Infections, antibiotics, tobacco, genetic factors and risk of lada : latent autoimmune diabetes in adults, and type 2 diabetes

Diabetes is a spectrum of chronic diseases characterized by hyperglycaemia. The aetiology and pathogenesis differ between types of diabetes, but all can lead to severe complications. Latent autoimmune diabetes in adults (LADA) is the most prevalent type of autoimmune diabetes with onset in adulthood, yet risk factors are largely unknown. Therefore, this thesis was devoted to the study of potential risk factors for LADA compared to type 2 diabetes.

The Swedish Epidemiological Study of Risk Factors for LADA and type 2 diabetes (ESTRID) constituted the foundation of the four studies in this thesis. ESTRID is a case-control study with incident cases of LADA and type 2 diabetes along with control participants from the general population. Study I, II, and IV were complemented with incident cases of LADA and type 2 diabetes as well as diabetes-free individuals from the Norwegian cohort study HUNT. Study I and II investigated the role of tobacco use and genetic susceptibility for the risk of LADA, using data from ESTRID and HUNT. These analyses were supported by Mendelian randomization studies based on data from genome-wide association studies. In Study III and IV, data from national and regional health registers were linked to ESTRID and HUNT to investigate the association between LADA and prior infections and antibiotic exposure. Results for LADA were compared to those for type 2 diabetes in all four studies.

We found that smoking increases the risk of LADA, particularly in those with genetic susceptibility conferred by risk genes associated with autoimmunity, type 2 diabetes, or insulin resistance. The increased risk of LADA and type 2 diabetes in smokers seen in the observational data was confirmed in the Mendelian randomization studies. In contrast, no increased risk of LADA was observed with infections or antibiotic exposure up to 10 years prior to diagnosis, neither in those with high genetic risk nor in those with low-moderate risk. Instead, a reduced risk associated with antibiotic exposure 6-10 years prior to diagnosis was observed.

In conclusion, tobacco use, which is associated with type 2 diabetes and insulin resistance, seems to increase the risk of LADA. Genetic susceptibility plays a role by aggravating these associations. However, infections and antibiotic exposure, previously linked to type 1 diabetes, were not associated with LADA. Further studies are needed to confirm these results, particularly the finding of a reduced risk of LADA with prior exposure to antibiotics.

List of scientific papers

I. Edstorp, J., Wei, Y., Ahlqvist, E., Alfredsson, L., Grill, V., Groop, L., Carlsson, S. (2023). Smoking, use of smokeless tobacco, HLA genotypes and incidence of latent autoimmune diabetes in adults. Diabetologia. 66(1), 70-81. doi:10.1007/s00125-022-05763-w.
https://doi.org/10.1007/s00125-022-05763-w

II. Edstorp, J., Ahlqvist, E., Alfredsson, L., Mansour Aly, D., Grill, V., Rasouli, B., Carlsson, S. (2023). Incidence of LADA and Type 2 Diabetes in Relation to Tobacco Use and Genetic Susceptibility to Type 2 Diabetes and Related Traits: Findings From a Swedish Case-Control Study and the Norwegian HUNT Study. Diabetes Care. 46(5), 1028-1036. doi:10.2337/dc22-2284.
https://doi.org/10.2337/dc22-2284

III. Edstorp, J., Rossides, M., Ahlqvist, E., Rasouli, B., Tuomi, T., & Carlsson, S. (2024). Does a prior diagnosis of infectious disease confer an increased risk of latent autoimmune diabetes in adults? Diabetes Metab Res Rev. 40(3), e3758. doi:10.1002/dmrr.3758.
https://doi.org/10.1002/dmrr.3758

IV. Edstorp, J., Rossides, M., Ahlqvist, E., Alfredsson, L., Askling, J., Di Giuseppe, D., Carlsson, S. Exposure to antibiotics and the risk of latent autoimmune diabetes in adults and type 2 diabetes - results from a Swedish case-control study and the Norwegian HUNT study. [Manuscript]