Experimental diabetes induced by alloxan and streptozotocin: The current state of the art.

The dual burden of tuberculosis and diabetes has attracted much attention in the past decade as diabetes prevalence has increased dramatically in countries already afflicted with a high burden of tuberculosis. The confluence of these two major diseases presents a serious threat to global public health; at the same time it also presents an opportunity to learn more about the key elements of human immunity to tuberculosis that may be relevant to the general population. Some effects of diabetes on innate and adaptive immunity which are potentially relevant to tuberculosis defense have been identified, but have yet to be verified in humans and are unlikely to fully explain the interaction of these two disease states. This review provides an update on the clinical and epidemiological features of tuberculosis in the diabetic population and relates them to recent advances in understanding the mechanistic basis of tuberculosis susceptibility and other complications of diabetes. Issues that merit further investigation, such as geographic host and pathogen differences in the diabetes/tuberculosis interaction, the role of hyperglycemia-induced epigenetic reprogramming in immune dysfunction and the impact of diabetes on lung injury and fibrosis caused by tuberculosis, are highlighted in this review.

/pdf/diabetes-and-immunity-to-tuberculosis-3nihlp7rrp.pdf

Diabetes and immunity to tuberculosis.

The increase in type 2 diabetes mellitus (DM) patients in countries where tuberculosis (TB) is also endemic has led to the reemerging importance of DM as a risk factor for TB. DM causes a 3-fold increase in TB risk and a 2-fold increase in adverse TB treatment outcomes. Given the sheer numbers of DM patients worldwide, there are now more TB patients with TB-DM comorbidity than TB-HIV coinfection. There is an urgent need to implement strategies for TB prevention and control among the millions of DM patients exposed to Mycobacterium tuberculosis. This chapter summarizes the current epidemiological, clinical, and immunological knowledge on TB and DM and their clinical and public health implications. These include the underlying mechanisms for TB risk in DM patients and their clinical and sociodemographic characteristics that distinguish them from TB patients without DM. TB-DM comorbidity is posing a new challenge for integrating the short-term care for TB with the long-term care for DM, particularly in low- and middle-income countries.

Diabetes and Tuberculosis.

Type 2 diabetes mellitus(DM) is a major risk factor for the development of active pulmonary tuberculosis (TB), with development of DM pandemic in countries where TB is also endemic. Understanding the impact of DM on TB and the determinants of co-morbidity is essential in responding to this growing public health problem with improved therapeutic approaches. Despite the clinical and public health significance posed by the dual burden of TB and DM, little is known about the immunological and biochemical mechanisms of susceptibility. One possible mechanism is that an impaired immune response in patients with DM facilitates either primary infection with Mycobacterium tuberculosis or reactivation of latent TB. Diabetes is associated with immune dysfunction and alterations in the components of the immune system, including altered levels of specific cytokines and chemokines. Some effects of DM on adaptive immunity that are potentially relevant to TB defence have been identified in humans. In this review, we summarize current findings regarding the alterations in the innate and adaptive immune responses and immunological mechanisms of susceptibility of patients with DM to M. tuberculosis infection and disease.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/imm.12762

Influence of diabetes mellitus on immunity to human tuberculosis.

The interaction between diabetes and major world infections like TB is a major public health concern because of rapidly rising levels of diabetes. The dual burden of tuberculosis (TB) and diabetes mellitus (DM) has become a major global public health problem. Diabetes mellitus is a major risk factor for the development of active and latent tuberculosis. Immune mechanisms contributing to the increased susceptibility of diabetic patients to TB are due to the defects in bacterial recognition, phagocytic activity, and cellular activation which results in impaired production of chemokines and cytokines. The initiation of adaptive immunity is delayed by impaired antigen-presenting cell (APC) recruitment and function in hyperglycemic host, which results in reduced frequencies of Th1, Th2, and Th17 cells and its secretion of cytokines having a great role in activation of macrophage and inflammatory response of tuberculosis. In addition, impaired immune response and killing of intracellular bacteria potentially increase bacterial load, chronic inflammation, and central necrosis that facilitate bacterial dissemination and miliary tuberculosis. Understanding of the immunological and biochemical basis of TB susceptibility in diabetic patients will tell us the rational development of implementation and therapeutic strategies to alleviate the dual burden of the diseases. Therefore, the aim of this review was focused on the association between diabetes and tuberculosis, focusing on epidemiology, pathogenesis, and immune dysfunction in diabetes mellitus, and its association with susceptibility, severity, and treatment outcome failure to tuberculosis.

/pdf/immunological-impacts-of-diabetes-on-the-susceptibility-of-1bpxjyh331.pdf

Immunological Impacts of Diabetes on the Susceptibility of Mycobacterium tuberculosis.

Impaired glucose tolerance and type 2 diabetes were induced in guinea pigs to model the emerging comorbidity of Mycobacterium tuberculosis infection in diabetic patients. Type 2 diabetes mellitus was induced by low-dose streptozotocin in guinea pigs rendered glucose intolerant by first feeding a high-fat, high-carbohydrate diet before M. tuberculosis exposure. M. tuberculosis infection of diabetic guinea pigs resulted in severe and rapidly progressive tuberculosis (TB) with a shortened survival interval, more severe pulmonary and extrapulmonary pathology, and a higher bacterial burden compared with glucose-intolerant and nondiabetic controls. Compared with nondiabetics, diabetic guinea pigs with TB had an exacerbated proinflammatory response with more severe granulocytic inflammation and higher gene expression for the cytokines/chemokines interferon-γ, IL-17A, IL-8, and IL-10 in the lung and for interferon-γ, tumor necrosis factor-α, IL-8, and monocyte chemoattractant protein-1 in the spleen. TB disease progression in guinea pigs with impaired glucose tolerance was similar to that of nondiabetic controls in the early stages of infection but was more severe by day 90. The guinea pig model of type 2 diabetes–TB comorbidity mimics important features of the naturally occurring disease in humans. This model will be beneficial in understanding the complex pathogenesis of TB in diabetic patients and to test new strategies to improve TB and diabetes control when the two diseases occur together.

Increased severity of tuberculosis in Guinea pigs with type 2 diabetes: a model of diabetes-tuberculosis comorbidity.

Hyperglycemia, the diagnostic feature of diabetes also occurs in non-diabetics associated with chronic inflammation and systemic insulin resistance. Since the increased risk of active TB in diabetics has been linked to the severity and duration of hyperglycemia, we investigated what effect diet-induced hyperglycemia had on the severity of Mycobacterium tuberculosis (Mtb) infection in non-diabetic guinea pigs. Post-prandial hyperglycemia was induced in guinea pigs on normal chow by feeding a 40% sucrose solution daily or water as a carrier control. Sucrose feeding was initiated on the day of aerosol exposure to the H37Rv strain of Mtb and continued for 30 or 60 days of infection. Despite more severe hyperglycemia in sucrose-fed animals on day 30, there was no significant difference in lung bacterial or lesion burden until day 60. However the higher spleen and lymph node bacterial and lesion burden at day 30 indicated earlier and more severe extrapulmonary TB in sucrose-fed animals. In both sucrose- and water-fed animals, serum free fatty acids, important mediators of insulin resistance, were increased by day 30 and remained elevated until day 60 of infection. Hyperglycemia mediated by Mtb infection resulted in accumulation of advanced glycation end products (AGEs) in lung granulomas, which was exacerbated by sucrose feeding. However, tissue and serum AGEs were elevated in both sucrose and water-fed guinea pigs by day 60. These data indicate that Mtb infection alone induces insulin resistance and chronic hyperglycemia, which is exacerbated by sucrose feeding. Moreover, Mtb infection alone resulted in the accumulation tissue and serum AGEs, which are also central to the pathogenesis of diabetes and diabetic complications. The exacerbation of insulin resistance and hyperglycemia by Mtb infection alone may explain why TB is more severe in diabetics with poorly controlled hyperglycemia compared to non-diabetics and patients with properly controlled blood glucose levels.

Non-diabetic hyperglycemia exacerbates disease severity in Mycobacterium tuberculosis infected guinea pigs.

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Increased severity of tuberculosis in Guinea pigs with type 2 diabetes: a model of diabetes-tuberculosis comorbidity.

Non-diabetic hyperglycemia exacerbates disease severity in Mycobacterium tuberculosis infected guinea pigs.