Glutathione deficiency in type 2 diabetes impairs cytokine responses and control of intracellular bacteria
Kai Soo Tan, … , Sylvie Alonso, Yunn-Hwen Gan
Kai Soo Tan, … , Sylvie Alonso, Yunn-Hwen Gan
Published May 1, 2012
Citation Information: J Clin Invest. 2012;122(6):2289-2300. https://doi.org/10.1172/JCI57817.
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Research Article Metabolism

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

Abstract

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.

Authors

Kai Soo Tan, Kok Onn Lee, Kee Chung Low, Akshamal Mihiranga Gamage, Yichun Liu, Gek-Yen Gladys Tan, Hui Qi Vanessa Koh, Sylvie Alonso, Yunn-Hwen Gan

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Figure 3

Diabetic PBMCs infected with B. pseudomallei or M. tuberculosis show defective IL-12 and IFN-γ production.

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Diabetic PBMCs infected with B. pseudomallei or M. tuberculosis show def...
PBMCs isolated from healthy (n = 5) or diabetic (n = 5) individuals were infected ex vivo with either B. pseudomallei, S. enterica, or M. tuberculosis for 24 hours. (A) IL-12 and (B) IFN-γ production were determined by ELISA. (C) Primary monocytes isolated from either healthy (n = 5) or diabetic (n = 5) individuals were treated with PAM3CSK4 (1 μg/ml), UP-LPS (1 μg/ml), or flagellin (1 μg/ml) for 24 hours. (D) Primary monocytes isolated from a healthy donor were left untreated or treated with MyD88 inhibitor peptide (100 μM) 6 hours prior to treatments with B. pseudomallei, S. enterica, or PAM3CSK4 for 24 hours. (E) Primary monocytes from a healthy donor were left untreated or pretreated with TRIF inhibitor peptide alone (25 μM) or a mixture of TRIF (25 μM) and MyD88 inhibitor (100 μM) peptides 6 hours prior to KHW or LPS treatments. (F) Primary monocytes isolated from donors were stimulated with PAM3CSK4 (1 μg/ml) or poly(I:C) (50 μg/ml) for 24 hours. All experiments with primary monocytes involved priming the cells with IFN-γ (100 ng/ml). Each symbol represents data obtained from 1 study subject. Horizontal lines for the dot plots show the mean values for that particular experimental group. Data for the bar charts are presented as mean ± SEM. **P < 0.01; *P < 0.05; n.s. = P > 0.05.