The mechanisms of amyloid toxicity in pancreatic islets – identifying the protective signaling pathways in islet α-cells

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dc.contributor.authorMoni, Mukta
dc.contributor.examiningcommitteeDolinsky, Vernon (Pharmacology and Therapeutics)en_US
dc.contributor.examiningcommitteeDoucette, Christine (Physiology and Pathophysiology)en_US
dc.contributor.examiningcommitteeLakowski, Ted (Pharmacy)en_US
dc.contributor.supervisorMarzban, Lucy
dc.date.accessioned2023-05-31T16:50:58Z
dc.date.available2023-05-31T16:50:58Z
dc.date.copyright2023-05-26
dc.date.issued2023-05-26
dc.date.submitted2023-05-26T17:06:55Zen_US
dc.degree.disciplinePharmacyen_US
dc.degree.levelMaster of Science (M.Sc.)en_US
dc.description.abstractType 2 diabetes (T2D) is characterized by peripheral insulin resistance, and progressive β-cell loss and dysfunction, associated with islet inflammation, leading to hyperglycemia. One of the factors that contribute to β-cell failure in T2D is islet amyloid deposition. Islet amyloid is formed by aggregation of a β-cell hormone, islet amyloid polypeptide (IAPP). Islet amyloid also forms during culture and following transplantation into patients with type 1 diabetes (T1D), potentially leading to islet graft failure. Amyloid triggers islet inflammation by promoting the production of proinflammatory cytokines, mainly interleukin-1 beta (IL-1β). Binding of IL-1β to interleukin-1 receptor-1 (IL-1R1), leads to activation of IL-1β signaling, upregulation of the Fas cell death receptor and activation of the Fas-mediated apoptotic pathway in β-cells. Interestingly, islet α-cells are much less susceptible than β-cells to the cytotoxic effects of amyloid and other β-cell apoptotic factors such as elevated glucose. The hypothesis of this MSc project is that lower expression of IL-1R1 and/or Fas receptor in islet α-cells than β-cells may protect α-cells from amyloid-induced apoptosis, leading to better survival of α-cells during amyloid formation in T2D. Transformed mouse αTC1-6 and rat INS-1 β-cells were cultured without (control) or with exogenous hIAPP or IL-1β at two glucose concentrations (11.1 or 25 mmol/l). Fas and IL-1R1 were detected by double-immunolabelling for insulin or glucagon and each IL-1R1 or Fas. IL-1R1 immunoreactivity was detected in both αTC1-6 cells and INS-1 β-cells under basal condition and following treatment with hIAPP or IL-1β. IL-1R1 immunoreactivity was markedly higher in INS-1 β-cells than αTC1-6 cells in all conditions. Also, the number of Fas-positive cells was markedly lower in αTC1-6 cells than INS-1 β-cells following treatment with hIAPP or IL-1β. Finally, αTC1-6 cells had lower rate of apoptosis than INS-1 β-cells following treatment with hIAPP or IL-1β. In summary, these data suggest that the higher susceptibility of β-cells to hIAPP aggregates or elevated IL-1β might be, at least partially, due to the higher expression of IL-1R1 and Fas in β-cells than α-cells.en_US
dc.description.noteOctober 2023en_US
dc.identifier.urihttp://hdl.handle.net/1993/37359
dc.language.isoengen_US
dc.rightsopen accessen_US
dc.subjectDiabetesen_US
dc.subjectType 1 diabetesen_US
dc.subjectType 2 diabetesen_US
dc.subjectIslet inflammationen_US
dc.subjectIL-1betaen_US
dc.subjectIL-1 receptor 1en_US
dc.subjectIslet amyloiden_US
dc.subjectBeta cell apoptosisen_US
dc.subjectFas receptoren_US
dc.subjectAlpha cellen_US
dc.titleThe mechanisms of amyloid toxicity in pancreatic islets – identifying the protective signaling pathways in islet α-cellsen_US
dc.typemaster thesisen_US
local.subject.manitobanoen_US
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