No 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.

OBJECTIVEGlucagon-like peptide (GLP)-1 receptor is encoded by GLP1R. The effect of genetic variation at this locus on the response to GLP-1 is unknown. This study assessed the effect of GLP1R polymorphisms on insulin secretion in response to hyperglycemia and to infused GLP-1 in nondiabetic subjects.RESEARCH DESIGN AND METHODSEighty-eight healthy individuals (aged 26.3 ± 0.6 years, fasting glucose 4.83 ± 0.04 mmol/l) were studied using a hyperglycemic clamp. GLP-1 was infused for the last 2 h of the study (0.75 pmol/kg/min over 121–180 min, 1.5 pmol/kg/min over 181–240 min). β-Cell responsivity (ΦTotal) was measured using a C-peptide minimal model. The effect of 21 tag single nucleotide polymorphisms (SNPs) in GLP1R on ΦTotal was examined.RESULTSTwo SNPs (rs6923761 and rs3765467) were nominally associated with altered β-cell responsivity in response to GLP-1 infusion.CONCLUSIONSVariation in GLP1R may alter insulin secretion in response to exogenous GLP-1. Future studies will determine whether such variation accounts for interindividual differences in response to GLP-1–based therapy.

The primary factor determining survival after TP is the aetiology necessitating TP, i.e. pancreatic malignancy. Most respondents used complex insulin programmes, but hypoglycaemia continues to be a problem.

Mycobacterium tuberculosis (M. tb), the causative bacterial agent responsible for tuberculosis (TB) continues to afflict millions of people worldwide. Although the human immune system plays a critical role in containing M. tb infection, elimination proves immensely more challenging. Consequently, there has been a worldwide effort to eradicate, and limit the spread of M. tb through the conventional use of first-line antibiotics. Unfortunately, with the emergence of drug resistant and multi-drug resistant strains of M. tb the archetypical antibiotics no longer provide the same ascendancy as they once did. Furthermore, when administered, these first-line antibiotics commonly present severe complications and side effects. The biological antioxidant glutathione (GSH) however, has been demonstrated to have a profound mycobactericidal effect with no reported adverse consequences. Therefore, we examined if N-Acetyl Cysteine (NAC), the molecular precursor to GSH, when supplemented in combination with suboptimal levels of standalone first-line antibiotics would be sufficient to completely clear M. tb infection within in vitro derived granulomas from healthy subjects and individuals with type 2 diabetes (T2DM). Our results revealed that by virtue of immune modulation, the addition of NAC to subprime levels of isoniazid (INH) and rifampicin (RIF) was indeed capable of inducing complete clearance of M. tb among healthy individuals.