Olle Korsgren's projects – The etiology of type 1 diabetes

In collaboration with Gun Frisk, IGP

At present our understanding of the etiology of type 1 diabetes (TID) is limited and originates to a large extent from information gained in two animal models, i.e. the NOD mouse and the BB rat. In both models a progressive immune mediated destruction of the beta cells occurs. Unfortunately, these small animal models of TID show little similarity with the human disease. In human pancreatic specimens obtained at the onset of TID insulitis is discrete and heterogeneous in time and space. Immune therapy (CsA or anti-CD3 antibodies) causes only transient preservation of beta-cell function but cannot reverse the disease.

The mechanism(s) responsible for the selective destruction of the pancreatic beta cells in humans remains unknown. Genetic factors cannot explain the rapidly increase in incidence or the low concordance rate for development of TID in identical twins. Therefore, environmental factors are most likely implicated in the etiology of TID. The growing awareness of the disparities between the currently available animal models and human TID makes it imperative to access human tissues, i.e. pancreas, isolated islets, regional lymph nodes, intestine, spleen and peripheral blood, to unravel the mechanisms causing TID and to develop efficient approaches to halt or even reverse the disease.

The Nordic Network for Clinical Islet Transplantation (NNCIT) serves a population of about 20 million people. The core islet isolation laboratory at Uppsala University annually receives about 200 human pancreases for islet preparation. Islets not used for clinical transplantation is, if an informed consent is available, released for research. At present over 1 500 pancreases have been processed and tissues stored. Screening for islet autoantigens (IA2 and GAD) is performed in parallel with islet isolation to secure tissues from these donors for TID research. Retrospectively, about 5% of the donors are positive for at least one of the islet autoantigens. Over the years we have obtained pancreases from several patients with newly diagnosed or longstanding TID.

Rediscovery of Type I Diabetes in humans

The unique opportunity to study ongoing pathogenic processes in the pancreas of organ donors dying at onset of T1D have provided important mechanistic insights in the progression of the disease. A significant number of remaining β-cells in the islets were found. Ultrastructural analysis revealed very few apoptotic beta cells.

However, most beta cells show signs of extensive autophagy, i.e. decomposed and edematous endocrine cytoplasm, fused insulin granules, vacuolization. Isolated islets did not secrete insulin in response to glucose, suggesting a functional β-cell block, a condition known to increase autophagy. Bleedings and swollen endocrine cells were found in many islets, (see image on the right), which is in line with historical observations in T1D pancreases reported already in the early 20th century by A. Weichselbaum and in the classic work from 1965 by W. Gepts. Surprisingly, this phenomenon, termed hydropic degeneration, has attracted little attention during the last decades (Notably, it is absent in rodent TID!).

Slightly elevated numbers of infiltrating immune cells, dominated by cytotoxic T lymphocytes and macrophages were found. No evidence for proliferating endocrine cells was found. Staining with antibodies against enteroviruses (EV) revealed several distinctly positive islet cells in pancreas from newly diagnosed T1D donors, but not in matched non-TID controls. Up-regulation of Toll-like receptor 3, and several chemokines (e.g. IP-10, MCP-1, Rantes, IL-6 and IL-8) in isolated islets were detected, indicating a local activation of the innate immune response. Glucagon, somatostatin and PP cells, as well as exocrine cells, were morphologically unaffected.

The time-course for development of TID in humans and the superimposed adverse effects on remaining beta cells induced by the metabolic derangements (glucose- and lipotoxicity) will be defined in our effort to delineate the etiological factor(s) of TID. Moreover, we have access to EV strains isolated from T1D children at onset, isolated human pancreatic islets from T1D patients and from autoantibody positive and healthy organ donors. Collectively, this unique material enables us to study the innate and acquired immunity at a prediabetic state, at onset of TID and in islets infected in vitro with EV.