Unique Reciprocal Association Seen Between Latent Tuberculosis Infection and Diabetes Is Due to Immunoendocrine Modulation (DM-LTB-1).

Aim: The prevalence of latent tuberculosis infection (LTBI) among diabetes patients is poorly studied. In the present study, the prevalence of LTBI among pre-diabetes and diabetes patients was studied, along with immunoendocrine biomarkers (n = 804). Methods: LTBI was screened by Quantiferon TB gold in Normal glucose tolerance [(NGT); n = 170, [Pre-diabetes (PDM; n = 209), Newly diagnosed diabetes (NDM; n = 165) and Known diabetes (KDM; n = 260) subjects. CRP, TNF-α, IL-6, IL-1ß, IFN-ß, IL-12, IFN-γ, IL-2, insulin, leptin, and adiponectin levels in serum and IFN-γ levels in quantiferon supernatants were quantified by ELISA. The expression of T-bet was quantified using qRT-PCR. Serum TBARS and nitrite levels were quantified by colorimetry. Results: The LTBI prevalence was 32% in NGT, 23% in PDM, 24% in NDM, and 32% in KDM groups, with an adjusted OR of 0.61 (p < 0.05). Downregulation of CRP, TNF-α, and nitrites and upregulation of adiponectin could be responsible for LTBI mediated protection against insulin resistance (IR), while the high levels of IL-1ß, IL-12, and leptin could be responsible for IR mediated anti-TB immunity. The defective antigen-specific IFN-γ response, as seen in the KDM group, could be responsible for the low detection rate of LTBI and high probability of endogenous reactivation. Conclusion: There appears to be a biphasic relationship between diabetes-latent tuberculosis: At the early stages of diabetes it is reciprocal, while at a late stage it is synergistic, this important phenomenon obviously needs further research.

Serum levels of novel anti-inflammatory cytokine Interleukin-38 in diabetes patients infected with latent tuberculosis (DM-LTB-3).

IL-38 is a recently discovered, novel anti-inflammatory cytokine, which belongs to the IL-1ß family. The role played by this cytokine in diabetes-tuberculosis nexus is not known. Serum levels of IL-38, TNF-α, IL-6, and IL-1ß in Normal Glucose Tolerance (NGT) and chronic Diabetes (DM) subjects, both with and without latent tuberculosis (LTB) (n = 256) were quantified by ELISA. While, serum levels of IL-38 were significantly reduced, the levels of TNF-α, IL-6, and IL-1ß were not altered, in LTB infected diabetes patients. While no significant secretion of IL-38 was detected in the quantiferon supernatant, secretion of TNF-α, IL-6, and IL-1ß was significantly reduced in LTB infected diabetes patients. The decreased systemic levels of IL-38 and reduced in vitro secretion of other pro-inflammatory cytokines might represent a crucial pathway associated with diabetes-tuberculosis nexus.

Anti-inflammatory cytokines IL-27, IL-10, IL-1Ra and TGF-ß in subjects with increasing grades of glucose intolerence (DM-LTB-2).

Anti-inflammatory cytokines act as double edged swords- they can dampen inflammation but can also suppress immunity. The role played by these cytokines in latent TB infected (LTBI) subjects, with various grades of glucose intolerance was studied. Both serum levels and recall-secretion of IL-27, IL-10, IL-1Ra and TGF-ß in Normal Glucose Tolerance (NGT), Pre-Diabetes (PDM), Newly diagnosed Diabetes (NDM) and Known Diabetes (KDM) subjects, both with and without LTBI (n = 382), were quantified by ELISA. All the subjects were screened for LTBI by QuantiFERON-TB Gold test. Serum levels of IL-27, IL-10 and IL-1Ra were significantly elevated in the LTB-PDM, compared to LTB-NGT group. Increased IL-27 and IL-10 levels and decreased levels of TGF-ß were seen in the LTB-NDM, compared to LTB-NGT group. Decreased serum levels of IL-27 and increased levels of IL-1Ra and TGF-ß were seen in the LTB-KDM, compared to LTB-NGT group. TB antigens induced the secretion of IL-1Ra in LTB+ subjects in the NGT, PDM and NDM groups, but not in the KDM group. Co-morbidity with LTBI brought about (diabetic) stage-specific modulation, in these cytokine levels. Major defects in the circulating levels and recall secretion of anti-inflammatory cytokines, as seen in LTB+KDM subjects, could fuel DM-TB synergy.

Microbially produced glucagon-like peptide 1 improves glucose tolerance in mice.

OBJECTIVE: The enteroendocrine hormone glucagon-like peptide 1 (GLP-1) is an attractive anti-diabetic therapy. Here, we generated a recombinant Lactococcus lactis strain genetically modified to produce GLP-1 and investigated its ability to improve glucose tolerance in mice on chow or high-fat diet (HFD). METHODS: We transformed L. lactis FI5876 with either empty vector (pUK200) or murine GLP-1 expression vector to generate LL-UK200 and LL-GLP1, respectively, and determined their potential to induce insulin secretion by incubating primary islets from wild-type (WT) and GLP-1 receptor knockout (GLP1R-KO) mice with culture supernatant of these strains. In addition, we administered these strains to mice on chow or HFD. At the end of the study period, we measured plasma GLP-1 levels, performed intraperitoneal glucose tolerance and insulin tolerance tests, and determined hepatic expression of the gluconeogenic genes G6pc and Pepck. RESULTS: Insulin release from primary islets of WT but not GLP1R-KO mice was higher following incubation with culture supernatant from LL-GLP1 compared with LL-UK200. In mice on chow, supplementation with LL-GLP1 versus LL-UK200 promoted increased vena porta levels of GLP-1 in both WT and GLP1R-KO mice; however, LL-GLP1 promoted improved glucose tolerance in WT but not in GLP1R-KO mice, indicating a requirement for the GLP-1 receptor. In mice on HFD and thus with impaired glucose tolerance, supplementation with LL-GLP1 versus LL-UK200 promoted a pronounced improvement in glucose tolerance together with increased insulin levels. Supplementation with LL-GLP1 versus LL-UK200 did not affect insulin tolerance but resulted in reduced expression of G6pc in both chow and HFD-fed mice. CONCLUSIONS: The L. lactis strain genetically modified to produce GLP-1 is capable of stimulating insulin secretion from islets and improving glucose tolerance in mice.