The review explains that the tiny protein MOTS‑c, made by mitochondria, is often low in people with type‑2 diabetes and may contribute to the disease and heart problems. Lab studies in animals show that giving extra MOTS‑c can improve blood sugar control, boost metabolism, and protect the heart, and researchers have tried several doses and timing schedules. However, there are no human trials yet, so the information is mostly a guide for future experiments rather than a ready‑to‑use supplement plan.

Diabetes mellitus is a major global health issue with complex aetiology and a higher risk of consequent health complications. Advances in research and knowledge prompt new therapies to focus beyond glycemic control to include organ-protective therapies better optimise treatment outcomes. MOTS-c, a recently discovered mitochondria-derived peptide, plays a key role in regulating metabolic homeostasis and stress response. Emerging evidence suggests that insufficient MOTS-c production from dysfunctional mitochondria contributes to the pathological development of diabetes and its complications through its regulatory effects on cellular retrograde signalling. This review systematically classifies and analyses the various associations of MOTS-c with T2DM risk factors and summarises the relevant changes in a novel tabular format. In addition, the key role of MOTS-c in the major diabetes-related complications is specifically explored, with a special focus on its protective and therapeutic potential in diabetic cardiomyopathy. Beyond summarising its multifaceted roles, this review also uniquely compiles and discusses the distinct exogenous MOTS-c therapeutic approaches, including varying doses and dosing schedules, applied in preclinical metabolic disease studies, thereby providing valuable insights into future translational research.