A new study of type 2 diabetes (T2D) in Japanese populations has uncovered a previously uncharacterized genetic variant that puts male carriers at greater risk for the disease and the mechanism by which it occurs. The effect of the variant was most pronounced in sedentary men; those with the variant had a 65% higher rate of T2D than sedentary men without it.
Researchers from the University of Southern California and colleagues in Japan, led by Professor Noriyuki Fuku at Juntendo University, found higher rates of harmful abdominal fat and T2D in Japanese men with a specific variant of the mitochondrial gene. This variant at the site of the mitochondrial peptide MOTS-c occurs only in East Asian populations and has been shown in human and mouse data to prevent the normal production of MOTS-c and reduce the beneficial effects of exercise. Mimicking peptides usually prevents weight gain and normalizes metabolism. In addition, carriers of the deleterious variant secreted high levels of a bioinactive form of the peptide to compensate for its deficiency.
The results, published January 19 in the journal Aging, also suggest that moderate to high levels of daily physical activity may offset the increased risk of the variant allele. Researchers say this underscores the power of gene-environment interactions and highlights the role exercise can play in preventing the disease.
“Our study suggests that people with this particular variant can change their genetic risk by introducing an exercise program,” said co-lead author Su-Jeong Kim, a research fellow at USC Leonard Davis School. “A deeper understanding of the effects of this genetic variation will lay a foundation 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. It is estimated that 7-10% of East Asians wear this variant, and the research team believes their results are generalizable to other East Asians, including Koreans and North Chinese. According to the International Diabetes Federation, nearly 40% of global T2D cases come from the region that includes China, Korea, and Japan.
“This is particularly noteworthy because, while East Asian populations have lower mean body mass index (BMI) than Caucasian populations, they are more susceptible to T2D,” said co-senior author Pinchas Cohen, professor of gerontology, medicine and Life Sciences Dean of USC Leonard Davis School. “These results provide us with a better understanding of how mitochondrial genetic variants can contribute to disease, as well as insights into how precision medicine-based therapies can be developed to treat them, including replacing the defective peptide with drugs that mimic its effects . “
These findings were specific to men. The variant had no effect on women in either 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.
More about MOTS-C
MOTS-c is one of several recently identified hormones encoded in the DNA of mitochondria, the “powerhouses” of cells that convert food into energy. Most other hormones are encoded in the DNA in the nucleus. Cohen and Changhan David Lee, an assistant professor at USC Leonard Davis School, first described MOTS-c in 2015 along with its role in restoring insulin sensitivity and combating diet-related and age-related insulin resistance – effects often associated with exercise . In a separate article published January 20 in Nature Communication, the same authors showed that MOTS-c has “exercise mimetic” activities.
The current work in Aging found that a variant in the coding region of MOTS-c was responsible for changing the amino acid of the MOTS-c peptide. Individuals who carried the C allele instead of the predominant A allele produced a form of MOTS-c called K14Q MOTS-c that lacked the health benefits of the more common form.
The study found that the C-allele MOTS-c variant was less effective as a metabolic regulator in cell and animal models and is associated with suppressed insulin sensitizing effects and higher body fat. In male mice, MOTS-c administration significantly reduced weight gain from a high-fat diet. In contrast, K14Q MOTS-c failed to protect against weight gain caused by a high-fat diet. In addition, mice given MOTS-c performed better in glucose tolerance tests than mice injected with K14Q.
“We have shown that K14Q MOTS-c has a smaller impact on insulin sensitivity and weight gain compared to the more common form of MOTS-c in mice, and we speculate that this variant increases the prevalence of T2D in sedentary men because the C- Allele carriers that produce the less effective form of MOTS-c, ”said Kim.
Researchers next examined the effect of the C-allele variant on T2D in three cohorts of people of Japanese ancestry: the Japan Multi-Institutional Collaborative Cohort Study (J-MICC), which included 4,963 men and 6,889 women; Japanese-American subjects in the Multiethnic Cohort (MEC) study involving 1,810 men and 1,577 women of Japanese descent in the United States; and the Tohoku Medical Megabank Project (TMM), which involves 4,471 men and 7,817 women.
The meta-analysis of the three cohorts showed that men with the C allele had higher T2D rates. Regardless of the training status, the C allele increased the risk of T2D by more than a third.
The J-MICC study included measurements of daily activities. The researchers did a comparison and found that among the least active men, those with the C allele had a 65% higher rate of T2D than men with the A allele. This higher rate of disease was not observed in C-allele males who were exposed to moderate to vigorous physical activity for more than 40 minutes daily.
These results strongly suggest that a combination of a sedentary lifestyle and the C-allele variant contributes to an increased risk of T2D, according to the researchers, who believe the variant may have evolved into the most suitable living conditions which are characterized by a highly active lifestyle and limited caloric intake. In the past this may have been beneficial, but it is said to be a metabolic burden in the 21st century.
“With MOTS-c analogs currently in clinical development for the treatment of T2D complications, the finding that activity levels may affect T2D risk in carriers of this SNP may influence future clinical trials,” said Cohen. “This novel discovery suggests that additional ethnically specific mitochondrial variants may be involved in the risk of metabolic disorders. It also provides a blueprint for additional study of the mechanisms behind mitochondrial disease regulation and the search for potential mitochondrial-based therapeutics. “
Kim’s co-senior author was Hirofumi Zempo from Juntendo University in Chiba, Japan, and Cohen’s co-senior author was Keitaro Tanaka from Saga University in Saga, Japan. Other co-authors were Junxiang Wan, Kelvin Yen, Brendan Miller, Roberto Vicinanza, Jialin Xiao, Hemal H. Mehta and Changhan Lee from the USC Leonard Davis School; Eri Miyamoto-Mikami, Hiroshi Kumagai, and Hisashi Naito from Juntendo University; Yuichiro Nishida and Megumi Hara from Saga University; Yasuki Higaki from Fukuoka University in Japan; Yesha M. Patel and Veronica W. Setiawan of USC’s Keck School of Medicine; Timothy M. Moore and Andrea L. Hevener of UCLA’s David Geffen School of Medicine; Yoichi Sutoh and Atsushi Shimizu from Iwate Medical University, Japan; Kaname Kojima and Kengo Kinoshita from Tohoku University in Miyagi, Japan; Yasumichi Arai and Nobuyoshi Hirose from 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 Japan Society for the Advancement of Science (JSPS) KAKENHI grants (17015018, 221S0001, 16H06277, and 17H01554 to Tanaka, 16K09058 to Hara, 16K13052 to Fuku, and 18K17943 to Zempo) and the MEXT program for the Strategic Research Foundation at private universities (at Juntendo University). Kumagai received a JSPS Fellowship Grant (17J10817). This work was also supported by a Glenn / AFAR postdoctoral fellowship program in translational research on aging for Kim and by the grant of P01AG034906 and U54CA233465 to Cohen. Cohen is a co-founder, shareholder, and board member of Cohbar Inc. Lee is an advisor and shareholder of CohBar Inc. CohBar develops analogues of mitochondrial peptides, including MOTS-c, for metabolic diseases of aging.
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