The Role of Laminin Alpha 4 in Beta-cell Function and Survival

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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 β-cell secretory function and survival are critical for the development of hyperglycemia. The mechanisms underlying β-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 β cell. The islet ECM component laminin normally enhances insulin release and β-cell survival. My preliminary data in islet endothelial cells from animal models of type 2 diabetes show for the first time that laminin α4 production is decreased. Additionally, culturing primary islet endothelial cells in high glucose also results in decreased laminin α4 production. Knockdown of laminin α4 in immortalized islet endothelial cells results in impaired insulin release, and insulin release is impaired in laminin α4-knockout mice. Thus, I hypothesize that increasing laminin α4 production in islet endothelial-derived ECM will improve β-cell function under hyperglycemic conditions. I will address this hypothesis by undertaking studies to determine if overexpression of laminin α4 in primary islet endothelial cells cultured in high glucose is sufficient to improve β-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 α4 improves insulin release in vivo. I anticipate that these studies will demonstrate for the first time that increasing expression of laminin α4 is sufficient to improve β-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 β-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.