The comorbidity of tuberculosis (TB) and diabetes mellitus (DM) has become a public health issue of global concern in recent years. The association between TB and DM was well known in the early 20th century and forgotten in the second half of the 20th century as treatment advanced (1). However, due to changes in people’s lifestyle and diet in recent years, the incidence of DM is increasing yearly, and the immune function of the body of patients with DM is poor, which increases the risk of TB infection (2). Studies have shown that DM can increase the risk of developing TB in infected patients by 3 to 4 times (3). The occurrence of DM may reduce the cure rate and increase the mortality and relapse rates during the treatment of TB patients (4). In the context of the overlap and increasing number of these two diseases, TB combined with DM represents a worldwide health threat (5). The relationships between blood glucose level and glycemic control status and TB cavity formation, sputum positivity and lesion site distribution in patients with TB combined with DM are contradictory, not entirely clear, and worthy of study.

In this study, we found that TB combined with DM accounted for 11.3% of the total hospitalized TB patients in the same period. Previous studies have reported that of the 1.5 million people who die from TB each year, 10% to 25% also have diabetes (9), the pooled prevalence of DM among total TB patients was 12.77% (95% CI 6.91-18.62%) (10), among adult TB patients was 5.1% (95% CI: 2.7%, 7.5%) (11), and among newly diagnosed TB patients was up to 54% (12). On the other hand, patients with DM have a threefold-fold increased risk of developing TB (13) and a 1.5-fold increased risk of developing active TB compared to those without DM (95% CI 1.28-1.76) (14). The pooled prevalence of TB among DM patients was 4.14% (95% CI 2.45-5.83%) (10), and the pooled effect showed a significant association between DM and latent TB infection (for cross-sectional studies, OR = 1.55, 95% CI: 1.30-1.84; for cohort studies, RR = 1.62, 95% CI: 1.02-2.56; rates range from 28.2% to 42.4%) (15, 16).

Type 1 diabetes patients were included in the study, accounting for only 0.97% of the total hospitalized TB patients in this cohort, of them 99.03% had type 2 DM. The average age was 29 years, significantly younger than those with type 2 DM, but there were not differences in cavity incidence, sputum situation and lesion location between different type DM groups. (As shown in Table 2 ).

In this study, we also found that only 15.8% (537/3393) of patients with TB combined with DM had good glycemic control, and 68.2% (2314/3393) and 16.0% (542/3393) of patients had fair glycemic control and poor glycemic control, respectively. (As shown in Table 1 ). In a recent study among newly diagnosed TB cases, only 25% of patients had normal blood glucose levels (10–12). The prevalence of persistent dysglycemia (PD)is 29.6% in patients with tuberculosis (17).

In this study, the characteristics of TB combined with DM were predominant in men aged 45 to 74 years, with a 16.8% cavity incidence rate, 52.2% sputum positive rate, 30.4% intrapulmonary lesion rate and 68.1% intra and extrapulmonary lesion rate. (As shown in Table 1 ). Those patients whose age were 18-44 years old and 45-59 old had higher percentage of cavity incidence, 19.24% and 18.25%, respectively, and those patients whose age were younger 18 years old had the highest sputum positive rate (85.71%). (As shown in Table 3 ). One study found that patients with both TB and diabetes were more likely to have clinical manifestations such as pulmonary cavitation (adjusted ratio aOR 2.26, 95% CI 1.04-4.90) and hemoptysis (aOR 2.21, 95% CI 1.02-4.78) (18), but there was no significant difference in the positive rate of sputum between the TB-DM and TB-NDM groups (2).

In this study, we found that poor glycemic control and higher FPG and HbA1c were associated with cavity formation, sputum positivity, and more lesions in patients with TB and DM. (As shown in Tables 4 , 5 ). These findings are also consistent with previous studies. One previous study found that pulmonary lobe lesion and cavity formation rates were significantly higher in patients with TB-DM with poor glycemic control than in patients with TB-NDM and TB-DM with normal glycemic control (2). Other previous studies found that concurrence of TB and DM can vary or even worsen the clinical manifestations of the disease, including increased sweats, weight loss, prolonged fever duration and dyspnea (19), have more severe lung involvement, such as more parenchymal lesions and cavities (20, 21), bilateral pulmonary involvement and advanced extensive pulmonary lesions affecting all lobes in CT scans (22), and delay both sputum smear and culture conversion time (9). These characteristics could aggravate if the TB-DM patient has poor glycemic control (23–26). Additionally, TB-DM patients are at a higher risk (twofold) of TB drug resistance (27). Other studies found that controlled potential confounders found a two- to fivefold mortality risk in TB-DM patients compared to non-TB-DM patients (4). All these findings regarding the severity of the clinical presentation translate into adverse treatment outcomes in TB-DM patients, such as an increased risk of delayed mycobacterial clearance, treatment failure, death, relapse, reinfection, and drug resistance (4, 28, 29). TB exerts its effects by complicating glycemic control in DM patients, and persistent dysglycemia (PD)is associated with more lung lesion types, higher bacillary loads, and unfavorable TB treatment outcomes. After adjusting for age, smoking, hemoglobin levels, and smear grade, PD was independently associated with unfavorable treatment outcomes (adjusted odds ratio (aOR): 6.1; 95% CI: 1.9–19.6) (17).

In this study, we also found that in patients with TB and DM cavity formation, sputum positivity and more lesions in turn make glycemic control more difficult. (As shown in Tables 4 , 5 ). Hyperglycemia has been assumed to favor the growth and propagation of MTB (30). Good glycemic control of diabetic patients enhances cellular immune function and the body’s tissue repair ability, accelerates the absorption of lesions, and restores the body’s ability to resist infection, thus enhancing the overall efficacy of the treatment.

Immunity is altered in diabetic patients at many levels, such as depressed polymorphonuclear leukocyte function, chemotaxis, affected leukocyte adherence, and phagocytosis. Cellular innate immunity dysregulation coupled with an increased glucose concentration environment contributes to the increased prevalence of TB infection (9). DM may reduce the control of persistent inflammation in TB through insufficient local IL-10 production in the lung, which could result in pulmonary impairment and aggravation of TB-DM disease (31). Dysglycemia in DM patients was postulated to damage their innate or adaptive immunity and could trigger a hyper inflammatory state (32, 33). It was reported that the synthesis of cytokines in pulmonary TB with DM patients showed significant changes compared to pulmonary TB without DM, such as IL-2, IL-6, IL-17, TNF-α and IFN-γ (34, 35). In addition, a previous study showed that the plasmatic increase in IL-15 could be related to the inflammatory state characteristics among DM and TB patients (36). Furthermore, a hyper inflammatory state of diabetic patients may favor the reactivation of TB (37, 38). The absolute counts of T lymphocytes, CD8+ T lymphocytes, and B lymphocytes in patients with TB-DM were markedly lower than those in patients with TB-NDM. The absolute counts of T lymphocytes and CD8+ T lymphocytes in patients with TB-DM and hyperglycemia were lower than those in patients with euglycemia. Linear regression analysis revealed that the absolute counts of total T lymphocytes, CD8+ T lymphocytes, and NK cells in patients with TB-DM significantly decreased with increasing FPG levels (2). In addition, the immunological hypothesis that may explain the DM and LTBI relationship is based on glycation of the CD271 domain of mesenchymal stem cells in uncontrolled DM patients, which may change their lifespan, becoming a potential niche for MTB in LTBI (5, 39). Thus, improving glucose control may overturn the harm caused to the immunological balance and diminish vulnerability to infectious agents (9).

However, there are still some limitations of this study. First, it was a single-center, retrospective study, and all the inherent limitations of retrospective studies are unavoidable. Second, follow-up was short, only during hospitalization, and did not complete the entire period of TB treatment. Third, the effects of diabetes course, family history of diabetes and hypoglycemic regimen on TB disease progression were not analyzed. Despite these limitations, we report several novel findings: TB combined with DM accounted for 11.3% of the total hospitalized TB patients in the same period and had a relatively high cavity formation rate, sputum positive rate and lesion rate. In this large sample size TB combined with DM cohort, overall glycemic control was poor: only 15.8% of patients had good glycemic control, and 16.0% of patients and 68.2% of patients had fair glycemic control and poor glycemic control, respectively. (As shown in Table 1 ). Poor glycemic control and hyperglycemia could promote TB disease progression manifested in increasing cavity formation, sputum positivity, and more lesions in those patients. On the other hand, TB disease severity, including the presence of cavities, positive sputum and widespread lesions, could make glycemic control difficult.

TB combined with DM is predominant in men over 44 years of age, with poor overall glycemic control, a relatively high cavity incidence rate, a high rate of sputum positivity and the presence of intrapulmonary and extrapulmonary lesions being more common. Hyperglycemia and poor glycemic control at admission may promote cavity formation, positive sputum and spread of lesions. Conversely, the presence of cavities, positive sputum and widespread lesions are detrimental to glycemic control. Strict glycemic control for these patients is necessary to reduce the incidence of cavitation and to promote negative sputum conversion.

All data, models, or code generated or used during the study are available from the corresponding author by request: DL, e-mail: liudf312@126.com.

This study was approved by the Ethics Committee of the Public and Health Clinic Centre of Chengdu (ethics approval number:YJ-K2022-52-01). Because this study was a retrospective cohort study and most of the subjects could not be contacted, the Ethics Commission of the hospital waived written informed consent. All of the participants understand that the information will be published without their child’s or ward’s/their relative’s (circle as appropriate) name attached but that full anonymity cannot be guaranteed. All of the participants understand that the text and any pictures or videos published in the article will be freely available on the internet and may be seen by the general public. The pictures, videos and text may also appear on other websites or in print and may be translated into other languages or used for commercial purposes.

Concept and design: FM, LL, GW, XR, MY, QC, XP, DL. Data acquisition: FM, LL, GW, XR, MY, QC, XP, DL. Data analysis and interpretation: FM, LL, GW, XR, MY, QC, XP, DL. Drafting manuscript: FM, LL, GW, XR, DL. Administrative, technical, or material support: FM, LL, GW, XP, DL. Study supervision: XP, DL. All authors contributed to the article and approved the submitted version.