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Permanent link (DOI): https://doi.org/10.7939/R3KH8B

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The Role of Intestinal Derived Remnant Lipoproteins in the Progression of Atherosclerosis in Animal Models of Type 1 and Type 2 Diabetes. Open Access

Descriptions

Other title
Subject/Keyword
Arterial Retention
Metabolic Syndrome
Atherosclerosis
apoB48 Remnants
Type of item
Thesis
Degree grantor
University of Alberta
Author or creator
Mangat, Rabban
Supervisor and department
Proctor, Spencer (Agricultural, Food and Nutritional Science)
Examining committee member and department
Russell, Jim (Professor Emeritus)
Davidge, Sandra (Obstetrics / Gynecology/Physiology)
Tannock, Lisa (Endocrinology and Molecular Medicine, University of Kentucky)
Lehner, Richard (Pediatrics/Cell Biology)
Department
Department of Agricultural, Food and Nutritional Science
Specialization

Date accepted
2011-06-08T17:51:50Z
Graduation date
2011-11
Degree
Doctor of Philosophy
Degree level
Doctoral
Abstract
Introduction: Subjects with insulin resistance (IR) and diabetes are at increased risk of cardiovascular disease (CVD) than those without diabetes, however the mechanistic basis remains elusive. Despite LDL-cholesterol lowering by statin therapy, two-thirds of all CVD events remain, constituting a significant 'residual risk' for CVD. This ‘residual risk’ has been found to be greater for patients with diabetes than those without diabetes. This suggests the role for alternative sources of lipoprotein-derived cholesterol in CVD during diabetes. Both type-1 diabetic as well as IR subjects have been found to have increased plasma concentrations of fasting intestinal derived apoB48 containing remnants (CM-r). However it is not known if the diabetic metabolic milieu indeed increases the susceptibility of the arteries to CM-r and if these indeed bind to arterial proteoglycans (PGs). Objectives: To determine arterial retention of CM-r in type-1 diabetes and IR using ex vivo perfusion methodology in a streptozotocin rat model of type 1 diabetes and JCR-LA-cp rat model of IR. To determine the direct binding affinity and capacity of CM-r to biglycan using an in vitro approach. Methods and Results: We observed increased arterial CM-R retention in type 1 diabetic vessels as well as in IR vessels when compared to control vessels. The retained CM-r colocalized with arterial biglycan in type 1 diabetic vessels and a direct correlation was observed between the CM-r and the presence of glycated proteins in type I diabetic arteries. The increased arterial CM-r retention in the IR rats was associated with increased arterial biglycan protein content. We have conclusively demonstrated for the first time that CM-r indeed bind to human biglycan. Conclusion: Tight glycemic control in patients with type 1 diabetes can alleviate CVD by reducing hyperglycemia and subsequent retention of CM-r. A significant increase in biglycan protein core content during IR is suggestive of early vascular remodeling and may help to explain how CM-r accumulate more readily during diabetes induced CVD. Based on the results from this study, individuals with IR may be at increased risk for atherogenesis due to increased atherogenicity of the post-prandial CM-r when compared to normal population.
Language
English
DOI
doi:10.7939/R3KH8B
Rights
License granted by Rabban Mangat (rmangat@ualberta.ca) on 2011-06-07T21:18:12Z (GMT): Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of the above terms. The author reserves all other publication and other rights in association with the copyright in the thesis, and except as herein provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.
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File size: 15856257
Last modified: 2015:10:12 15:04:43-06:00
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File author: Rabban Mangat
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