Elucidation of novel factors driving inflammation and pancreatic beta-cell death in type 2 diabetes

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López, L., 2019. Elucidation of novel factors driving inflammation and pancreatic beta-cell death in type 2 diabetes. PhD, Nottingham Trent University.

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Abstract

Type 2 diabetes (T2D) is a chronic metabolic disorder where failure to maintain normal glucose homeostasis is associated with, and exacerbated by, obesity and the concomitant elevated free fatty acid (FFA) concentrations typically found in these patients (Olokoba et al 2012). 463 million people are currently estimated to be living with diabetes, of which 229 million are undiagnosed. Importantly, around 90% of all cases are T2D cases.

Hyperglycaemia and hyperlipidaemia together contribute to a decline in pancreatic insulin-producing beta cell (β-cell) mass through activation of pro-inflammatory signalling pathways. Glucolipotoxicity (GLT) is the term given to the combined and damaging effect of increased glucose and FA levels on pancreatic β-cells (Poitout et al 2010). There are however a large number of molecules potentially able to modulate these pro inflammatory pathways, and the mechanism(s) by which GLT induces inflammation remains poorly defined.

Utilising Illumina HiSeq next generation sequencing technology, I have analysed the β-cell transcriptome to identify those genes and proteins most sensitive to high glucose and FA environment. Data shows that of those molecules potentially able to activate inflammatory pathways, the S100 family of proteins are amongst the most highly upregulated by GLT. Independent PCR and immunoblot analysis have further confirmed upregulation of the three most highly expressed family members, namely S100A3, A4 and A5. Importantly, my data has established a link between S100A4 and NF-κB activation that is driven by glucose and FAs.

In order to determine wider mechanisms involved in the activation of NF-κB by S100A4, predictive pathway interaction maps have been generated for S100A4 based on the RNAseq data. This approach has uncovered a potentially novel interaction with a pro inflammatory transcription factor not previously associated with T2D, HIF-1α, thereby establishing a link between inflammation and hypoxia, and by extent, between T2D and cancer. This provides a valuable strategy that can be further exploited to discover novel potential targets for therapeutic intervention in the treatment of T2D.

Item Type:	Thesis
Creators:	López, L.
Date:	September 2019
Rights:	This work is the intellectual property of the author. You may copy up to 5% of this work for private study, or personal, non-commercial research. Any re-use of the information contained within this document should be fully referenced, quoting the author, title, university, degree level and pagination. Queries or requests for any other use, or if a more substantial copy is required, should be directed in the owner(s) of the Intellectual Property Rights.
Divisions:	Schools > School of Science and Technology
Record created by:	Linda Sullivan
Date Added:	20 May 2020 14:44
Last Modified:	20 May 2020 14:44
URI:	https://irep.ntu.ac.uk/id/eprint/39881