The ubiquitous parasitic protozoan, Toxoplasma gondii, is one of the most successful microorganism on the planet owing to quite a lot of compatibility to many host species, especially mammals, various transmission pathways (e.g. food, water, congenital, blood transfusion, organs transplant, etc.) and approximately involving one-third of the human population.1–4 Being the category B priority pathogen with zoonotic significance, Toxoplasma has frequently been associated with congenital complications (such as hydrocephalus, stillbirth and abortion) as well as neuropathic anomalies, predominantly in high risk populations, i.e. pregnant women and immunocompromised hosts.2,5–7 While unusual, there are some evidence that T. gondii parasites may possibly have an undiscovered role in the putative pathogenesis of autoimmune diseases.8

A group of chronic metabolic disorders, specified as “Diabetes”, are of medical importance with widespread distribution, especially in persons with high-calorie diets. They are distinguished by hyperglycemia elicited by the deficiencies in the insulin hormone release (type 1 diabetes) and/or failure to respond properly to insulin in target cells (type 2 diabetes), and this condition is probably overwhelmed by genetic elements, autoimmune processes, and environmental factors. According to scientific evaluations, it is anticipated that the number of diabetic patients will reach 522 million individuals by 2030.9 Recently, some reports have spotlighted the probable relevance of diabetes mellitus (DM) and infectious agents like Helicobacter pylori10 and Coxsakie B4 virus.11 In this case, the Apicomplexan parasite, T. gondii, has been proposed as a likely cause of diabetes, and existing information nearly predicate on this issue.12–16 Hence, this review was intended to shed light on the possible association between toxoplasmosis and diabetes.

Based on inclusion criteria, a total number of 7 out of 1377 studies were qualified to be ultimately included in this systematic review and meta-analysis,12,14,18–22 as demonstrated in Supplementary Fig. 1. The specifications of each study comprising the number of cases and controls as well as the number of IgG positive individuals, the utilized method and obtained p-value have been summarized in Table 1. Out of 2248 persons tested for toxoplasmosis infection, 717 were positive for T. gondii infection, 202 had type 1, and 1158 had type 2 DM; out of 888 healthy individuals 280 positive for T. gondii infection. The heterogeneity was statistically significant, for both type 1, I2=94.7% and Q=38.09 (p<0.001), and type 2 DM, I2=88.1% and Q=25.26 (p<0.001) (Table 2 and Supplementary Fig. 2). Accordingly, we calculated a common OR by random effects model at 1.10 (95% CI=0.13–9.57) with p=0.929 and 2.39 (95% CI=1.20–4.75) with p=0.013 for type 1 and type 2 DM, respectively (Table 2 and Supplementary Fig. 2). Also the calculated common OR (random effects model) for both type 1 and 2 diabetes was 1.86 (95% CI=0.93–3.74) with p=0.0796. The test of publication bias was clearly not significant in this case, p=0.335 (Supplementary Fig. 3). Also, the chart of forest plot has been illustrated in supplementary Fig. 2. The status of toxoplasmosis infection was based on ELISA IgG, except for one paper in which the Bio-Plex 2200 kits were employed.

A possible association between toxoplasmosis and DM would entail significant clinical consequences, shedding light on the complicated pathogenesis of DM. Overall, the current hypothesis suggests that toxoplasmosis increases susceptibility to acquiring diabetes and, on the other hand, diabetic patients are more vulnerable to opportunistic infections such as toxoplasmosis.12–14,22–24 Subsequently, to elucidate this association, various empirical evidence have been appraised and proposed as plausible pathophysiological mechanisms, including: (1) infected white blood cells represent enhanced migratory feature, leading to the easier spread of Toxoplasma in body organs, e.g. pancreas13; (2) a clinically conspicuous autoimmune process could be ignited by T. gondii infection, trending immune machinery toward autoantibody production, for instance against β-cells of Langerhans islets13; (3) in light of ex vivod-glucose and insulin dose-responsive experiment in 3T3-L1 cells, better replication of Toxoplasma occurs in insulin-producing β-cells, leading to activation of autoimmunity pathways as well as provoking the inflammation of Langerhans islets (insulitis) and ultimately developing diabetes23; (4) a possibility, is that T. gondii itself may invade and destroy pancreatic β-cells directly, instigating pancreatitis and more importantly, diabetes25; (5) production of reactive oxygen species (ROS) and nitric oxide (NO) is induced by diabetes, and these agents, as stimulant for intra-cellular pathogens, can re-activate latent, cysts of parasites, again initiating acute infection26; (6) given the inability of neutrophils to correctly perform phagocytosis and intra-cellular killing in progressive phase of diabetes, there may be increased responsiveness to intra-cellular pathogens such as Candida and Toxoplasma,27 and (7) the opsonization activity and leukocyte cytotoxicity of diabetic patients required for elimination of pathogens are considerably subsided, hence they would be more prone to opportunistic infections.12,27,28

In the included studies (Tables 1 and 2), the OR in type 1 DM individuals was 1.10 (95% CI=0.13–9.57) with p=0.929, while this ratio in type 2 DM patients was 2.39 (95% CI=1.20–4.75) with p=0.013. Thus, the risk of type 1 and 2 diabetes with previous Toxoplasma exposure would be 1.10 and 2.39 fold higher, respectively, than for unexposed persons. However, no statistically significant association between chronic toxoplasmosis and type 1 DM was held on random effects model. In this case, the highest OR (5.066) was reported in the study by Gokce et al.14 (p<0.001) and the lowest OR (0.083) in the study by Krause et al.21 (p<0.001). According to the estimated OR by Krause et al.21 there is no association between toxoplasmosis and diabetes and it is hypothesized that the patients’ younger ages as well as uncommon route of infection may have remarkably biased their results. Recently, some researchers have demonstrated the influence of parasite genotypes on behavior, psychomotor performance, physiology, and overall health of their host. Hence, the strain of Toxoplasma should be considered as an influential parameter in relation to diabetes.15,16,29–32

Despite of the lack of remarkable correlation between chronic toxoplasmosis and type 1 diabetes in the current meta-analysis, ex vivo studies strongly demonstrate the presence of this relationship.13,24 Therefore, further studies are needed in the future. There were several limitations in our study, including (1) small sample sizes in included studies and no further details about disease condition and duration in cases; (2) the variable quality of reporting of studies; (3) variable methodology to define Toxoplasma infection; and (4) lack of representativeness of cases and controls as they were selected from restricted communities, thus limiting external validity of the results.

Based on currently available results, no statistically significant association was observed between chronic toxoplasmosis and type 1 DM; of course there remain many questions to be answered in future investigations.

The authors declare no conflicts of interest.