Glutathione deficiency in type 2 diabetes impairs cytokine responses and control of intracellular bacteria

• Published in: The Journal of clinical investigation Vol. 122; no. 6; pp. 2289 - 2300
• Main Authors: Tan, Kai Soo, Lee, Kok Onn, Low, Kee Chung, Gamage, Akshamal Mihiranga, Liu, Yichun, Tan, Gek-Yen Gladys, Koh, Hui Qi Vanessa, Alonso, Sylvie, Gan, Yunn-Hwen
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.06.2012
• Subjects: Adult; Aged; Animals; Antibiotics; Bacteria; Bacterial infections; Biomedical research; Burkholderia pseudomallei; Care and treatment; Cytokines; Diabetes; Diabetes Complications - metabolism; Diabetes Complications - microbiology; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - microbiology; Diabetes Mellitus, Type 2 - pathology; Diagnosis; Disease; Disease Susceptibility - etiology; Disease Susceptibility - metabolism; Disease Susceptibility - microbiology; Disease Susceptibility - pathology; Female; Glutathione; Glutathione - deficiency; Health aspects; Humans; Infections; Interferon-gamma - metabolism; Interleukin-12 - metabolism; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - microbiology; Male; Melioidosis - etiology; Melioidosis - metabolism; Melioidosis - microbiology; Melioidosis - pathology; Mice; Neutrophils; Physiological aspects; Properties; Salmonella enterica; Salmonella Infections - etiology; Salmonella Infections - metabolism; Salmonella Infections - pathology; Toll-Like Receptors - metabolism; Tuberculosis; Type 2 diabetes; Singapore
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci57817

Individuals with type 2 diabetes are at increased risk of acquiring melioidosis, a disease caused by Burkholderia pseudomallei infection. Although up to half of melioidosis patients have underlying diabetes, the mechanisms involved in this increased susceptibility are unknown. We found that B. pseudomallei-infected PBMCs from diabetic patients were impaired in IL-12p70 production, which resulted in decreased IFN-γ induction and poor bacterial killing. The defect was specific to the IL-12-IFN-γ axis. Defective IL-12 production was also observed during Mycobacterium tuberculosis infection, in which diabetes is likewise known to be a strong risk factor. In contrast, IL-12 production in diabetic cells was not affected upon Salmonella enterica infection or in response to TLR2, -3, -4, and -5 ligands. Poor IL-12 production correlated with a deficiency in intracellular reduced glutathione (GSH) concentrations in diabetic patients. Addition of GSH or N-acetylcysteine to PBMCs selectively restored IL-12 and IFN-γ production and improved bacterial killing. Furthermore, the depletion of GSH in mice led to increased susceptibility to melioidosis, reduced production of IL-12p70, and poorer disease outcome. Our data thus establish a link between GSH deficiency in diabetes and increased susceptibility to melioidosis that may open up new therapeutic avenues to protect diabetic patients against some intracellular bacterial pathogens.