Fibrosis is the most frequent lesion in the islets of type 2 diabetics (T2D) and contributes to the age-dependent impairment of islet function. Defects in islet vasculature compromise exchanges between the endocrine cells and the blood, disrupt islet architecture and ultimately lead to endocrine cell death. An important component of the vasculature is the pericyte, a contractile smooth muscle-like cell that wraps small blood vessels. In different organs, pericytes have been shown to differentiate into myofibroblasts, leading to fibrosis and organ dysfunction. Whether islet pericytes also contribute to the profibrotic myofibroblast pool that causes islet fibrosis observed during aging and T2D has not been determined. The long-term goal of this proposal is to understand the role of vascular dysfunction in aging and diabetes. The objectives of this project are to determine how the islet pericyte phenotype changes during insulin resistant states (such as aging and T2D) and what causes the changes, using a combination of in vitro and in vivo approaches. The central hypothesis is that, during aging or T2D, the excessive exposure to insulin exacerbates signaling through the mammalian target of rapamycin (mTOR) in pericytes, which makes them differentiate into myofibroblasts. In our model, as hyperinsulinemia develops to compensate for insulin resistance, islet pericytes are exposed to higher levels of insulin. Insulin overactivates mTOR signaling in pericytes, which favors their differentiation into myofibroblasts and proliferation of these profibrotic cells. The rationale for the proposed research is that the results will make a lasting impact on our understanding of the role of the pericyte in islet biology. If the hypothesis is correct, it would demonstrate the fundamental contribution of pericytes to islet fibrosis and diabetes pathogenesis. The proposed research is therefore relevant to the mission of the NIH that pertains to the pursuit of fundamental knowledge about the nature and behavior of living systems. Guided by strong preliminary data, our central hypothesis will be tested by pursuing two specific aims: 1) Identify age- and diabetes-induced changes in the phenotype of the islet pericyte; 2) Determine the role of mTOR-dependent insulin signaling in pericyte transdifferentiation. Under the first aim, we will examine changes in the pericyte phenotype in aged and T2D mouse and human islets, and directly visualize the phenotypic transition from pericytes to myofibroblasts in vivo. Under the second aim, we will determine if direct in vitro and in vivo stimulation of islet pericytes with insulin triggers a pro-fibrotic myofibroblast-like phenotype. We will further manipulate mTOR signaling in pericytes in vivo and measure the effects on vascular function and glucose homeostasis. The proposed research is significant because pericytes can be targeted to limit the generation of myofibroblasts and interstitial collagen accumulation during islet fibrosis that accompanies aging and T2D. Importantly, these studies have the potential to impact the way diabetes is treated.
The proposed work will elucidate the role of the islet pericyte in health, aging and disease. The proposed studies will determine the mechanisms that trigger pericyte differentiation into profibrotic myofibroblasts. This research proposal has the potential to change our understanding of the importance of the islet vasculature in the pathogenesis of type 2 diabetes. As a major expected outcome, as pericytes can be targeted to limit fibrosis, these studies will likely impact the way diabetes is treated.
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| Weitz, Jonathan R; Makhmutova, Madina; Almaça, Joana et al. (2018) Mouse pancreatic islet macrophages use locally released ATP to monitor beta cell activity. Diabetologia 61:182-192 |
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