Logo: to the web site of Uppsala University

Type 1 diabetes is characterized by impaired glycemic control due to an absence of insulin production. It is traditionally attributed to an autoimmune-mediated destruction of pancreatic β-cells. Research has shifted focus towards elucidating the role of genetic predispositions, viral exposures, and other possible triggers in type 1 diabetes pathogenesis.

This doctoral thesis aimed to investigate the influence of innate immune responses on the development of type 1 diabetes. The study utilized a novel animal model for type 1 diabetes and human pancreatic tissue obtained from the Nordic network for islet transplantation and the DiViD study.

Paper I sought to investigate a potential link between insulitis and the innate immune system using a novel animal model and compare the outcome with type 1 diabetes in humans. Macrophages and neutrophils were seen in the acute phase. A few islets were observed with peri insulitis three weeks later. Similar inflammation patterns in both human and rat subjects were observed. Upregulation of genes associated with bacterial response in both human and rat tissues was observed. Observed findings indicate a bridge between innate immunity and adaptive immunity in the development upon onset of type 1 diabetes.

Paper II aimed to characterize the differential expression profiles of the defensin system within human pancreas from individuals diagnosed with type 1 diabetes of different ages compared to normoglycemic-matched controls. Individuals with type 1 diabetes have reduced expression of several defensins in both the pancreatic islets and the exocrine parenchyma. This suggests a compromised innate immune system, tentatively predisposing them to heightened susceptibility to microbial threats and increased pro-inflammatory stress on the pancreas.

Paper III focused on quantifying the prevalence and spatial distribution of δ-cells in human pancreas from individuals diagnosed with type 1 diabetes compared to normoglycemic controls. The δ-to-α-cell connections and single δ-cell density in the exocrine area of the pancreas were increased. Additionally, isolated islets from an individual with type 1 diabetes showed impaired glucagon secretion at low glucose levels, but elevated secretion with a somatostatin receptor inhibitor. These findings suggest a disruption in paracrine control which affects glucagon secretion in individuals with type 1 diabetes.

In conclusion, several aspects of innate immunity and islet architecture were studied regarding human type 1 diabetes. Obtained findings suggest a dysregulation of innate immunity, however, further research is warranted to fully clarify the bridge between innate and adaptive immunity in the etiology of type 1 diabetes.