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Title: Effects of novel peptide therapeutics and epigallocatechin on diabetes and cognitive dysfunction
Author: Pathak, Nupur Madhur
ISNI:       0000 0004 6057 484X
Awarding Body: Ulster University
Current Institution: Ulster University
Date of Award: 2016
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The prevalence of type 2 diabetes (T2DM) has increased alarmingly in the past two decades. In addition, there is now a strong link between cognitive impairment and T2DM. This not only highlights the pharmacologic shortcomings of current therapies, but also demonstrates the imperative need to develop novel therapeutics that can address T2DM associated complications including cognitive and hippocampal dysfunctions. In this regard, proglucagon derived hormones, especially GLP-1 mimetics, have received much attention in the recent past. Therefore, this thesis has evaluated the actions of novel proglucagon derived dual acting hybrid analogues, either alone or in combination with known pharmacological regulators on metabolic effects together with hippocampal associated memory and cognitive functions. In this thesis we have developed, characterised and tested the therapeutic efficacy of novel and stable proglucagon derived analogues that are dual receptor acting namely, (DS2)Oxm[K-y-glu-Pal], (DS2)Oxm), (D-Ser2) glucagon-exe and A/-ac(D-Ala2)GIP/GLP-l-exe). Furthermore, we have also identified the therapeutic competence of a combination regimen of an established GLP-1 analogue, exendin 4 along with green tea derived epigallocatechin-3-gallate (EGCG). When tested in diet induced model of type 2 diabetes, all analogues on their own (at 25 nmol/kg bw; twice daily) as well as exendin 4 (25 nmol/kg bw) in combination with EGCG (50 mg/kg bw) reduced non fasting blood glucose, body fat, body weight, improved glucose tolerance and enhanced insulin sensitivity. Therapeutic intervention with (DS2)Oxm[K-y- glu-Pal], (DS2)Oxm), induced an increases the gene expression of markers involved in the memory processing and insulin action in the hippocampus whilst enhancing synaptic plasticity, neurogenesis and reducing oxidative stress. Also, four week treatment with N-ac(D-Ala2)GIP/GLP-l-exe and a combination regimen of exendin 4 and EGCG markedly reduced hippocampal oxidative stress, enhanced synaptic plasticity and increased neurogenesis of progenitor neuronal cells. Assessment of learning and memory parameters revealed enhanced recognition memory and learning ability in treated mice. Notably, the observed biological parameters were superior with combined treatments compared with individual therapies. In conclusion, this thesis has demonstrated that novel proglucagon derived peptides can not only provide metabolic protection under type 2 diabetes but also hold the potential to counter the underlying hippocampal associated cognitive decline.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available