Relation between type 2 diabetes and m.1382 A>C polymorphism which occurs amino acid replacement (K14Q) of mitochondria‐derived MOTS‐c
Authors: Zempo Hirofumi , Fuku Niroyuki , Nishida Yuichiro , Higaki Yasuki , Naito Hisashi , Hara Megumi , Tanaka Keitaro 
Published: November 2023

IntroductionThe onset of type 2 diabetes is influenced by genetic background. However, it is not well defined. Low mitochondrial function has been related to insulin resistance. Recently, Lee et al. (Cell Metabolism, 2015) reported that mitochondrial derived peptide mitochondrial open‐reading‐frame of the twelve s rRNA –c (MOTS‐c) enhances muscular insulin sensitivity in mice. Actually, MOTS‐c which comprises 16 amino acid residues, also circulates in human blood. 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 amino‐acid 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.AimThis 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.Methods and ResultsStudy 1: Prevalence of type 2 diabetes in m.1382A>C genotype of JapaneseThis study examined 12, 069 community‐dwelling Japanese individuals (5078 men and 6991 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%). A tendency relation was found between m.1382 A>C polymorphism and prevalence of type 2 diabetes in men. Subjects with C allele had a higher prevalence of type 2 diabetes than those with A allele (P = .20). However, no relation was found for women. 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, 18.5%; A allele, 11.2%; odds ratio = 1.8 (95% CI: 1.1–2.9; P = .02).Study 2: Effect of MOTS‐c [K/Q14] on glucose tolerance test in miceTen‐week old male C57BL/6 J 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 7 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. Preliminary results of glucose tolerance tests showed MOTS‐c [K14] enhanced murine glucose clearance compared to vehicle. However, MOTS‐c [Q14] did not enhance glucose clearance.ConclusionEpidemiological studies have revealed that m.1382 A>C polymorphism is associated with type 2 diabetes with lower MVPA in men, but not in women 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.