BACKGROUND: People living with diabetes have an increased risk of developing active tuberculosis and are more likely to have poor tuberculosis-treatment outcomes, which may impact on control of tuberculosis as the prevalence of diabetes is increasing worldwide. Blood transcriptomes are altered in active tuberculosis patients relative to healthy individuals. The effects of diabetes and intermediate hyperglycaemia on this transcriptomic signature were investigated to enhance understanding of immunological susceptibility in diabetes-tuberculosis comorbidity. METHODS: Whole blood samples were collected from active tuberculosis patients with diabetes (HbA1c ≥6.5%) or intermediate hyperglycaemia (HbA1c 5.7-6.5%), tuberculosis-only patients and healthy controls in four countries: South Africa, Romania, Indonesia and Peru. Differential blood gene expression was determined by RNA-seq (n=249). RESULTS: Diabetes increased the magnitude of gene expression change in the host transcriptome in tuberculosis, notably showing an increase in genes associated with innate inflammatory and decrease in adaptive immune responses. Strikingly, patients with intermediate hyperglycaemia and tuberculosis exhibited blood transcriptomes much more similar to diabetes-tuberculosis patients than to patients with only tuberculosis. Both diabetes-tuberculosis and intermediate hyperglycaemia-tuberculosis patients had a decreased type I interferon response relative to tuberculosis-only patients. CONCLUSIONS: Co-morbidity in individuals with both tuberculosis and diabetes is associated with altered transcriptomes, with an expected enhanced inflammation in the presence of both conditions, but also reduced type 1 interferon responses in co-morbid patients, suggesting an unexpected uncoupling of the TB transcriptome phenotype. These immunological dysfunctions are also present in individuals with intermediate hyperglycaemia, showing that altered immunity to tuberculosis may also be present in this group. The TB disease outcomes in individuals with intermediate hyperglycaemia diagnosed with TB should be investigated further.