Journal Article

Pre-Diabetes Increases Tuberculosis Disease Severity, While High Body Fat Without Impaired Glucose Tolerance Is Protective

Ngo, Minh Dao, Bartlett, Stacey, Ronacher, Katharina, Chen, Chen, Sinha, Roma, Donovan, Meg L., Keshvari, Sahar, Short, Kirsty R., Bielefeldt-Ohmann, Helle, Kling, Jessica C., Blumenthal, Antje, Hasnain, Sumaira Z.

2021

Overview

Type 2 diabetes (T2D) is a well-known risk factor for tuberculosis (TB), but little is known about pre-diabetes and the relative contribution of impaired glucose tolerance vs. obesity towards susceptibility to TB. Here, we developed a preclinical model of pre-diabetes and TB. Mice fed a high fat diet (HFD) for 12 weeks presented with impaired glucose tolerance and hyperinsulinemia compared to mice fed normal chow diet (NCD). Infection with M. tuberculosis (Mtb) H 37 R v after the onset of dysglycemia was associated with significantly increased lung pathology, lower concentrations of TNF-α, IFN-γ, IFN-β and IL-10 and a trend towards higher bacterial burden at 3 weeks post infection. To determine whether the increased susceptibility of pre-diabetic mice to TB is reversible and is associated with dysglycemia or increased body fat mass, we performed a diet reversal experiment. Pre-diabetic mice were fed a NCD for 10 additional weeks (HFD/NCD) at which point glucose tolerance was restored, but body fat mass remained higher compared to control mice that consumed NCD throughout the entire experiment (NCD/NCD). Upon Mtb infection HFD/NCD mice had significantly lower bacterial burden compared to NCD/NCD mice and this was accompanied by restored IFN-γ responses. Our findings demonstrate that pre-diabetes increases susceptibility to TB, but a high body mass index without dysglycemia is protective. This murine model offers the opportunity to further study the underlying immunological, metabolic and endocrine mechanisms of this association.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Animal models / Animals / Body composition / Body fat / Body mass index / Cellular and Infection Microbiology / Cytokines / Diabetes / Diabetes mellitus (non-insulin dependent) / Diet / disease severity / Drug resistance / Experiments / Gene expression / Glucose / Glucose tolerance / Glycerol / High fat diet / Hyperinsulinemia / Immunological tolerance / Immunology / impaired glucose tolerance / Infections / Insulin / Lungs / Mycobacterium tuberculosis / Obesity / pre-diabetes / Reagents / Risk factors / Tuberculosis / Tumor necrosis factor-α / β-Interferon / γ-Interferon