Infections, antibiotics, tobacco, genetic factors and risk of lada : latent autoimmune diabetes in adults, and type 2 diabetes
Edstorp, Jessica
2024-05-17
09.00
Inghesalen, Widerströmska huset, floor 2, Karolinska Institutet, Solna
Institutet för miljömedicin / Institute of Environmental Medicine
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.