Lower expression of Th1-related cytokines and inducible nitric oxide synthase in mice with streptozotocin-induced diabetes mellitus infected with Mycobacterium tuberculosis

Clin Exp Immunol. 2005 Jan;139(1):57-64. doi: 10.1111/j.1365-2249.2005.02677.x.


Diabetes mellitus is an important predisposing factor for tuberculosis. The aim of this study was to investigate the mechanism underlying this association using a murine model. Mice with streptozotocin-induced diabetes mellitus were prone to Mycobacterium tuberculosis infection, as indicated by increased numbers of live bacteria in lung, liver and spleen. In diabetic mice, the levels of IL-12 and IFN-gamma in the lung, liver and spleen were lower than those in control animals on day 14 postinfection, while the opposite was true for IL-4 levels in the lung and liver. The expression pattern of inducible nitric oxide synthase (iNOS), in the two mice types was as for IL-12 and IFN-gamma. In addition, peritoneal exudate cells obtained from diabetic mice produced lower amounts of IL-12 and NO than those from control mice, when stimulated in vitro with M. bovis BCG. Spleen cells from diabetic mice infected with M. tuberculosis produced a significantly lower amount of IFN-gamma upon restimulation with purified protein derivatives (PPD) than those from infected nondiabetic mice. Interestingly, addition of high glucose levels (33 mM) to the cultures of PPD-restimulated spleen cells reduced the synthesis of IFN-gamma only in diabetic mice, and not in nondiabetic mice. Finally, control of blood glucose levels by insulin therapy resulted in improvement of the impaired host protection and Th1-related cytokine synthesis. Our results suggest that the reduced production of Th1-related cytokines and NO account for the hampered host defense against M. tuberculosis infection under diabetic conditions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Cytokines / analysis*
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / immunology*
  • Disease Susceptibility / immunology
  • Hypoglycemic Agents / pharmacology
  • Insulin / pharmacology
  • Interferon-gamma / analysis
  • Interleukin-12 / analysis
  • Interleukin-4 / analysis
  • Liver / immunology
  • Lung / immunology
  • Mice
  • Mice, Inbred ICR
  • Nitric Oxide / analysis
  • Nitric Oxide Synthase / analysis*
  • Nitric Oxide Synthase Type II
  • Spleen / immunology
  • Th1 Cells / immunology*
  • Th2 Cells / immunology
  • Tuberculin / immunology
  • Tuberculosis / etiology
  • Tuberculosis / immunology*


  • Blood Glucose
  • Cytokines
  • Hypoglycemic Agents
  • Insulin
  • Tuberculin
  • Interleukin-12
  • Interleukin-4
  • Nitric Oxide
  • Interferon-gamma
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse