Type 1 diabetes (T1D) is a major autoimmune disease that poses significant challenges to afflicted individuals, to the development of effective therapeutic interventions, and to public health initiatives at large. Initiated and perpetuated by a complex interplay of genetic and environmental risk factors, insulin-secreting pancreatic beta-cells are progressively destroyed by aberrant immune responses leading to elevated blood glucose levels as well as serious disturbances of protein, fat and carbohydrate metabolism. At present, no cure or effective prevention is available and despite insulin treatment, serious long-term complications are frequent. Adding further urgency is an annual 2-5% worldwide increase of T1D incidence over the past few decades, a phenomenon that can only be explained by altered environmental exposures and resultant interactions with genetic variants that predispose to T1D development. However, in contrast to genetic risk factors and autoimmune responses, the identities and pathogenic contributions of specific risk factors remain poorly defined. To address this shortcoming, we have developed a research plan that will provide the foundation for arguably the first ?exposure map? of the human pancreas in health and disease. In specific, we will use a combination of advanced immunohistochemistry (IHC) and laser-ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to conduct an elemental biomaging analysis of healthy as well as pre-diabetic and recent onset type 1 diabetic pancreata.
In Specific Aim 1, we will interrogate pancreatic tissue slides from healthy (non-diabetic) donors by IHC to identify microanatomical landmarks and tissue properties that will serve as geospatial referents for complementary LA-ICP-MS analyses that will reveal the identity, abundance and distribution of >20 essential elements and metal toxicants.
In Specific Aim 2, we will conduct similar experiments with pancreatic tissues from pre-diabetic and T1D donors. Altogether, and as supported by our preliminary data, these analyses are expected to reveal definable patterns of essential element/metal toxicant distribution that co-localize with microanatomical structures and particular histological tissue properties, and therefore may provide initial evidence for the potential pathogenic involvement of selected metal toxicants or a combination thereof. For the efficient and cost-effective pursuit of these aims, we have established access to rare pre/diabetic and corresponding pancreatic control tissues through the Network of Pancreatic Organ Donors with Diabetes (nPOD), and we have developed a validated workflow for integrated IHC, LA-ICP-MS and advanced image analyses. Thus, we have created what we believe to be a promising conceptual and practical framework that may serve as an important foundation for future exposure analyses that seek to clarify aspects of T1D pathogenesis and to develop effective preventive treatment modalities.
The natural history of type 1 diabetes (T1D) is shaped by complex interactions between environmental risk factors and predisposing genetic variants. Although the precise contribution of specific environmental risk factors remains poorly understood, they constitute the apparent agents for the rising T1D incidence observed over the past few decades. Here, we propose to conduct the first ?exposure analysis? of the healthy and pre/diabetic human pancreas. By correlating in situ pathology with the microanatomical distribution of essential elements and metal toxicants, our work will create a foundation for future investigations that will address the specific pathogenetic role of defined toxicants and that therefore may precipitate the development of targeted prevention strategies for individuals at risk for T1D.
