Skeletal morbidity and its determinants in type 1 diabetes

Chen, Suet Ching (2019) Skeletal morbidity and its determinants in type 1 diabetes. MD thesis, University of Glasgow.

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Printed Thesis Information: https://eleanor.lib.gla.ac.uk/record=b3367867

Abstract

Adults, and more recently, children with T1D have been found to have a significantly increased risk of fractures compared to the general population. The increased fracture risk is disproportioned to the marginal reduction in bone mineral density (BMD) observed in T1D suggesting that factors other than bone mineral status contribute to skeletal fragility. The National Institute of Health (NIH) Consensus Development Panel on Osteoporosis highlighted that bone strength is in fact dependent on two main factors: bone density and bone quality. Recognising the importance of bone quality as a factor determining bone health, this work set out to examine bone microarchitecture using novel imaging techniques of high-resolution magnetic resonance imaging (HR-MRI). Furthermore, HR-MRI enables the use of magnetic resonance spectroscopy (MRS) to quantify the amount of bone marrow fat, providing invaluable insight into the relationship between bone marrow adiposity and skeletal fragility. The background to this work, the current body of evidence and the rationale for the studies are therefore laid out in Chapter 1. All the methodology used in the thesis is summarised in Chapter 2, including the laboratory techniques carried out.

The clinical study was conducted in children with T1D as not only have these children been shown to have increased fracture risk, but also given that childhood and adolescence are important physiological periods for optimal bone development, it is therefore possible that they may be especially predisposed to abnormalities of bone health. The use of MRI as a research tool in children is relatively new, so I started this work exploring the practicality of this technique in children and using data from a previous HR-MRI study to determine the feasibility of partial set analysis of the images, the latter detailed in Chapter 3. This straight-forward exercise confirmed that partial MRI data sets can reliably represent a larger complete set of images when assessing trabecular bone microarchitecture parameters.

The overall objective of this thesis is to assess the bone health of children with Type 1 diabetes, by using HR-MRI to study the trabecular bone microarchitecture, in addition to bone mineral density and bone turnover status as detailed in Chapter 4. A cross-sectional case control study was conducted in 32 children with T1D and compared to 26 healthy age- and gender- matched controls. The primary hypothesis of the study was proven, in that children with T1D were found to have poorer bone microarchitecture with lower trabecular bone volume compared to the controls. Children with T1D also had lower number of trabeculae and the trabeculae were spaced further apart from one another. Although this study demonstrated that children with T1D fracture more than children without the condition, it did not however show any relationship between the compromised bone microarchitecture to fracture. In fact, the children with T1D who fractured were found to have significantly lower bone mineral density and poorer glycaemic control. There was also no significant disparity in the bone marrow adiposity between the two groups.

In parallel, I performed one year of laboratory-based experiments to study the differentiation of mesenchymal stem cells (MSCs), which are the precursors to bone (osteoblasts) and fat cells (adipocytes), as detailed in Chapter 5. My main aim was to study the effects of metformin, a drug increasingly used in patients with T1D, on the MSC differentiation in order to determine if metformin may have a therapeutic bone protective role. My studies successfully demonstrated in vitro that metformin exerted reciprocal control over the osteogenic transcription factor Runx2, and the adipogenic transcription factor, PPARγ; promoting osteogenesis through an increase in Runx2 transcriptional activities, independently of Runx2 protein expression, and suppressing adipogenesis, through suppression of PPARγ protein expression and activity. I proceeded to study the underlying molecular mechanisms of the metformin action, starting with AMP-activated protein kinase (AMPK) given that metformin is a known AMPK activator. To our fascination, the study found that the suppression of adipogenesis by metformin appeared to be independent of AMPK activation but rather through the suppression of the mTOR/p70S6K signalling pathway.

Chapter 6 summarised all my work for this thesis, highlighting its strengths and limitations as well as providing my perspectives into the future directions of this work.

Item Type: Thesis (MD)
Qualification Level: Doctoral
Keywords: Diabetes, bones, MRI, metformin, osteogenesis, adipogenesis.
Subjects: Q Science > Q Science (General)
R Medicine > R Medicine (General)
R Medicine > RJ Pediatrics
R Medicine > RJ Pediatrics > RJ101 Child Health. Child health services
R Medicine > RM Therapeutics. Pharmacology
R Medicine > RZ Other systems of medicine
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Supervisor's Name: Ahmed, Professor Syed Faisal and Yarwood, Professor Stephen
Date of Award: 2019
Depositing User: Dr Suet Ching Chen
Unique ID: glathesis:2019-75042
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 02 Oct 2019 15:36
Last Modified: 10 Dec 2019 10:55
Thesis DOI: 10.5525/gla.thesis.75042
URI: http://theses.gla.ac.uk/id/eprint/75042
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