Objective
The objective of this proposal is to understand what goes wrong with blood vessels in pancreatic islets during type 1 diabetes. Determining what drives vascular changes in the islet and whether these changes impact the vascular permeability and facilitate immune cell infiltration are the main objectives of the application. This knowledge may be used in the future to develop new strategies to prevent or delay the onset of type 1 diabetes.
Background Rationale
Pancreatic islets are clusters of cells that secrete hormones that help regulating glucose homeostasis. Islets need their blood vessels to function. Not only are islet blood important to sense nutrients but also to deliver secreted hormones (insulin, glucagon) into the bloodstream. Many studies have shown that islet blood vessels are dysfunctional early in diabetes, but we do not know if these alterations contribute to the development type 1 diabetes. Preliminary data from our lab indicate that the islet pericyte, a major regulator of microvascular homeostasis, undergoes functional changes in the pre-diabetic state in humans. Moreover, changes in pericyte function impact islet blood flow, plasma hormone levels, and glucose tolerance in mice. For these reasons, the goal of this proposal is to explore the potential pathogenic role of a defective vasculature due to pericyte dysfunction on the pancreatic islet. Without knowing how a pathological vasculature affects the secretory activity and survival of islet endocrine cells, the model of diabetes pathogenesis is incomplete.
Description of Project
Pancreatic islets are clusters of endocrine cells that produce the hormones insulin and glucagon in response to changes in blood glucose levels. In type 1 diabetes, an autoimmune disease, the cells that produce insulin are attacked by immune cells, leading to a chronic increase in blood glucose concentration. Blood vessels in islets are very important for them to function properly. Poor blood vessel function is characteristic of type 1 diabetic donors and these alterations are usually seen as complications of this disease. However, in a recent study that used human pancreas samples from organ donors, we found that alterations in blood vessel composition and function are already present in islets in individuals with signs of autoimmunity but before the development of symptoms. The mechanisms leading to vascular problems have not been identified yet and this will be the focus of this proposal. Elucidating them will shed new light into our understanding of type 1 diabetes pathogenesis. The hypothesis of this proposal is that, during the development of type 1 diabetes, a molecule called endothelin-1 that closes blood vessels, named endothelin-1, is elevated in the pancreas, abolishing dynamic changes of islet blood vessels and contributing to blood vessel instability and facilitating immune cell infiltration. This hypothesis will be tested in two specific aims where we will examine changes in blood vessel function in the living mouse and ex vivo using pancreas slices. These studies may reveal a pathogenic role for defects associated with blood vessels, which could constitute potential therapeutic targets to prevent or delay T1D onset.
Anticipated Outcome
We expect our studies to establish that vascular insults are not only a consequence but also a cause of diabetes. These would suggest that strategies that preserve the stability and function of the islet vasculature could have therapeutic or preventive potentials.
Relevance to T1D
It has been 100 years that insulin was discovered but we still do not fully understand how type 1 diabetes develops. Most of the studies in the field focus on understanding what happens to beta cells, the cells that produce insulin, and on why they are attacked by the immune system. We think that blood vessels may play a role in this process. Their dysfunction may contribute to beta cell stress and lead to exhaustion or facilitate immune cell entry into the islet tissue and auto-immune attack. We therefore believe that exploring how blood vessel function changes during type 1 diabetes and potential causes for vascular dysfunction are crucial for our understanding of this disease which still has no cure.