The re-emerging association between tuberculosis and diabetes: Lessons from past centuries

Abstract

The association between tuberculosis (TB) and diabetes mellitus (DM) had a common place in the literature up to the first half of the 20th century, but virtually disappeared with the discovery of insulin to treat DM and antibiotics to cure TB. In the late 1990s the literature began to re-emerge with the worldwide increase in type 2 DM, particularly in TB-endemic countries. Today, type 2 DM is the most prevalent comorbidity among TB patients and the World Health Organization considers it a threat to TB control. We summarize the literature on TB and DM up to the 1960s. Then we evaluate unique aspects of this comorbidity in older times, such as the frequent diabetic comas that suggest challenges for proper DM management as insulin was being implemented, or the absence of antibiotics to cure TB. Despite the unique aspects of each study period, the literature across times is consistent in key aspects of the association. Namely, a higher TB prevalence among DM (versus non-DM patients), the importance of glucose control and chronic DM on TB susceptibility and the higher risk of death among patients with the co-morbidity. From the older literature, we can infer the likely contribution of type 1 DM to TB (in addition to type 2), regardless of their differing autoimmune or metabolic pathophysiology, respectively. Furthermore, in the older literature there was a notable reporting of DM development among TB patients, even though DM usually preceded TB. This observation deserves further epidemiological and basic studies to elucidate this intriguing aspect of the relationship between TB and DM.

Keywords: Death; History; Treatment outcomes; Tuberculosis; Type 1 diabetes; Type 2 diabetes.

Figure 1.. The re-emerging association between TB and DM based on indexed publications.

The number of “journal articles” published in English with titles containing the words “diabetes” and “tuberculosis” and indexed in PubMed between 1900 and 2017 is plotted by year. The association between TB and DM was first reported by Avicenna in the 10^th century (not shown) and the comorbidity had a common place in the literature up to the first half of the 20^th century. In 1921 insulin was introduced to treat DM, which appeared to reduce the prevalence of TB in these patients due improvements in glucose control. With the additional discovery of antibiotics to cure TB between the 1940s and 1970s, the literature on the comorbidity virtually disappeared. In the 1980s and 1990s the emergence of HIV took center stage in the TB literature, but in the early 2000s there was a re-emergence in publications that paralleled the contemporary DM pandemic. RIF, rifampicin; INH, isoniazid, EMB, ethambutol; PZA, pyrazinamide.

Figure 2.. Meta-analysis of TB prevalence by DM status based on autopsy studies (1859-1934).

The proportion of TB in the general population or in DM patients only was evaluated for studies published between 1859 and 1934. All studies conducted autopsies to diagnose TB. Studies are listed in chronological order to show the parallel reduction in TB prevalence in the general population or in DM patients at the turn of the 20th century. TB refers to autopsy findings suggestive of active or inactive TB; ES, Estimation of proportion; Data on TB proportion and population sizes was obtained from the literature reviews from Root (1932) and the autopsy study done by Root (1932).

Figure 3.. Proportion of active TB among DM patients by severity or duration of DM, stratified by age.

A. Severity of DM at the time of TB diagnosis, defined by Boucot et al as mild if requiring no insulin, moderate if requiring <40 U and severe if requiring ≥ 40 U. In Silwer and Oscarsson, mild DM was defined as requiring less than 20 U of insulin, severe DM if requiring ≥ 40 U, had tendency to acidosis, repeated comma attacks and was difficult to regulate, and moderate DM was the category in between mild and severe. B. History of DM prior to TB development. In Silwer and Oscarsson, < 10 yrs with DM refers to 5-9 years.

Figure 4.. From chronic glucose excess to glucotoxicity that can lead to compromised immunity.

During normoglycemia, glucose is oxidized through the glycolysis, tricarboxylic acid cycle and oxidative phosphorylation for efficient generation of ATP and reducing power (green text). During the chronic hyperglycemia resulting from type 1 or type 2 DM, excess glucose swamps the glycolytic pathway and inhibits the catabolism of glyceraldehydes, leading to the abnormal and excess shunting of the up-stream metabolic intermediates to other pathways (red font). These shunting pathways enhance the accumulation of reactive oxygen species that cause chronic oxidative stress. The reactive oxidative species cause micro- and macrovascular damage and induce chronic inflammation (referred to meta-inflammation in the case of metabolic alterations associated with type 2 DM). We posit that these alterations jointly contribute to compromised immune responses, contributing to the higher risk of DM patients to TB, particularly those with poor glucose control. P, phosphate group; PKC, protein kinase C; AGE, Advanced glycation end product; RAGE, receptor for AGE.; TCA, tricarboxylic acid cycle; Only selected intermediates of the glycolysis pathway are shown.