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J Nutr Hum Health 2017 Volume 1 Issue 2
Notes:
July 24-26, 2017 | Vancouver, Canada
International conference on
DIABETES, NUTRITION, METABOLISM & MEDICARE
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 amyloid-
induced β-cell death in vivo.
Methodology:
We performeddetailedmechanistic 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.
lucy.marzban@ubc.caRecent advances in the understanding and management of islet amyloid β-cell toxicity in type 2
diabetes and islet transplantation
Lucy Marzban
University of British Columbia, Canada