As a clinical association is thought to exist between diabetes and tuberculosis, this study was set up to examine whether GK/Jcl diabetic rats are more susceptible to Mycobacterium tuberculosis infection than non-diabetic rats. GK/Jcl diabetic rats were infected aerially with M. tuberculosis and their capacity to control mycobacterial growth, granuloma formation, cytokine secretion by alveolar macrophages and nitric oxide (NO) production was examined. The rats developed large granulomas but not necrotic lesions in their lungs, liver or spleen. This is consistent with a significant increase in number of colony-forming units of M. tuberculosis in the lungs (p<0.01). Expression levels of interferon-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-12 mRNA were lower in GK/Jcl diabetic rats than those in control Wistar rats. Alveolar macrophages from GK/Jcl rats secreted less TNF-α and IL-12, and produced less NO compared with those from Wistar rats. No significant difference was observed between phagocytosis of tubercle bacilli by alveolar macrophages from GK/Jcl or Wistar rats. These data show that there is a close association between experimental tuberculosis and diabetes in animals, and that alveolar macrophages from GK/Jcl diabetic rats are not fully activated by M. tuberculosis infection.