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

J Clin Invest. 2012 Jun;122(6):2289-300. doi: 10.1172/JCI57817. Epub 2012 May 1.


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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Burkholderia pseudomallei*
  • Diabetes Complications / metabolism*
  • Diabetes Complications / microbiology
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diabetes Mellitus, Type 2 / microbiology
  • Diabetes Mellitus, Type 2 / pathology
  • Disease Susceptibility / etiology
  • Disease Susceptibility / metabolism*
  • Disease Susceptibility / microbiology
  • Disease Susceptibility / pathology
  • Female
  • Glutathione / deficiency*
  • Humans
  • Interferon-gamma / metabolism*
  • Interleukin-12 / metabolism*
  • Leukocytes, Mononuclear / metabolism
  • Leukocytes, Mononuclear / microbiology
  • Male
  • Melioidosis / etiology
  • Melioidosis / metabolism*
  • Melioidosis / microbiology
  • Melioidosis / pathology
  • Mice
  • Salmonella Infections / etiology
  • Salmonella Infections / metabolism
  • Salmonella Infections / pathology
  • Salmonella enterica
  • Toll-Like Receptors / metabolism


  • Toll-Like Receptors
  • Interleukin-12
  • Interferon-gamma
  • Glutathione