Metabolism as a missing link between diabetes, tuberculosis, and drug resistance?

Diabetes affects approximately one in ten adults globally, and its prevalence is expected to rise substantially over the coming decades. Diabetes doubles the risk of tuberculosis and is also associated with drug-resistant tuberculosis, adding to the global health and socioeconomic impact of tuberculosis. Increased exposure to drug-resistant Mycobacterium tuberculosis isolates or selection of resistance mutations owing to non-adherence or low drug levels during treatment are unlikely to fully explain this association. Instead, we hypothesise that metabolism is the missing link. First, diabetes might provide a more permissive immunometabolic environment for M tuberculosis, which could compensate for the metabolic fitness costs of some drug resistance mutations. Second, the higher mutational burden of M tuberculosis reported in individuals with diabetes and tuberculosis might lead to greater antibiotic resistance. Finally, drug tolerance might be favoured in diabetes and act as an intermediate step towards canonical drug resistance mutations. These hypotheses can be tested through comprehensive epidemiological studies, phenotypic testing and sequencing of M tuberculosis isolates from people with and without diabetes, and experimental in vitro or animal studies. A better understanding of these mechanisms could improve prevention and treatment of drug-resistant tuberculosis among people with diabetes.