Gestational diabetes mellitus (GDM), defined as glucose intolerance first identified during pregnancy, is an escalating problem worldwide which affects 5-20% of all pregnant women. It is associated with long-term consequences such as obesity, metabolic syndrome and type 2 diabetes in both the mother and affected offspring, the latter mediated in part by birthweight (“diabetes begets diabetes”). However, selective screening strategies based on established risk factors for GDM, accurately identify only around 60% of cases suggesting that there are other mechanisms involved. The aim of my thesis was to investigate the role of 2 novel biomarkers, vitamin B12 (B12) and glucagon-like peptide (GLP-1) in the development of GDM and related metabolic outcomes. A systematic review and meta-analysis showed that B12 insufficiency in pregnancy was in the order of 20-30% across the world and was associated with marginally higher, but significant, odds of low birthweight babies but these findings may be isolated to high-risk countries. In a local UK population, B12 insufficiency was independently associated with obesity, 2.6-fold higher risk of GDM and fetal macrosomia. A nationwide survey of women of child-bearing age confirmed that 12% were B12 insufficient with associated hyperhomocysteinaemia, despite apparently adequate dietary intakes of B12. This warrants urgent review of the recommended nutrient intake guidelines to optimise B12 status prior to conception. In the second part of my thesis, it was shown that overall GLP-1 response during a diagnostic glucose tolerance test is reduced in GDM women compared to controls, with a decrease in the early phase particularly predictive of post-prandial glucose levels. This potentially provides a novel mechanism to explain the delayed first phase insulin response which has been noted in GDM and T2D. Finally, to better understand how GLP-1 may exert a protective effect on the vascular complications of hyperglycaemia, a basic science project was carried out which demonstrated that liraglutide, a GLP-1 receptor agonist, enhanced the AMPK and phospho-AKT signaling pathways thereby contributing to the reduction of oxidative cell damage. In summary, this thesis supports the hypothesis there are multiple mechanisms which give rise to GDM (e.g. predominant insulin resistance or insulin secretion or combination of factors) and biomarkers such as B12 and GLP-1 can be clinically useful in identification of high-risk women. If proven in larger prospective studies, with measurements of the biomarkers from early pregnancy, these markers may be used to risk-stratify these women with the ultimate goal of reducing the transgenerational perpetuation of diabetes.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:720526 |
| Date | January 2017 |
| Creators | Sukumar, Nithya |
| Publisher | University of Warwick |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://wrap.warwick.ac.uk/90895/ |
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