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.

Glutathione and glutathione derivatives in immunotherapy

“…GSH levels appear to be diminished by at least two different mechanisms: direct effects of glucose and insulin on GSH synthesis, and by the consumption of a cofactor required for GSH regeneration from GSSG (i.e., NAPDH) via the polyol pathway. Similar to what occurs in HIV-positive subjects, in diabetics, GSH deficiency in the PBMCs accounts for their impaired ability to control infection caused by M. tb and other intracellular bacterial pathogens via a defect in IL-12 production (Tan et al, 2012;Lagman et al, 2015). Interestingly, aldose reductase activity appears to be regulated by S-glutathionylation providing an additional link between GSH and these disease states (Cappiello et al, 2001;Giral et al, 2008).…”

Diabetes Mellitus as Hub for Tuberculosis Infection: A Snapshot

“…However, it was observed that the increment in the GSH level advances the action against MTB infections. Moreover, cytokines accountable for MTB infection at cellular level, such as TNF- α , IL-1 β , IL-2, IFN- γ , and IL-12, were found to be altered in DM type 2 individuals; interestingly the augmented level of some immunosuppressive cytokines such as IL-10 was also found in the same individual [44]. Even short chain fatty acid could also be responsible for the enhanced susceptibility of MTB where the effect of butyrate on different immunologic condition of cytokines in PBMC of diabetic individuals was studied.…”

Anti̇oksi̇danlar

“…Glutamin-sistein ligazın katalitik alt birimi, katalitik aktivite için sistein ve glutaminin bağlanmasından sorumludur. Glutamin-sistein ligazın düzen-leyici alt birimi ise GCLC'nin etkisini artırır (32,33).…”