Bacterial endotoxins in type 1 diabetes

Around one-third of patients with type 1 diabetes develop diabetic nephropathy. Even though the pathogenesis of diabetic nephropathy is not fully understood, the process involves several environmental factors. Low grade inflammation has been linked to many metabolic diseases and is also evident in patients with type 1 diabetes, especially in the presence of nephropathy. Bacterial lipopolysaccharides (LPS) are powerful triggers of inflammation, but whether low grade inflammation is caused by these components is an open question. The aim of this thesis was to examine the relationship between LPS and the development of diabetic nephropathy, inflammation, vascular function, lipid metabolism, and intestinal homeostasis in patients with type 1 diabetes. The studies are part of the ongoing Finnish Diabetic Nephropathy Study (FinnDiane), a nationwide, multicenter study that aims to identify genetic and environmental risk factors for the development of diabetic complications in patients with type 1 diabetes. Study I was a follow-up study, and Studies II IV were cross-sectional in their design. Renal status was verified at follow-up by laboratory data and a review of all available medical files (Study I). Study II included, in addition to patients with type 1 diabetes, patients with IgA glomerulonephritis and non-diabetic control subjects. The participants in Studies III and IV had three consecutive high-fat meals and were followed for 10 hours postprandially. Factors associated with endotoxemia, vascular function, inflammation, and lipid metabolism were investigated. For all studies, LPS was measured by the limulus amebocyte lysate (LAL) assay from serum samples. In the patients with type 1 diabetes, high serum LPS activity at baseline was associated with the development of microalbuminuria during the follow-up. High serum LPS was also associated with features of the metabolic syndrome in both the patients with type 1 diabetes and the overweight non-diabetic controls. Of note, no accumulation of LPS in the circulation was evident in response to three high-fat meals. However, the patients with type 1 diabetes showed altered postprandial lipid metabolism and vascular response. Moreover, factors associated with gut homeostasis were altered in the patients with type 1 diabetes compared to the non-diabetic controls. We show that high serum LPS is associated with the development of diabetic nephropathy and features of the metabolic syndrome. The metabolic syndrome is associated with insulin resistance, and it is a risk factor for both diabetic nephropathy and cardiovascular disease. Endotoxins may affect the development of diabetic nephropathy through the direct disruption of the filtration barrier, but also through insulin resistance at both the tissue and systemic levels. In response to acute high-fat feeding, no evidence for LPS accumulation was seen. However, unfavorable changes in lipid metabolism and vascular response in patients with type 1 diabetes may render them at higher cardio-metabolic risk. This risk may be further enhanced by adverse changes in both inflammatory and protective factors in the gut, leading to a possibly higher gut permeability and an increase in circulating endotoxins.