title: Investigating the causes for decreased levels of glutathione in individuals with type II diabetes.
abstract: Tuberculosis (TB) remains an eminent global burden with one third of the world's population latently infected with Mycobacterium tuberculosis (M. tb). Individuals with compromised immune systems are especially vulnerable to M. tb infection. In fact, individuals with Type 2 Diabetes Mellitus (T2DM) are two to three times more susceptible to TB than those without T2DM. In this study, we report that individuals with T2DM have lower levels of glutathione (GSH) due to compromised levels of GSH synthesis and metabolism enzymes. Transforming growth factor beta (TGF-β), a cytokine that is known to decrease the expression of the catalytic subunit of glutamine-cysteine ligase (GCLC) was found in increased levels in the plasma samples from individuals with T2DM, explaining the possible underlying mechanism that is responsible for decreased levels of GSH in individuals with T2DM. Moreover, increased levels of pro-inflammatory cytokines such as interleukin-6 (IL-6) and interleukin-17 (IL-17) were observed in plasma samples isolated from individuals with T2DM. Increased levels of IL-6 and IL-17 was accompanied by enhanced production of free radicals further indicating an alternative mechanism for the decreased levels of GSH in individuals with T2DM. Augmenting the levels of GSH in macrophages isolated from individuals with T2DM resulted in improved control of M. tb infection. Furthermore, cytokines that are responsible for controlling M. tb infection at the cellular and granuloma level such as tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin-2 (IL-2), interferon-gamma (IFN-γ), and interleukin-12 (IL-12), were found to be compromised in plasma samples isolated from individuals with T2DM. On the other hand, interleukin-10 (IL-10), an immunosuppressive cytokine was increased in plasma samples isolated from individuals with T2DM. Overall, these findings suggest that lower levels of GSH in individuals with T2DM lead to their increased susceptibility to M. tb infection.
authors: Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, United States of America; Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, United States of America.
authors: Minette
authors: M
authors: Lagman
authors: Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, United States of America.
authors: Judy
authors: J
authors: Ly
authors: Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, United States of America.
authors: Tommy
authors: T
authors: Saing
authors: Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, United States of America; Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, United States of America.
authors: Manpreet
authors: M
authors: Kaur Singh
authors: Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, United States of America; Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, United States of America.
authors: Enrique
authors: E
authors: Vera Tudela
authors: Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, United States of America.
authors: Devin
authors: D
authors: Morris
authors: Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, United States of America; Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, United States of America.
authors: Po-Ting
authors: PT
authors: Chi
authors: Western Diabetes Institute, Pomona, California, United States of America.
authors: Cesar
authors: C
authors: Ochoa
authors: Western Diabetes Institute, Pomona, California, United States of America.
authors: Airani
authors: A
authors: Sathananthan
authors: Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, California, United States of America; Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, California, United States of America.
authors: Vishwanath
authors: V
authors: Venketaraman
mesh_terms: D000328:Adult; D015153:Blotting, Western; D016207:Cytokines / Q000097:blood*; D048909:Diabetes Complications / Q000276:immunology / Q000382:microbiology*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004198:Disease Susceptibility / Q000276:immunology; D005434:Flow Cytometry; D005978:Glutathione / Q000097:blood / Q000172:deficiency*; D006801:Humans; D015151:Immunoblotting; D020381:Interleukin-17 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008264:Macrophages / Q000378:metabolism; D008875:Middle Aged; D017382:Reactive Oxygen Species / Q000097:blood; D012394:Rosaniline Dyes; D016212:Transforming Growth Factor beta / Q000097:blood*; D014376:Tuberculosis / Q000209:etiology / Q000276:immunology*
chemical_list: D016207:Cytokines; D020381:Interleukin-17; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D012394:Rosaniline Dyes; D016212:Transforming Growth Factor beta; C048139:Coomassie blue; D005978:Glutathione