Mitochondrial mutation increases the risk of diabetes in Japanese men

A new study of Type 2 diabetes (T2D) in Japanese populations has found a previously unidentified genetic variant that puts male carriers at greater risk for the disease, as well as the way in which it does so. The effect of the change was more pronounced in sedentary men; those with the variant had a 65% higher rate of T2D than sedentary men without.

Researchers from the University of Southern California, along with colleagues in Japan, led by Professor Noriyuki Fuku of Juntendo University, found higher levels of harmful belly fat and T2D among Japanese men with specific mitochondrial gene variation. This variant, at the site of the mitochondrial peptide MOTS-c, is found only in East Asian populations and has been shown, in both human and mouse data, to inhibit normal MOTS-c production, and to reduce the beneficial action of exercise- peptide imitation usually plays a role in preventing weight gain and normalizing metabolism. In addition, carriers of the destructive variable were receiving high levels of the bioactive form of the peptide in an attempt to compensate for its deficiency.

The findings, published January 19 in the journal Growing older, also suggests that moderate to strong levels of daily physical activity may counteract the increased risk posed by the variable allele. Researchers say this highlights the power of gene-environmental interactions and clarifies the role of exercise in preventing the disease.

“Our study suggests that people with this particular difference can alter their genetic risk by adopting an exercise regimen,” said co-author Su-Jeong Kim, research assistant professor at Leonard Davis School USC. “A deeper understanding of the effects of this genetic modification will provide a basis for developing physical activity strategies to maximize the benefits of exercise in T2D.”

The study also provides a possible explanation for why T2D is more common in East Asian populations. This variability is estimated at 7-10% of East Asians and the research team estimates that their results are common to other East Asians, including Koreans and North Chinese. According to the International Diabetes Federation, nearly 40% of the world’s T2D cases come from the region that includes China, Korea and Japan.

“This is particularly interesting because, while East Asian populations have a lower average body mass index (BMI) than Caucasian populations, they are more prone to T2D,” said co-author Pinchas Cohen, professor of gerontology , medicine and biological sciences and dean of USC Leonard Davis SchoolC. “These results give us both a better understanding of how mitochondrial genetic differences can contribute to diseases and insights for the development of precision-based therapies for their treatment, leading to into drugs similar to its actions to replace the defective peptide. “

These decisions were unique to men. The variance did not affect females in the human or mouse data. Researchers speculate that this is due to an interaction between mitochondrial peptides and hormones but say the mechanism is currently unclear.

MOTS-c is one of several recently announced hormones encoded in the DNA of mitochondria, the “powerhouses” of cells that convert food into energy; most other hormones are encoded in DNA in the nucleus. Cohen and Changhan David Lee, assistant professor at USC’s Leonard Davis School, first described MOTS-c in 2015, along with its role in restoring insulin sensitivity and lowering insomnia. diet-dependent and age-dependent insulin resistance – effects that are usually associated with exercise. In a separate paper published on January 20, in Nature Communication, the same authors showed that MOTS-c has “mimetic exercise” functions.

The standard paper in Aging found that a variable at the MOTS-c coding region was responsible for the amino acid modification of the MOTS-c peptide. Individuals carrying the allele C, rather than the more common allele A, produced a form of MOTS-c called K14Q MOTS-c that did not have health-promoting properties of the most common form.

The study found that the C allele variable MOTS-c was not as effective as a metabolic regulator in cell and animal models and is associated with the effects of suppressed insulin sensitivity and higher body fat. In male mice, administration of MOTS-c significantly reduced weight gain from a high-fat diet. In contrast, K14Q MOTS-c failed to protect against weight gain induced by a high-fat diet. In addition, MOTS-c-administered mice performed better on glucose tolerance tests than K14Q injection mice.

“We showed that K14Q MOTS-c has less effect on insulin sensitivity and weight gain compared to the most common form of MOTS-c in mice and maintains that this variant increases the frequency of T2D in sedentary men because C allele carriers produce the less effective form of MOTS-c, “Kim said.

The researchers again studied the effect of the C allele differentiation on T2D in three groups of people of Japanese descent: the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study, which provides included 4,963 men and 6,889 women; Japanese-American subjects in the Multiethnic Cohort (MEC) study, which includes 1,810 men and 1,577 women of Japanese descent living in the US; and the Tohoku Medical Megabank (TMM) project, which includes 4,471 males and 7,817 females.

A meta-analysis of the three groups showed that men with the C-allele had higher levels of T2D. Regardless of exercise status, the C-allele increased T2D risk by more than one-third.

The J-MICC study included measures of daily activity. The researchers compared and found that, among the least active men, those with the C allele had a 65% higher T2D level than the men with the A allele. The disease rate was no higher. this height was seen in C-allele men who engaged in more than 40 minutes of moderate to vigorous physical activity.

These findings strongly suggest that a combination of a sedentary lifestyle and the variable C allele contributes to an increased risk of T2D, according to the researchers, who say the variant may be proceed to respond to optimal living conditions characterized by highly active lifestyles and limited caloric intake. In the past this may have been an advantage, but in the twenty – first century, it is a metabolic burden, they say.

“With the presence of MOTS-c analogues currently in clinical development for the treatment of T2D disorders, the recognition that activity levels may influence T2D risk in carriers of this SNP may inform clinical trials in the future, “Cohen said. “This novel finding suggests that additional mitochondrial changes specific to rats may be involved in the risk of metabolic disease. It also provides a plan for further studies of the mechanisms that is behind how mitochondria manage disease and finding mitochondria-based treatment. “

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Co-author Kim Hirofumi Zempo of Juntendo University in Chiba, Japan, and Cohen co-author Keitaro Tanaka of Saga University in Saga, Japan. Other coauthors included Junxiang Wan, Kelvin Yen, Brendan Miller, Roberto Vicinanza, Jialin Xiao, Hemal H. Mehta, and Changhan Lee from USC Leonard Davis School; Eri Miyamoto-Mikami, Hiroshi Kumagai and Hisashi Naito of Juntendo University; Yuichiro Nishida and Megumi Hara of Saga University; Yasuki Higaki of Fukuoka University in Japan; Yesha M. Patel and Veronica W. Setiawan of USC Keck School of Medicine; Timothy M. Moore and Andrea L. Hevener from UCLA David Geffen School of Medicine; Yoichi Sutoh and Atsushi Shimizu of Iwate Medical University, Japan; Kaname Kojima and Kengo Kinoshita from Tohoku University in Miyagi, Japan; Yasumichi Arai and Nobuyoshi Hirose of Keio University School of Medicine in Tokyo, Japan; and Seiji Maeda from the University of Tsukuba, Japan.

This study was supported in part by the KAKENHI Grants of the Japan Society for the Advancement of Science (JSPS) (17015018, 221S0001, 16H06277, and 17H01554 to Tanaka; 16K09058 to Hara; 16K13052 to Fuku; and 18K17943 to Zempo) and by MEXT- Program for the Strategic Research Foundation at Private Universities (to Juntendo University). Kumagai received a Grant-In-Aid for JSPS relatives (17J10817). This work was also supported by the Glenn / AFAR Postdoctoral Fellowship Program for Translational Research on Aging to Kim and by the donation of P01AG034906 and U54CA233465 to Cohen. Cohen is a co-founder, stock owner and board member of Cohbar Inc. Lee is a consultant and shareholder of CohBar Inc. CohBar develops analogues of mitochondrial peptides, including MOTS-c, for metabolic diseases of aging.