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Title: Identification of novel targets for the treatment of type 2 diabetes
Author: Cripps, Michael J.
ISNI:       0000 0004 7965 9042
Awarding Body: Nottingham Trent University
Current Institution: Nottingham Trent University
Date of Award: 2019
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Introduction: With the worldwide prevalence of diabetes continuing to increase, and current treatments aimed at increasing insulin secretion often losing effectiveness over time, it is imperative to develop new therapeutic strategies that function through independent mechanisms to those already developed. Methods and aims: Isolated CD1 mouse islets, INS-1 β-cells and C2C12 skeletal muscle cells were cultured in control or glucolipotoxic environments as a model of type 2 diabetes. Using a combined approach of transcriptomics, PCR analysis, protein expression, fluorescent probes, in silico modelling, and cellular function assays, new therapeutic targets and treatments to augment insulin secretion in type 2 diabetes have been identified. Results: Carnosine and β-alanine supplementation was shown to inhibit reactive species generation and to increase stimulated insulin secretion. Importantly it was also able to reverse glucolipotoxicity-associated inhibition of insulin secretion typically seen in type 2 diabetes. However, due to rapid hydrolysis of carnosine by carnosinase enzymes in the body, these treatment strategies are likely to be of only modest benefit to patients. In silico derived compounds designed to inhibit carnosinase-2 activity had surprisingly little effect on reactive species scavenging or cellular function in β-cells however. Nevertheless, carnosinase inhibitors may still offer a III realistic treatment strategy in patients, as β-cells are limited by carnosine concentrations ~1,000 fold lower than those observed in tissues linked to insulin resistance, such as skeletal muscle. Illumina HiSeq gene expression analysis identified trace amine associated receptor (TAAR) expression as being significantly downregulated by glucolipotoxicity. Furthermore, TAARs were shown to regulate insulin secretion through adenylyl cyclase activation and cAMP mediated enhanced insulin secretion. Addition of physiological TAAR ligands was also shown to be able to amplify secretagogue-stimulated insulin release. Conclusion: This body of work will pave the way for future studies seeking to develop and further characterise carnosine and novel carnosine derived analogs as potential therapeutic agents to reverse glucolipotoxic cellular dysfunction. Modulation of heterotrimeric G-protein coupled receptor signalling through TAAR agonists may also represent a new therapeutic strategy to combat type 2 diabetes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available