The prevalence of type 2 diabetes is increasing rapidly in the United States, affecting at least 8% of the population. The pathogenesis of the disease includes obesity and insulin resistance, but impairments in ?-cell secretory function and survival are critical for the development of hyperglycemia. The mechanisms underlying ?-cell dysfunction and death remain incompletely understood, and improving our knowledge of these is fundamental for the development of better therapies for this potentially debilitating disease. The islet extracellular matrix (ECM), synthesized almost exclusively by the islet endothelial cell, is an important source of signals for the ? cell. The islet ECM component laminin normally enhances insulin release and ?-cell survival. My preliminary data in islet endothelial cells from animal models of type 2 diabetes show for the first time that laminin ?4 production is decreased. Additionally, culturing primary islet endothelial cells in high glucose also results in decreased laminin ?4 production. Knockdown of laminin ?4 in immortalized islet endothelial cells results in impaired insulin release, and insulin release is impaired in laminin ?4-knockout mice. Thus, I hypothesize that increasing laminin ?4 production in islet endothelial-derived ECM will improve ?-cell function under hyperglycemic conditions. I will address this hypothesis by undertaking studies to determine if overexpression of laminin ?4 in primary islet endothelial cells cultured in high glucose is sufficient to improve ?-cell function in vitro. Critically, I will also determine if infection of islet endothelial cells with a long-term cell-specific AAV expression of laminin ?4 improves insulin release in vivo. I anticipate that these studies will demonstrate for the first time that increasing expression of laminin ?4 is sufficient to improve ?-cell function and survival under diabetic conditions. This proposal outlines a comprehensive thirteen month plan focused on scientific and professional development. The proposed studies will expand our understanding of the islet endothelial cell's contribution to ?-cell function and survival, while facilitating my acquisition of scientific skills in islet biology, a new field for me. Dr. Hull's expertise in islet biology together with the exceptional mentoring environment provided by her and my co-sponsor Dr. Kahn, will contribute to the completion of this project, and to my career development. Participation in seminars, lab meetings, regional and national meetings, and events sponsored by the NIDDK- funded Diabetes Research Center (DRC) and Nutrition Obesity Research Center (NORC) at the University of Washington will contribute to a rich training and career development experience. Together, these activities will enable me to successfully compete for a Career Development (K) Award and progress towards my goal of becoming an independent investigator in metabolism with a focus on islet biology.

Public Health Relevance

Islet ? cells exist in close proximity to an extracellular matrix (ECM), which provides critical signals for secretory function and survival. Our preliminary data show that ECM components including laminin are decreased in animal models of type 2 diabetes, and laminin ?4 knockdown impairs insulin release both in vitro and in vivo. The proposed studies will determine if restoration of laminin ?4 in islet endothelial cells can rescue ?-cell function in vitro and in vivo. These studies will potentially yield novel targets for interventions aimed at ameliorating ?-cell dysfunction and death, which can ultimately be utilized to treat patients with type 2 diabetes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZDK1)
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Castle, Arthur
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University of Washington
Internal Medicine/Medicine
Schools of Medicine
United States
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Hogan, Meghan F; Liu, Amy W; Peters, Michael J et al. (2017) Markers of Islet Endothelial Dysfunction Occur in Male B6.BKS(D)-Leprdb/J Mice and May Contribute to Reduced Insulin Release. Endocrinology 158:293-303
Templin, Andrew T; Samarasekera, Tanya; Meier, Daniel T et al. (2017) Apoptosis Repressor With Caspase Recruitment Domain Ameliorates Amyloid-Induced ?-Cell Apoptosis and JNK Pathway Activation. Diabetes 66:2636-2645
Hogan, Meghan F; Hull, Rebecca L (2017) The islet endothelial cell: a novel contributor to beta cell secretory dysfunction in diabetes. Diabetologia 60:952-959