The Intracellular Growth ofM. tuberculosisIs More Associated with High Glucose Levels Than with Impaired Responses of Monocytes from T2D Patients

Abstract

Diabetes mellitus, a metabolic disease characterized by hyperglycemia and poor glucose control, is a risk factor forMycobacterium tuberculosis(M. tuberculosis) infection and the development of active tuberculosis. To evaluate whetherM. tuberculosisinfection susceptibility is associated with an intrinsic factor in monocytes from type 2 diabetes (T2D) patients or it is associated with hyperglycemiaper se, we analyzed TLR-2 and TLR-4 expression by flow cytometry and the cytokines IL-1β, IL-6, IL-8, IL-10, and TNF-αby cytometric bead array assays, either stimulated with TLR-2 and TLR-4 ligands or infected withM. tuberculosisin the whole blood from T2D patients (n=43) and healthy subjects (n=26) or in CD14+ monocytes from healthy subjects cultured in high glucose (HG) (30 mM). The intracellular growth ofM. tuberculosiswas evaluated by CFU counts at 0, 1, and 3 days in both monocytes from T2D patients and monocytes from healthy subjects cultured in HG. We did not find significant differences in TLR expression, cytokine production, or growth ofM. tuberculosisin monocytes from T2D patients compared with those in monocytes from healthy subjects. Despite these results,in vitroassays of monocytes cultured with 30 mM glucose led to significantly increased TLR-2 and TLR-4 basal expression compared to those of monocytes cultured with 11 mM glucose (P<0.05). Conversely, the production of IL-6 by TLR-2 ligand stimulation, of IL-1β, IL-6, and IL-8 by TLR-4 ligand stimulation, and of IL-8 byM. tuberculosisinfection significantly decreased in monocytes cultured in HG (P<0.05). Additionally, the intracellular survival ofM. tuberculosisincreased in monocytes in HG after day 3 of culture (P<0.05). In conclusion, HG decreased IL-8 production and the intracellular growth control ofM. tuberculosisby monocytes, supporting the hypothesis that hyperglycemia plays an important role in the impaired immune responses toM. tuberculosisin patients with T2D.