduction in skeletal muscle insulin sensitivity and a 65% decrease in β-cell function in mutation carriers. Liver and adipose tissue insulin sensitivity remained unaffected. Muscle mitochondrial content was lower, but oxidative phosphorylation capacity per mitochondrion and reactive oxygen species emission were preserved. 

These findings indicate that reduced muscle mitochondrial quantity, rather than intrinsic mitochondrial dysfunction, contributes to insulin resistance in m.3243A>G carriers. This unique human model offers insight into mitochondrial roles in common insulin resistance and may guide development of mitochondria-targeted interventions.