Date of Award
MD (Medical Doctor)
Professor Seamus Sreenan
mRNA, Serum, Diabetes Type 1, Diabetes Type 2, Proteomics, Metabolomics
While there is consensus on what biological parameters are consistent with diagnosis of diabetes, there is a scarcity of biomarkers which might identify different biochemical phenotypes of disease, underlying β cell mass or propensity to complications in diabetes. The studies presented in this thesis were undertaken based on observations from our research group’s previous study, which identifed differentially expressed mRNAs in extracellular medium of glucose-responsive vs. glucose-non-responsive cell lines. As level of expression of mRNAs was dependent on glucose responsiveness and cell mass, we aimed to investigate whether similar mRNA expression pattern changes would be observed in human serum in patients with known diabetes.
We collected samples from patients with impaired fasting glucose, impaired glucose tolerance, newly diagnosed type 2 diabetes, newly diagnosed type 1 diabetes, poorly controlled type 2 diabetes and long-standing type 1 diabetes as well as healthy controls. In this work, I present findings from studies on patients newly diagnosed with type 2 diabetes, newly diagnosed type 1 diabetes and long-standing diabetes, compared to their healthy controls.
We have not found differential expression of mRNA identified in the cell lines study in our newly diagnosed type 2 diabetes patients and the research group’s decision was not to extend mRNA studies to other groups of subjects, which may be attempted with resolution of current financial constraints.
We also examined sera of patients with type 1 diabetes with proteomic and novel metabolomic methods. Proteomic analysis identified down-regulation of anticoagulant protein S in patients with newly diagnosed type 1 diabetes, but no reported thrombotic events. While proteomics also identified reduced levels of vitronectin in patients with established type 1 diabetes, this is of unknown signficance.
In metabolomic analysis, the most consistently altered metabolic pathway was the caffeine metabolism, with five caffeine metabolites being significantly down-regulated in patients with newly diagnosed type 1 diabetes, possibly indicating increased caffeine consumption by controls. Other pathways significantly altered were those of carbohydrate and lipid metabolism. 1,5-anhydroglucitol, a known marker of glycemic control, was unsurprisingly significantly down-regulated in patients with newly diagnosed type 1 diabetes, in conjunction with significantly raised glucose levels in these patients. Lipid metabolites were were lower in patients with type 1 diabetes than in controls; this was coupled with higher total and LDL cholesterol in controls than in patients with type 1 diabetes. Therefore it is unknown if changes in lipid metabolites are reflective of type 1 diabetes, or due to the high cholesterol in control samples.
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Rakovac Tisdall A. Serum messenger RNA, protein biomarkers and metabolomic profiling in diabetes mellitus [MD Thesis]. Dublin: Royal College of Surgeons in Ireland; 2015.