Date of Award

2014

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Dr Diarmuid Smith

Second Supervisor

Dr Philip M. Cummins

Funder/Sponsor

Health Research Board of Ireland

Keywords

Diabetes Mellitus, Type 2, Vascular Calcification, Insulin, Glucagon-Like Peptide 1.

Abstract

Background: The process of vascular calcification (VC) appears to involve certain vascular cell populations assuming an osteoblastic phenotype. Osteoprotegerin (OPG) has been proposed as an inhibitor of VC, potentially via blockade of either receptor activator of nuclear factor kappa-beta ligand (RANKL) or tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Treatments for type 2 diabetes mellitus (T2DM) such as insulin analogues and liraglutide are known to affect OPG, and may also affect VC. The aims of this thesis were to characterise the roles of OPG/RANKL/TRAIL in VC,and to measure how insulin and liraglutide affect coronary artery calcification (CAC) in T2DM.

Methods: Production and secretion of OPG/RANKL/TRAIL was measured in human aortic endothelial and smooth muscle cells (HAECs & HASMCs). RANKL, TRAIL, insulin glargine and liraglutide were added to HAECs and HASMCs, and osteoblastic transformation of HASMCs was measured via alkaline phosphatise activity in the cell media and messenger ribonucleic acid (mRNA) markers of osteoblastic activity. In a clinical study, patients with T2DM who were commencing either insulin analgoues or liraglutide had CAC scans at 0 and 16 months of treatment.

Results: OPG, but not TRAIL or RANKL was secreted in large amounts by HASMCs, and to a lesser extent by HAECs. The direct application of RANKL or TRAIL did not induce osteoblastic transformation of HASMCs, but application of RANKL to HAECs led to increased production of bone morphogenetic protein 2 (BMP-2), which in turn led to increased osteoblastic activity in HASMCs. Insulin glargine, but not liraglutide, decreased OPG production and increased osteoblastic activity in HASMCs in vitro, and insulin analogues, but not liraglutide, was associated with a trend towards accelerated CAC in the T2DM population.

Conclusions: OPG inhibits osteoblastic transformation of HASMCs via prevention of RANKL-induced BMP-2 release from HAECs. Insulin analogues increase VC in vitro and are associated with increased CAC in vivo in T2DM.

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Comments

A thesis submitted for the degree of Doctor of Philosophy from the Royal College of Surgeons in Ireland in 2014.

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