This is the first study to evaluate the association between serum IgE levels and DM in a general population. We found strong positive associations between total IgE, house dust mite and cockroach-specific IgE levels and DM, and these persisted after adjustment for many potential confounders, including lifestyle factors (alcohol consumption, smoking status, and regular exercise); socioeconomic status (income, educational level, and region of residence); and previous allergic disease. Moreover, cockroach-specific IgE was an independent risk factor for poor glycemic control in subjects with DM. We also found significant associations between metabolic syndrome and IgE sensitization. Our data suggest that IgE level may be an important independent risk factor for metabolic disease, especially DM, in Koreans.
Total IgE level is a biomarker closely associated with the inflammatory response to non-specific environmental factors as well as to reactions to specific allergens2. The serum IgE levels significantly increase in patients with coronary artery disease when compared to unaffected subjects19. IgE activates mast cells, which, experimentally, play a critical role in type 2 DM1. Genetic deficiency and pharmacological inactivation of mast cells prevented diet-induced type 2 DM in mice. A human epidemiological study has shown that patients with type 2 DM had increased levels of IgE and mast cell chymase2. The role of mast cells in diabetic nephropathy has been extensively reported3. Mast cells are uncommon in normal kidney tissue, but mast cell infiltration is a prominent and early response to renal injury. Mast cells trigger fibrosis and extracellular matrix accumulation in patients with diabetic nephropathy20. Therefore, it is possible that IgE participates directly in DM pathogenesis and in complications thereof.
However, it is equally possible that DM or high FBG levels trigger IgE sensitization. In mice with DM, high FBG levels impaired B-1 cell function; the immunoglobulin profile changed21,22. The numbers of B-1 cells decreased in patients with type 2 DM21,22. Gestational DM increased the risk of AD and allergen sensitization in early childhood23. Term infants of women with gestational DM were at a 7.6-fold increased risk of AD and a 5.9-fold increased risk of allergen sensitization. Prenatal exposure to high levels of glucose increased the risks of AD and sensitization in early life23. Mothers with gestational DM had higher levels of TNF-α, leptin, and visfatin and lower levels of adiponectin. Adiponectin attenuates allergic inflammation in murine models. Thus, it is possible that the changes in adipokine levels associated with gestational DM may affect immunological development in infancy23.
DM, obesity, and allergen sensitization share inflammatory pathways and mediators of immune responses. Increasing epidemiological evidence suggests that obesity increases the risks of asthma, atopic eczema, and allergic rhinitis. Obesity may trigger immunological changes, reducing antigen tolerance and skewing the immune system toward a T helper 2 (Th2) profile, which is associated with a cytokine release pattern increasing the risks of allergy and other immune-mediated diseases24. Previous studies have explored relationships between obesity and IgE sensitization3, but the data have been inconsistent. Vieira et al.25 found that the frequency of IgE-positivity in response to a balanced mixture of common aeroallergens was three-fold greater in obese than non-obese females. However, the total IgE concentration did not differ significantly between the groups. In the present study, central obesity, measured using waist circumference as a surrogate, was significantly (positively) correlated with total and all three allergen-specific IgE levels. We also found significant associations between metabolic syndrome and increased IgE.
Higher levels of allergic cockroach sensitization increased the risk of DM in the general population, and this association was stronger than that involving house dust mite sensitization. Cockroach extracts contain pepstatins, which are A-sensitive proteases activating the PAR-2 receptors; these, in turn, induce human eosinophil activation and degranulation. PAR-2 activation has been implicated in the potent allergenicity elicited by cockroaches26. PAR-2 contributes substantially to inflammatory and metabolic dysfunction, and PAR-2 antagonists inhibit diet-induced obesity, reverse IR, and glucose intolerance, and they beneficially modulate liver and pancreatic metabolic parameters27. Cockroach allergies are more common in infested areas. Low socioeconomic status has been independently associated with sensitization to cockroach allergens. We examined the effects of socioeconomic status on the association between IgE level and DM and found that neither household income nor educational level nor region of residence affected the observed associations. Sensitization of cockroach is an independent predictor of risk of DM regardless of total IgE. However, the question remains whether glucose intolerance can be improved by avoiding the sensitization of cockroaches.
A recent US population-based study7 showed that AD was associated with adult-onset diabetes (adjusted OR, 1.35; 95% CI, 1.13–1.62), reflecting higher levels of smoking and alcohol intake and a sedentary lifestyle7. In contrast, adult inpatients or outpatients with AD treated in a Danish national hospital were not at an increased risk of new-onset DM10. After adjustment for co-morbidities and medication use, the independent OR for DM decreased significantly (adjusted HR, 0.76; 95% CI, 0.68–0.83). However, in the present study, we found that increased IgE levels were associated with a rise in the prevalence of both DM (adjusted OR, 1.76; 95% CI, 1.18–2.61) and IR in a general population. IgE sensitization may explain the observed association between AD and the increased risk of DM.
B cells are emerging players in innate and adaptive immune responses associated with metabolic diseases, including obesity, type 2 DM and cardiovascular disease21. Immunoglobulin production is a prototypical function of B cells, and immunoglobulins also play an important role in inflammatory diseases including lupus, rheumatoid arthritis and atherosclerosis22. It was reported that decreased IgG and IgM, and increased IgA levels were independently related to the prevalence of type 2 DM22. But, no significant elevated IgE in patients with diabetes was observed in that study22. Although the reasons for this discrepancy with our results remain unclear, it may be due to the difference in the study population and the use of allergen-specific IgE. We have measured allergen-specific IgE as well as total IgE, and we found that cockroach specific IgE sensitization was significantly associated with DM. Mouse studies suggest that immature B cells in adults and neonatal B cells are more prone to IgE switching than mature B2 cells28. Immunoglobulin dysregulation might contribute to the development of DM. Further studies are needed to explore the causality and exact mechanisms of immunoglobulins in subjects with DM.
There are limitations to our study. First, this was a cross-sectional study, and, therefore, the association found between IgE sensitization and DM may not be causal. Second, we had no data on immune elements other than IgE. A previous study indicated that markers of inflammation (such as WBC counts) were associated with the development of DM in middle-aged adults29. WBC as a significant inflammatory factor is both accessible and affordable. Indeed, there was a significant difference of WBC counts between DM and non-DM subjects. So, we added WBC counts into model 4 of multivariate analysis. We found that increased total IgE and sensitization to cockroach remained significantly associated with DM after adjustment for WBC counts. Third, the history of steroid use was not available in this study. Fourth, the seasons of sample collection could not be discerned. According to previous studies conducted in Korea, not only pollens but also house dust mites demonstrate seasonal variation at indoor concentrations30. However, the rate of sensitization to cockroaches was similar for all seasons, except in summer30. Seasonal changes in sensitization to house dust mites have occurred in populations with allergies. We performed additional analysis after excluding the subjects with previous allergic diseases. The results were similar compared to the total population. Lastly, we could not differentiate type 1 or gestational from type 2 diabetes from the KNHANES data set. This study was conducted for adults over 30 years of age and prevalence of type 1 or gestational diabetes is relatively low. The prevalence of type 1 diabetes during 2011–2013 was about 0.02% of the total population in Korea31,32. However, we could not exclude the possibility that participants with type 1 or gestational diabetes were included in this study and the association of IgE with prevalence of diabetes differed according to diabetes type33.
In conclusion, we found that, independent of any previous allergic disease, an increased IgE level and sensitization to the cockroach were risk factors for DM. Sensitization to the cockroach was significantly associated with uncontrolled DM either before or after adjustment. As we used data from a nationally representative sample of the population and adjusted for multiple confounders, our results support the hypothesis that increased serum IgE levels are associated with DM in the general population.