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. / Nutrition and Metabolism
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:AEU.10048/1953 |
| Date | 11 1900 |
| Creators | Mangat, Rabban |
| Contributors | Proctor, Spencer (Agricultural, Food and Nutritional Science), Davidge, Sandra (Obstetrics / Gynecology/Physiology), Lehner, Richard (Pediatrics/Cell Biology), Russell, Jim (Professor Emeritus), Tannock, Lisa (Endocrinology and Molecular Medicine, University of Kentucky) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_US |
| Detected Language | English |
| Type | Thesis |
| Format | 15856257 bytes, application/pdf |
| Relation | Diabetic Medicine. 2011 Jan;28(1):61-72., Atheroscler Suppl. 2010 Jun;11(1):17-24., Biochem Soc Trans. 2007 Jun;35(Pt 3):477-81. |
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