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Aging-US: A pro-diabetogenic mtDNA polymorphism in mitochondrial-derived peptide

02-02-2021

Aging-US published "A pro-diabetogenic mtDNA polymorphism in the mitochondrial-derived peptide, MOTS-c" which reported that although ethnic specific mtDNA polymorphisms have been shown to contribute to T2D risk, the functional effects of the mtDNA polymorphisms and the therapeutic potential of mitochondrial-derived peptides at the mtDNA polymorphisms are underexplored.

Meta-analysis of three cohorts show that males but not females with the C-allele exhibit a higher prevalence of T2D.

In J-MICC, only males with the C-allele in the lowest tertile of physical activity increased their prevalence of T2D, demonstrating a kinesio-genomic interaction.

High-fat fed, male mice injected with MOTS-c showed reduced weight and improved glucose tolerance, but not K14Q-MOTS-c treated mice.

Thus, the m.1382A>C polymorphism is associated with susceptibility to T2D in men, possibly interacting with exercise, and contributing to the risk of T2D in sedentary males by reducing the activity of MOTS-c.

"The m.1382A>C polymorphism is associated with susceptibility to T2D in men, possibly interacting with exercise, and contributing to the risk of T2D in sedentary males by reducing the activity of MOTS-c."

Dr. Noriyuki Fuku from The Juntendo University and Dr. Pinchas Cohen from The University of Southern California said, "The prevalence of type 2 diabetes mellitus (T2D) is growing dramatically."

While diabetes syndromes directly caused by mutations in mtDNA are extremely rare, several genetic analyses reveal that mtDNA polymorphisms contribute to T2D risk in both European and Asian populations.

MOTS-c levels are correlated with insulin resistance, and circulating MOTS-c levels are reduced in obese male children.

Figure 5. The prevalence of type 2 diabetes in m.1382A>C polymorphism carriers. (A) Forest plot for meta-analysis (pooled random effects) on the prevalence of type 2 diabetes in males. Odds ratios are adjusted by age and BMI. Test for the pooled effect, Z = 2.86, p < 0.01. Heterogeneity was insignificant (I2 = 0%, p = 0.84). (B) Forest plot for meta-analysis (pooled random effects) on the prevalence of type 2 diabetes in female. Odds ratios are adjusted by age and BMI. Test for the pooled effect, Z = -0.46, p = 0.64. Heterogeneity was insignificant (I2 = 33.6%, p = 0.22). In Japan Multi-Institutional Collaborative Cohort (J-MICC) study, m.1382A>C polymorphism carriers divided by tertile of physical activity in (C) males and (D) females. Activity was assessed by the degree of moderate-to-vigorous intensity physical activity (MVPA). In men only, sedentary levels of MVPA were associated with an increased risk of diabetes in the C allele. Cochran-Armitage trend test of m.1382 C allele for men, χ2 = 6.26, p = 0.012. Cochran-Armitage trend test of m.1382 A allele for females, χ2 = 0.03, p = 0.861.

MOTS-c levels are inversely correlated with markers of insulin resistance and obesity including BMI, waist circumference, waist-to-hip ratio, fasting insulin level, HOMA-IR, HbA1c.

Although that study suggested an association between the haplogroup that includes mtDNA SNP at the MOTS-c region and T2D, the relation between the m.1382A>C polymorphism and human T2D pathophysiology was not explored.

Here, they elucidated the association between T2D and m.1382A>C in Japanese individuals and established the abnormal biological effects of the K14Q MOTS-c peptide variant – a consequence of the m.1382A>C polymorphism – on insulin action and adiposity in vitro and in vivo.

The Fuku/Cohen Research Team concluded in their Aging-US Research Paper, "we found that the C allele of the m.1382A>C polymorphism changes body composition and increases the risk of T2D in Japanese men, especially in sedentary individuals. This polymorphism causes an amino acid replacement from Lys (K) to Gln (Q) at amino acid 14 in the MOTS-c peptide, which renders it a less potent insulin-sensitizer compared to WT MOTS-c. A deeper understanding the effects of this genetic polymorphism will provide a basis for developing physical activity strategies to maximize the benefits of exercise in T2D."

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DOI - https://doi.org/10.18632/aging.202529

Full Text - https://www.aging-us.com/article/202529/text

Correspondence to: Noriyuki Fuku email: noriyuki.fuku@nifty.com and Pinchas Cohen email: hassy@usc.edu

Keywords: diabetes, mitochondrial DNA, polymorphism, MOTS-c insulin resistance

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