Recent advances in the understanding and management of islet amyloid ò-cell toxicity in type 2 diabetes and islet transplantation
International conference on DIABETES, NUTRITION, METABOLISM & MEDICARE
July 24-26, 2017 | Vancouver, Canada
Lucy Marzban
University of British Columbia, Canada
Scientific Tracks Abstracts : J Nutr Hum Health
Abstract:
Statement of the Problem: Islet amyloid forms by aggregation of the β-cell hormone human islet amyloid polypeptide (hIAPP). Amyloid formation is a pathologic characteristic of the pancreas in type 2 diabetes (T2D) but also forms in transplanted human islets. Islet amyloid is toxic to β-cells and contributes to progressive β-cell loss in both T2D and islet grafts. The current challenge in developing effective therapies to protect islets from amyloid toxicity is our limited knowledge of the mechanisms of amyloidinduced β-cell death in vivo. Methodology: We performed detailed mechanistic studies by using human islets from cadaveric donors and by generation of different transgenic mouse models, to investigate the apoptotic pathways that contribute to β-cell death caused by formation of hIAPP aggregates in islets and to develop new strategies to protect islets from amyloid toxicity. Findings: Based on our studies, we propose a new model that links amyloid formation and islet inflammation in T2D and islet grafts. Our studies show that amyloid formation in human islets promotes interleukin (IL)-1β production which leads to β-cell upregulation of the Fas cell death receptor and activation of the Fas-mediated apoptotic pathway initiated by caspase-8. We further demonstrate that amyloid formation disrupts the balance between IL-1β and natural IL-1 receptor antagonist (IL-1Ra). Moreover, impaired processing of prohIAPP associated with β-cell dysfunction potentiates amyloid formation and aggravates IL-1β production. Finally, we provide evidence to suggest that glucagon-like peptide (GLP)-1 agonists and IL-1R antagonists can effectively protect human islets from amyloid toxicity and introduce new strategies that focus on targeting amyloid apoptotic signaling pathway. Conclusion & Significance: In summary, amyloid formation is closely linked to islet inflammation and plays a significant role in progressive loss of β-cells in T2D and islet grafts. GLP-1 agonists and IL-1R antagonists may efficiently protect human islets from amyloid toxicity in early stages of T2D and clinical islet transplantation.
Biography:
Lucy Marzban is an Associate Professor in the Faculty of Medicine, University of British Columbia, Canada. She is a diabetes investigator with expertise in the areas of islet biology, pathology and pharmacology. Her research program focuses on identifying the mechanisms underlying islet β-cell death in diabetes. In past ten years, her team has intensively investigated the mechanisms by which formation of toxic protein aggregates named islet amyloid causes β-cell death in patients with type 2 diabetes and transplanted human islets in patients with type 1 diabetes. Her studies have led to development of a very interesting model and new strategies to prevent progressive β-cell loss in pathologic conditions associated with islet amyloid formation.
Email: lucy.marzban@ubc.ca
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