Bacterial infections in type 1 diabetes and their association with micro- and macrovascular complications

Background. Individuals with diabetes are more susceptible to bacterial infections compared with the general population. In individuals without diabetes, these infections have been associated with micro- and macrovascular diseases, such as chronic kidney disease and cardiovascular disease. However, the role of bacterial infections in the aetiology of these diseases is unclear, and may be profound in individuals with diabetes, who suffer from both bacterial infections as well as micro- and macrovascular disease more frequently compared to the general population. Furthermore, the prevalence of bacterial infections in individuals with specifically type 1 diabetes and the impact of hyperglycaemia on infection frequency is also far from established. Finally, the potential genetic factors affecting infection susceptibility in diabetes are yet to be discovered. Aim. The aim of this thesis was to investigate the frequency of bacterial infections in individuals with type 1 diabetes and how the infections associate with and potentially affect the risk of developing diabetic kidney disease, coronary heart disease, and diabetic retinopathy. Moreover, we investigated whether common variations in the genome were associated with the susceptibility to bacterial infections observed in diabetes. Methods. The studies presented in this thesis were conducted within the national multicentre study FinnDiane (Finnish Diabetic Nephropathy Study Group). The FinnDiane cohort consists of individuals with type 1 diabetes, recruited from all over Finland as well as non-diabetic control subjects from the general population. For all individuals included in the studies, data on bacterial infections treated both outside and within hospitals were collected from two nationwide registries: The national Finnish Hospital Discharge Register (Finnish Care Register for Health Care, HILMO) and the Finnish National Drug Prescription Register (KELA). Data on the emergence or progression of chronic diabetic complications as well as relevant clinical risk factors were collected during baseline and prospective clinical study visits, as well as from medical files collected from primary health care centres and hospitals across the country. Genomic DNA was extracted from blood leukocytes and bacterial lipopolysaccharide (LPS) activity was determined from serum samples during the baseline visit. Results. Bacterial infections were found to be roughly two times more common in individuals with type 1 diabetes, compared to non-diabetic control subjects. Infections were more frequent in individuals with diabetic kidney disease and/or poor glucose control. Frequent antibiotic purchases and high LPS-activity were found to be independent risk factors for incident coronary heart disease as well as severe diabetic retinopathy in type 1 diabetes. Genome-wide association studies (GWAS) on individuals with diabetes revealed a potential association between variants on chromosome 2 and a reduced infection susceptibility. This association between the genetic loci and infection frequency was possibly mediated through the regulation of the IRAK1-pathway. Conclusion. Bacterial infections are more frequent in individuals with type 1 diabetes than in the general population. Frequent antibiotic purchases and high levels of LPS-activity associate with the development of both micro- and macrovascular complications. Genetic factors on chromosome 2 may further influence the susceptibility to bacterial infections present in diabetes.