Mitochondrial DNA Variability and ART Influence Diabetes Risk in Men With HIV

Overview

This study found that African mitochondrial DNA haplogroup L3 significantly increases the risk of incident type 2 diabetes mellitus (DM) in men with HIV. Additionally, exposure to mitochondrial-toxic antiretroviral drugs (D-drugs) independently elevates DM risk in this population.

Background

Diabetes mellitus is more prevalent in people with HIV (PWH) compared to those without HIV, contributing to increased mortality. Mitochondrial dysfunction plays a key role in DM pathophysiology, and mitochondrial DNA (mtDNA) haplogroups reflect genetic variation that may influence disease susceptibility. Certain antiretroviral therapies, especially nucleoside reverse transcriptase inhibitors known as D-drugs, have mitochondrial toxicity that could exacerbate DM risk in PWH.

Data Highlights

Key Findings

• African mtDNA haplogroup L3 is associated with nearly double the risk of incident type 2 DM in men with HIV compared to other African haplogroups.
• Exposure to mitochondrial-toxic D-drugs independently increases the risk of developing DM by approximately 2.8-fold in men with HIV.
• The study adjusted for confounders including age, BMI, hepatitis B and C status, smoking, and HIV-specific factors.
• Previous research showed haplogroup L2 was protective in women with HIV, highlighting sex-specific genetic effects.
• MtDNA haplogroups and mitochondrial-toxic ART exposure represent important factors influencing DM risk in aging men with HIV.

Clinical Implications

Clinicians should consider mitochondrial genetic background and history of exposure to mitochondrial-toxic ART when assessing diabetes risk in men with HIV. Avoidance or careful monitoring of D-drugs may be warranted to reduce DM incidence. Genetic testing for mtDNA haplogroups could potentially inform personalized risk stratification and management strategies in this population.

Conclusion

African mtDNA haplogroup L3 and prior exposure to mitochondrial-toxic D-drugs independently increase the risk of incident type 2 diabetes in men with HIV. These findings underscore the importance of mitochondrial genetics and ART history in diabetes risk assessment among aging PWH.

References

1. Miller et al. 2024 -- Influence of Mitochondrial DNA Variability and Antiretroviral Treatment on Diabetes Risk in Men With and Without HIV