ABSTRACT
Susceptibility to a Pulmonary Infection in Type 2 Diabetes
Epidemiological studies indicate a strong association between chronic low-grade inflammation and type 2 diabetes (T2DM). Molecular models suggest that obesity induces this chronic inflammatory state, which promotes insulin resistance and T2DM. Another hallmark of T2DM is higher susceptibility, morbidity and even mortality to infections, including pulmonary tuberculosis (TB). T2DM and TB are common among the minority population from the Texas/Mexico border, we recently showed that DM is two-four times more prevalent among Mexican Americans with TB than in the general population, and that these patients with self-reported DM and TB present with more severe clinical manifestations, have delayed response to drug therapy, and a significantly higher chance of relapsing or developing drug resistant TB.
We have now established prospective cohorts of TB patients in local clinics, and are confirming that as many as 40% have pre-diabetes or T2DM. The underlying mechanism for the association between T2DM and TB is unclear, but one possible explanation is immune compromise in patients with T2DM that permits mycobacterial replication. Coincidently, the same cytokines that are chronically up-regulated in patients with T2DM, are also critical for establishment of a compact granuloma that contains mycobacteria and prevents its replication. In this pilot we will test the hypothesis that TB patients with poorly-controlled DM have alterations in their innate immune response that is associated with reduced ability to contain and clear mycobacteria, when compared with TB patients with no T2DM. Specifically, we will prospectively measure blood glucose and glycosylated hemoglobin (HbA1c) in patients with a recent diagnosis of TB, and characterize the effect that chronic hyperglycemia has on the initial, innate immune response to M. tuberculosis. We will specifically measure key innate immune response parameters known to be critical for mycobacterial containment (IL-1beta, TNF-alpha, IL-8, IL-6 and their cell sources), but that may be exhausted due to their chronic alteration in patients with T2DM.
The prospective studies we propose will provide the foundation for understanding how T2DM predisposes not just TB, but other pulmonary infections that are also more likely to affect DM patients.
