Randomized Trial of Metformin With Anti-Tuberculosis Drugs for Early Sputum Conversion in Adults With Pulmonary Tuberculosis.

BACKGROUND: Metformin, by reducing intracellular Mycobacterium tuberculosis growth, can be considered an adjunctive therapy to anti-tuberculosis treatment (ATT). We determined whether metformin with standard ATT reduces time to sputum culture conversion and tissue inflammation in adults with pulmonary tuberculosis (PTB). METHODS: In a randomized, 8-week, clinical trial, newly diagnosed, culture-positive PTB patients were randomized to standard ATT (HREZ = control arm) or standard ATT plus daily 1000 mg metformin (MET-HREZ = Metformin with Rifampicin [METRIF] arm) for 8 weeks during 2018-2020 at 5 sites in India. The primary end point was time to sputum culture conversion by liquid culture during 8 weeks of ATT. Plasma inflammatory markers were estimated in a subset. A Cox proportional hazard model was used to estimate time and predictors of culture conversion. RESULTS: Of the 322 patients randomized, 239 (74%) were male, and 212 (66%) had bilateral disease on chest radiograph with 54 (18%) showing cavitation. The median time to sputum culture conversion by liquid culture was 42 days in the METRIF arm and 41 days in the control arm (hazard ratio, 0.8; 95% confidence interval [CI], .624-1.019). After 8 weeks of ATT, cavitary lesions on X-ray (7, 5.3% vs 18, 12.9%; relative risk, 0.42; 95% CI, .18-.96; P = .041) and inflammatory markers were significantly lower in the METRIF arm. Higher body mass index and lower sputum smear grading were associated with faster sputum culture conversion. CONCLUSIONS: The addition of metformin to standard ATT did not hasten sputum culture conversion but diminished excess inflammation, thus reducing lung tissue damage as seen by faster clearance on X-ray and reduced inflammatory markers. CLINICAL TRIALS REGISTRATION: Clinical Trial Registry of India (CTRI/2018/01/011176).

Increased levels of serum granulocyte-macrophage colony-stimulating factor is associated with activated peripheral dendritic cells in type 2 diabetes subjects (CURES-99).

BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pro-inflammatory cytokine with growth factor-like properties for monocytes and dendritic cells (DCs). In the present study, serum GM-CSF levels and the activation status of DCs were studied in type 2 diabetes mellitus (T2DM) subjects. METHODS: Study subjects were recruited from the Chennai Urban Rural Epidemiology Study. Healthy controls (n=45) and T2DM patients (n=45) were included in the study. Serum levels of GM-CSF, interleukin-1ß, interleukin-6, and tumor necrosis factor-α were measured. Enumeration of circulating DCs (myeloid [m] and plasmocytoid [p]) and its surface antigen expression were quantified by flow cytometry. RESULTS: The serum GM-CSF levels were significantly higher among diabetes subjects compared with subjects without diabetes and showed a positive correlation with glycated hemoglobin (r=0.208, P=0.018). The serum GM-CSF levels were lower in subjects on combined insulin and oral hypoglycemic agents (OHA) treatment (1.09 pg/mL) compared with those taking OHA alone (1.9 pg/mL). The increased GM-CSF levels were associated with the activated phenotype of mDCs and pDCs, as determined by up-regulation of the lineage markers. CONCLUSION: The activated state of mDCs and pDCs seen among diabetes subjects might be due to the increased levels of GM-CSF and other pro-inflammatory cytokines.

Altered circulating levels of matrix metalloproteinases and inhibitors associated with elevated type 2 cytokines in lymphatic filarial disease.

BACKGROUND: Infection with Wuchereria bancrofti can cause severe disease characterized by subcutaneous fibrosis and extracellular matrix remodeling. Matrix metalloproteinases (MMPs) are a family of enzymes governing extracellular remodeling by regulating cellular homeostasis, inflammation, and tissue reorganization, while tissue-inhibitors of metalloproteinases (TIMPs) are endogenous regulators of MMPs. Homeostatic as well as inflammation-induced balance between MMPs and TIMPs is considered critical in mediating tissue pathology. METHODS: To elucidate the role of MMPs and TIMPs in filarial pathology, we compared the plasma levels of a panel of MMPs, TIMPs, other pro-fibrotic factors, and cytokines in individuals with chronic filarial pathology with (CP Ag+) or without (CP Ag-) active infection to those with clinically asymptomatic infections (INF) and in those without infection (endemic normal [EN]). Markers of pathogenesis were delineated based on comparisons between the two actively infected groups (CP Ag+ compared to INF) and those without active infection (CP Ag- compared to EN). RESULTS AND CONCLUSION: Our data reveal that an increase in circulating levels of MMPs and TIMPs is characteristic of the filarial disease process per se and not of active infection; however, filarial disease with active infection is specifically associated with increased ratios of MMP1/TIMP4 and MMP8/TIMP4 as well as with pro-fibrotic cytokines (IL-5, IL-13 and TGF-ß). Our data therefore suggest that while filarial lymphatic disease is characterized by a non-specific increase in plasma MMPs and TIMPs, the balance between MMPs and TIMPs is an important factor in regulating tissue pathology during active infection.

Decreased prevalence of lymphatic filariasis among diabetic subjects associated with a diminished pro-inflammatory cytokine response (CURES 83).

Epidemiological studies have shown an inverse correlation between the incidence of lymphatic filariasis (LF) and the incidence of allergies and autoimmunity. However, the interrelationship between LF and type-2 diabetes is not known and hence, a cross sectional study to assess the baseline prevalence and the correlates of sero-positivity of LF among diabetic subjects was carried out (n = 1416) as part of the CURES study. There was a significant decrease in the prevalence of LF among diabetic subjects (both newly diagnosed [5.7%] and those under treatment [4.3%]) compared to pre-diabetic subjects [9.1%] (p = 0.0095) and non-diabetic subjects [10.4%] (p = 0.0463). A significant decrease in filarial antigen load (p = 0.04) was also seen among diabetic subjects. Serum cytokine levels of the pro-inflammatory cytokines-IL-6 and GM-CSF-were significantly lower in diabetic subjects who were LF positive, compared to those who were LF negative. There were, however, no significant differences in the levels of anti-inflammatory cytokines-IL-10, IL-13 and TGF-beta-between the two groups. Although a direct causal link has yet to be shown, there appears to be a striking inverse relationship between the prevalence of LF and diabetes, which is reflected by a diminished pro-inflammatory cytokine response in Asian Indians with diabetes and concomitant LF.