title: Effect of oral N-acetyl cysteine supplementation in type 2 diabetic patients on intracellular glutathione content and innate immune responses to Burkholderia pseudomallei.
abstract: Type 2 diabetic patients have increased susceptibility to melioidosis, an infectious disease caused by Burkholderia pseudomallei. We had previously shown that peripheral blood mononuclear cells (PBMCs) from diabetic patients with poor glycemic control had a defective IL-12 and IFNγ response to B. pseudomallei infection, resulting in poor intracellular bacterial control. The impaired IL-12 response was due to glutathione (GSH) deficiency characterized by a low reduced to oxidized glutathione ratio (GSH ratio) and could be restored by the addition of reduced GSH to the infected cells. Our goal is to determine whether N-acetyl cysteine (NAC, a GSH pro-drug) supplementation in diabetic patients could improve their immune control of B. pseudomallei. Type 2 diabetic patients with poor glycemic control were given oral supplementation of NAC for six weeks at 1200 mg daily. Their PBMCs and subsets of immune cells showed a significant increase in free GSH concentration. However, the GSH ratio, IL-12 and IFNγ production, and intracellular bacterial killing upon ex-vivo infection did not improve. Thus, oral NAC supplementation in diabetic patients is sufficient to increase intracellular GSH content in blood cells. However, modulating the free GSH content is not sufficient to improve infection outcome as it is the GSH ratio that regulates the IL-12 response in monocytes.
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, MD7, 8 Medical Drive, Singapore 117597, Singapore.
authors.forename: Akshamal M
authors.initials: AM
authors.lastname: Gamage
authors.affiliation: Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 1E Kent Ridge Road NUHS Tower Block Level 10 Singapore 119228, Singapore.
authors.forename: Kok Onn
authors.initials: KO
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, MD7, 8 Medical Drive, Singapore 117597, Singapore; Immunology Program, National University of Singapore, Singapore. Electronic address: yunn_hwen_gan@nuhs.edu.sg.
authors.forename: Yunn-Hwen
authors.initials: YH
authors.lastname: Gan
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage*; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D016957:Burkholderia pseudomallei / Q000276:immunology*; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D008297:Male; D008875:Middle Aged
chemical_list: D018664:Interleukin-12; D007371:Interferon-gamma; D005978:Glutathione; D000111:Acetylcysteine
keywords: Bacterial infection; Burkholderia pseudomallei; Glutathione; Melioidosis; N-acetyl cysteine; Type 2 diabetes