The Role of the Pancreas Microenvironment in Regulating Islet Function and Survival in Type 1 Diabetes - Project Summary: Type 1 diabetes (T1D) is characterized by the immune-mediated loss of insulin-producing
β-cells in the islet. Loss of the peri-islet ECM has been well documented in recently diagnosed patients with T1D
and is associated with increased insulitis and β-cell death. In pre-symptomatic T1D, β-cell dysfunction and ER
stress occur prior to significant immune cell infiltration. Our preliminary results indicate that cytokine-stressed β-
cells express ECM degrading enzymes (including MMPs) that may contribute to loss of the peri-islet ECM prior
to the onset of insulitis and may facilitate infiltration of autoreactive immune cells and β-cell death. In the early
stages of T1D, islet infiltration correlates with loss of peri-islet laminin-10. Our preliminary data suggests that
loss of islet interactions with laminin-10 increases cytokine-induced death and increases the activity of protein
kinase C δ (PKCδ), where we have recently identified increases in PKCδ activity as a critical mediator of β-cell
death. Additionally, previous studies have shown that islet interactions with laminin increase glucose stimulated
insulin secretion (GSIS) via increased expression of glycolytic enzymes and mediate mitochondrial morphology
and function. Taken all together, this supports a role for loss of peri-islet laminin-10 in contributing to T1D
pathogenesis. We hypothesize that cytokine-stressed β-cells contribute to loss of the peri-islet ECM in
early T1D leading to decreases in β-cell function and survival. We propose the following 2 aims: 1)
Determine if cytokine-stressed β-cells degrade the peri-islet ECM in early T1D, and 2) Determine if loss of
laminin-10 interactions regulates islet survival and function in early T1D. Experiments for both aims will utilize
mouse and human islets encapsulated in a novel 3D biomimetic scaffold with laminin-10, as well as human
pancreas sections from the nPOD program. Aim 1 will determine if β-cell mediated degradation of the peri-islet
ECM precedes the onset of T1D. Aim 2 will determine the molecular mechanisms underlying islet dysfunction
and death with loss of peri-islet laminin-10 in T1D. The successful completion of this project will define a new
role for the β-cell in degrading the peri-islet ECM in early T1D that contributes to altered islet function and
survival. Our results will challenge the current paradigm that β-cells are innocent bystanders in T1D onset and
will provide novel therapeutic targets to halt immune infiltration of the islet and improve islet function and survival.
