An adverse immune-endocrine profile in patients with tuberculosis and type 2 diabetes

Summary

Diabetes is a risk factor for the development of pulmonary tuberculosis (TB) and both diseases present endocrine alterations likely to play a role in certain immuno-endocrine-metabolic associated disorders. Patients with TB, or with TB and type 2 diabetes (TB + T2DM) and healthy controls (HCo) were assessed for plasma levels of cortisol, dehydroepiandrosterone (DHEA), estradiol, testosterone, growth hormone (GH), prolactin, insulin-like growth factor-1 (IGF-1), cytokines (IL-6, IL-10, IFN-γ) and the specific lymphoproliferative capacity of peripheral blood mononuclear cells. All patients had higher levels of cortisol with a reduction in DHEA, thus resulting in an increased cortisol/DHEA ratio (Cort/DHEA). Increased prolactin and particularly GH levels were found in both groups of TB patients. This was not paralleled by increased concentrations of IGF, which remained within the levels of HCo. Estradiol levels were significantly augmented in patients TB, and significantly more in TB + T2DM, whereas testosterone levels were decreased in both groups of patients. IFN- γ and IL-6 concentrations were significantly increased in all TB, even further in TB + T2DM; while IL-10 was equally increased in both groups of TB patients. The in vitro specific proliferative capacity was decreased in both groups of patients as compared to that of HCo. The adverse immune-endocrine profile of TB seems to be slightly more pronounced in patients who also have T2DM.

Introduction

Pulmonary tuberculosis (TB) is a major cause of mortality around the world. In 2014, 1.5 million people died of TB (0.4 million HIV-positive) and 9.6 million people worldwide are estimated to have contracted the disease during this period [1]. The clinical manifestations are greatly influenced by the immune response to Mycobacterium tuberculosis, its etiologic agent, but the mechanisms underlying the outcome of the disease are not fully understood [2]. Endocrine responses during chronic infections such as lung tuberculosis are worth studying since some of the cytokines produced during this disease are likely to affect endocrine mechanisms that, in turn, influence the course of the infectious process [3], [4]. In fact, proinflammatory cytokines released from affected tissues that reach the central nervous system are known to influence the secretory activity of the hypothalamic–pituitary–adrenal (HPA) axis. The adrenal gland is responsible for the release of glucocorticoids (GCs), which generally inhibit or modulate inflammation, as well as dehydroepiandrosterone (DHEA), a steroid that counteracts GCs effects on cytokine production, but also exerts itself potent anti-inflammatory effects [3], [5]. Interactions between the endocrine and the immune system also involve the hypothalamic–pituitary–gonadal (HPG) axis, since macrophages and lymphocytes have receptors for gonadal steroids and these hormones can affect macrophage and lymphocyte development and function [6], [7].

By evaluating hormonal and cytokine levels in patients with TB, we have previously shown imbalanced immune-endocrine responses in which levels of pro-inflammatory cytokines, cortisol and estradiol concentrations were increased whereas testosterone and DHEA amounts were diminished in patients, together with an increased Cort/DHEA ratio even more pronounced in those with a severe disease [8].

Endocrine disturbances can also contribute to the pathology of patients with TB, as illustrated by the detrimental influence of type 2 diabetes mellitus (T2DM) on TB development. Several studies have shown that T2DM may be associated with an increased risk of developing active TB, whereas TB patients with concomitant diabetes are at higher rates of treatment failure and death [9], [10], [11].

Type 2 DM is characterized by the failure of beta cells to compensate for insulin resistance, with inflammatory or immunological factors being implied in such alterations [12]. Thus, the simultaneous occurrence of both diseases may impose a particular set of alterations in immune and endocrine parameters that is worth exploring.

On these bases, we analyzed the blood levels of several cytokines, hormones and the specific immune response to mycobacteria in the context of the TB and diabetes association. Studies included the assessment of the plasma levels of IL-6, IFN-γ and IL-10, adrenal (cortisol, DHEA) and gonadal (estradiol, testosterone) steroids, hormones involved in immune-metabolic effects like growth hormone (GH), prolactin and insulin-like growth factor-1 (IGF-1), in parallel to the specific lymphoproliferative capacity of peripheral blood mononuclear cells.