Introduction: The onset of type 2 diabetes is influenced by genetic background. However, it is not well defined. The mitochondrial derived peptide mitochondrial open-reading-frame of the twelve s rRNA-c (MOTS-c) which comprises 16 amino acid residues, have been showed that it enhances muscular insulin sensitivity in mice. We have more recently reported that East Asian specific m.1382 A>C polymorphism accompanies amino acid replacement from Lys (K) to Gln (Q) at the 14th aminoacid residue of the MOTS-c (Fuku et al., Aging Cell, 2015). However, the relation between m.1382 A>C polymorphism and type 2 diabetes remain unknown. Therefore, we hypothesized that amino acid replacement (K14Q) of the MOTS-c by m.1382 A>C polymorphism affects the onset of type 2 diabetes because of changing insulin sensitivity on the skeletal muscle and/or liver in East Asian populations.

Aim: This study was conducted to clarify the relation between type 2 diabetes and m.1382 A>C polymorphism [MOTS-c (K14Q)] in Japanese individuals and to investigate the effect of MOTS-c amino acid replacement (K14Q) on glucose metabolism.

　Epidemiological study (Prevalence of type 2 diabetes in m.1382 A>C genotype of Japanese): This study examined 12,068 community-dwelling Japanese individuals (5,078 men and 6,990 women; aged 40-69 years). m.1382 A>C genotype was determined using Luminex methods. Physical activity of participants was measured using an accelerometer. Results showed that type 2 diabetes in men (11.0%) was more prevalent than women (4.6%). Because moderate to vigorous intensity physical activity (MVPA) alters type 2 diabetes in men, we combined analyses MVPA and m.1382 A>C genotype. In the lowest tertile of MVPA, subjects with C allele had a significantly higher prevalence of type 2 diabetes than those with A allele in men (C allele, 18%; A allele, 11%; P=0.02).

　Animal study (Effect of MOTS-c [K/Q14] on glucose tolerance test in mice): Eight-week old male CD1 mice were used for this experiment. We used two synthetic MOTS-c peptides: K14 (wild type) and Q14 (mutant type). For glucose tolerance tests, mice were treated with MOTS-c [K14] (0.5 mg/kg/day; IP), MOTS-c [Q14] (0.5 mg/kg/day; IP), or vehicle (equal volume; IP), daily for 21 days. Then mice were injected with D-glucose (1 g/kg; IP). Blood was sampled from the tail at 0, 15, 30, 45, 60, 90, and 120 min post-glucose injection. Glucose tolerance tests showed that MOTS-c [Q14] worse glucose clearance compared to MOTS-c [K14] (P=0.01).

Conclusion: Epidemiological study have revealed that m.1382 A>C polymorphism is associated with type 2 diabetes with lower MVPA in men. An animal model showed that MOTS-c amino acid replacement (K14Q) affects glucose tolerance in male mice. Taken together, these results suggest that MOTS-c amino acid replacement (K14Q) by m.1382 A>C polymorphism may influence prevalence of type 2 diabetes in human.