[en] ("[en] AIMS/HYPOTHESIS: The islet vasculature, including its constituent islet endothelial cells, is a key contributor to the microenvironment necessary for normal beta cell health and function. In type 2 diabetes, islet amyloid polypeptide (IAPP) aggregates, forming amyloid deposits that accumulate between beta cells and islet capillaries. This process is known to be toxic to beta cells but its impact on the islet vasculature has not previously been studied. Here, we report the first characterisation of the effects of IAPP aggregation on islet endothelial cells/capillaries using cell-based and animal models.
METHODS: Primary and immortalised islet endothelial cells were treated with amyloidogenic human IAPP (hIAPP) alone or in the presence of the amyloid blocker Congo Red or the Toll-like receptor (TLR) 2/4 antagonist OxPAPc. Cell viability was determined0 along with mRNA and protein levels of inflammatory markers. Islet capillary abundance, morphology and pericyte coverage were determined in pancreases from transgenic mice with beta cell expression of hIAPP using conventional and confocal microscopy.
RESULTS: Aggregated hIAPP decreased endothelial cell viability in immortalised and primary islet endothelial cells (by 78% and 60%, respectively) and significantly increased expression of inflammatory markers Il6, Vcam1 and Edn1 mRNA relative to vehicle treatment in both cell types (p<0.05; n=4). Both cytotoxicity and the proinflammatory response were ameliorated by Congo Red (p<0.05; n=4); whereas TLR2/4-inhibition blocked inflammatory gene expression (p<0.05; n=6) without improving viability. Islets from high-fat-diet-fed amyloid-laden hIAPP transgenic mice also exhibited significantly increased expression of most markers of endothelial inflammation (p<0.05; n=5) along with decreased capillary density compared with non-transgenic littermates fed the same diet (p<0.01). Moreover, a 16% increase in capillary diameter was observed in amyloid-adjacent capillaries (p<0.01), accompanied by a doubling in pericyte structures positive for neuron-glial antigen 2 (p<0.001).
CONCLUSIONS/INTERPRETATION: Islet endothelial cells are susceptible to hIAPP-induced cytotoxicity and exhibit a TLR2/4-dependent proinflammatory response to aggregated hIAPP. Additionally, we observed amyloid-selective effects that decreased islet capillary density, accompanied by increased capillary diameter and increased pericyte number. Together, these data demonstrate that the islet vasculature is a target of the cytotoxic and proinflammatory effects of aggregated hIAPP that likely contribute to the detrimental effects of hIAPP aggregation on beta cell function and survival in type 2 diabetes.","[en] ","")
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Castillo, Joseph J ; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA ; Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA
Aplin, Alfred C ; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
Hackney, Daryl J; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA
Hogan, Meghan F ; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA ; Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA
Esser, Nathalie ; Centre Hospitalier Universitaire de Liège - CHU > > Service de diabétologie, nutrition, maladies métaboliques ; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA ; Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA
Templin, Andrew T ; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA ; Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA
Akter, Rehana ; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA ; Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA
Kahn, Steven E ; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA ; Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA
Raleigh, Daniel P ; Department of Chemistry, Stony Brook University, Stony Brook, NY, USA ; Research Department of Structural and Molecular Biology, University College London, London, UK
Zraika, Sakeneh ; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA ; Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA
Hull, Rebecca L ; Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USA. rhull@uw.edu ; Division of Metabolism, Endocrinology, and Nutrition, Department of Medicine, University of Washington, Seattle, WA, USA. rhull@uw.edu
Language :
English
Title :
Islet amyloid polypeptide aggregation exerts cytotoxic and proinflammatory effects on the islet vasculature in mice.
Publication date :
October 2022
Journal title :
Diabetologia
ISSN :
0012-186X
eISSN :
1432-0428
Publisher :
Springer Science and Business Media Deutschland GmbH, Germany
ADA - American Diabetes Association [US-VA] [US-VA] United States Department of Veterans Affairs [US-DC] [US-DC] NIDDK - National Institute of Diabetes and Digestive and Kidney Diseases [US-MD] [US-MD]
Funding text :
This work was supported by the Department of Veterans Affairs, VA Puget Sound Health Care System (Seattle, WA), VA Merit Reviews I01-BX004063 (RLH) and I01-BX001060 (SEK) and VA CDA-2 IK2 BX004659 (ATT). The work was also supported by National Institutes of Health grants R01 DK088082 (RLH), GM078114 (DPR), P30 DK017047 (Cellular and Molecular Imaging and Cell Function and Analysis Cores of the University of Washington Diabetes Research Center), P30EY0173 (Electron Microscopy Resource of the University of Washington Core for Vision Research) and the Seattle Institute for Biomedical and Clinical Research. JJC was supported by T32 HL007028. MFH was supported by F32 DK109584 and an ADA Postdoctoral Fellowship. The study sponsors/funders were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.
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