Sexual dimorphism in mitochondrial dysfunction and diabetes mellitus: evidence from a population-based cohort study

Shanjie Wang; JunChen Guo; Xiaoxuan Liu; Wei Tian; Yiying Zhang; Ye Wang; Yige Liu; Mingyan E; Shaohong Fang

doi:10.1186/s13098-023-01090-1

Sexual dimorphism in mitochondrial dysfunction and diabetes mellitus: evidence from a population-based cohort study

Diabetol Metab Syndr. 2023 Jun 1;15(1):114. doi: 10.1186/s13098-023-01090-1.

Authors

Shanjie Wang^#^{1

2}, JunChen Guo^#^{1

2}, Xiaoxuan Liu^{1

2}, Wei Tian³, Yiying Zhang⁴, Ye Wang^{1

2}, Yige Liu^{1

2}, Mingyan E⁵, Shaohong Fang^{6

7}

Affiliations

¹ Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150000, China.
² The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, 150000, China.
³ Department of Epidemiology and Biostatistics, School of Public Health, Jiamusi University, 154000, Jiamusi, China.
⁴ Department of Epidemiology and Biostatistics, School of Public Health, Harbin Medical University, Harbin, China.
⁵ Department of Thoracic Radiotherapy, Harbin Medical University Cancer Hospital, Harbin, Nangang District, China. emingyan0996@163.com.
⁶ Department of Cardiology, Second Affiliated Hospital of Harbin Medical University, Harbin, 150000, China. fangshaohong@hrbmu.edu.cn.
⁷ The Key Laboratory of Myocardial Ischemia, Chinese Ministry of Education, Harbin, 150000, China. fangshaohong@hrbmu.edu.cn.

^# Contributed equally.

Abstract

Background: Pathophysiological mechanisms underlying sex-based differences in diabetes remain poorly understood. Mitochondrial metabolite methylmalonic acid (MMA) accumulation reflects mitochondrial dysfunction which is involved in sex-specific pathophysiological responses biologically. We aimed to investigate the sex-specific associations between mortality risk and MMA in adults with the presence or absence of type 2 diabetes.

Methods: This cohort study included 24,164 adults (12,123 females and 12,041 males) from the NHANES study during 1999-2014. Both sexes were separately categorized as those with no diabetes, prediabetes, undiagnosed diabetes, and diagnosed diabetes. Circulating MMA level was measured at baseline by mass-spectrometric detection. Mortality status was ascertained from baseline until December 31, 2015.

Results: During a median follow-up of 11.1 years, 3375 deaths were documented. Males had a particularly higher mortality than females in adults with diagnosed diabetes compared to differences in those with no diabetes, prediabetes and undiagnosed diabetes (sex differences in mortality rate per 1000 person-years across diabetic status: 0.62, 1.44, 5.78, and 9.77, p < 0.001). Notably, the sex-specific difference in associations between MMA and mortality was significant only in adults with diagnosed diabetes (p for interaction = 0.028), not in adults with no diabetes and prediabetes. Adjusted HRs (95%CIs) per doubling of MMA for all-cause mortality were 1.19 (1.04-1.37) in females with diagnosed diabetes versus 1.58 (1.36-1.86) in male counterparts. In addition, MMA levels had an insignificant or weak correlation with sex hormone profiles at baseline, regardless of diabetes status and sex.

Conclusions: Sex difference in mortality risk was especially significant in diagnosed type 2 diabetes. Increasing equivalent exposure to mitochondrial metabolite MMA was associated with a greater excess risk of future mortality in males with diabetes than in females.

Keywords: Cardiometabolism; Cobalamin; Gender/Sex; Methylmalonic acid; Mitochondria; Mortality.

Abstract

Grants and funding