Insulin resistance: A potential marker and risk factor for active tuberculosis?

Abstract

Current tuberculosis control measures are focused on the prompt detection and treatment of active tuberculosis. Despite the measured success of this strategy, tuberculosis continues to be a public health issue of major significance around the world. This unwanted situation suggests the need to expand our control efforts by exploring specific markers for the disease. Insulin resistance is one such marker. Although insulin resistance has been implicated in various diseases, thus far, no attempt has been made to analyze what has proved to be a direct relationship between insulin resistance and Mycobacterium tuberculosis susceptibility. Several studies have shown the role of insulin not only in cellular metabolism but also, more importantly, in phagocytosis of M. tuberculosis. Therefore, we hypothesize that insulin resistance can be considered a potential risk factor for active M. tuberculosis infection.

Introduction

Mycobacterium tuberculosis (M. tuberculosis) infection is the leading infectious disease in the world; despite the availability of effective therapy, 10 million new tuberculosis (TB) cases and at least three million deaths from TB are reported each year, and TB is a major health problem in many countries [1]. In addition to the Bacillus Calmette-Guérin (BCG) vaccination, control measures are usually focused on the prompt diagnosis and treatment of those with infectious forms of the disease to prevent further dissemination. Undoubtedly, this strategy has saved many lives and achieved huge success. However, TB continues to be a public health issue of major significance around the world. This unwanted situation suggests the need to expand our control efforts by exploring individual determinants [2] and specific markers for the disease. Some factors, such as diabetes mellitus (DM) [2], AIDS [3], kidney disease [4], and cancer [5] have been shown to increase the risk of developing active TB. To date, however, the detailed mechanism of each relationship has not been well understood, and a defective immune system has been considered the common reason for the development of TB in these cases. During the process of M. tuberculosis infection, a key characteristic of the bacterium is that it multiplies intracellularly, primarily in macrophages, which are, by most accounts, the most important phagocytic cells involved in the host control of M. tuberculosis [6]. Once M. tuberculosis infection is established, the state of macrophage will be changed to adapt to a new environment that both macrophage and M. tuberculosis maintain.

Insulin is a hormone that has profound effects on both carbohydrate and lipid metabolism, as well as significant influences on protein and mineral metabolism in classically insulin-sensitive cells, including adipocytes, myocytes and hepatocytes. Interestingly, studies have suggested that insulin might also play an important role in regulating phagocytosis performed by macrophages [7], [8]. Macrophages isolated from a rat model for type 2 diabetes show decreased phagocytosis of microbes [9]. Moreover, pro-inflammatory activity is potentiated through the increased transcriptional activity of forkhead box protein O1 (FOXO1) in insulin resistant (IR) macrophages [10]. This, in turn, could potentiate the destructive capacity of macrophages against intracellular pathogens, including M. tuberculosis. IR is not a disease or a specific diagnosis; it is a condition in which the cells of the body become resistant to the effects of insulin; however, it has been implicated in various diseases, such as cardiovascular disease (CVD) [11], hypertension [12], polycystic ovarian syndrome (PCOS) [13], type 2 diabetes [14], obesity [15], and metabolic syndrome [12]. In particular, in the case of metabolic syndrome, systemic IR could be a disease state [16], [17] in which increased transforming growth factor beta levels [18] could attenuate macrophage-related innate and adaptive immune activities. More importantly, growing evidence has shown that mycobacterial infection could lead to DM [19], and if the development of DM is preceded by a form of IR, this would also involve macrophages. When patients with latent TB, a more common form of TB, develop IR, they tend to be more susceptible to developing active TB. In fact, adipose-tissue-specific persistence of M. tuberculosis could be a reason for the induction of systemic IR [20]. However, to our knowledge, there has been no attempt yet to analyze what has proved to be a direct relationship between IR and active TB. Therefore, we hypothesized that IR can be considered as a potential marker and risk factor for active TB.