Effects of novel peptide therapeutics andepigallocatechin on diabetes and cognitivedysfunction

Abstract

The prevalence of type 2 diabetes (T2DM) has increased alarmingly in the past twodecades. In addition, there is now a strong link between cognitive impairment and T2DM.This not only highlights the pharmacologic shortcomings of current therapies, but alsodemonstrates the imperative need to develop novel therapeutics that can address T2DMassociated complications including cognitive and hippocampal dysfunctions. In thisregard, proglucagon derived hormones, especially GLP-1 mimetics, have received muchattention in the recent past. Therefore, this thesis has evaluated the actions of novelproglucagon derived dual acting hybrid analogues, either alone or in combination withknown pharmacological regulators on metabolic effects together with hippocampalassociated memory and cognitive functions. In this thesis we have developed,characterised and tested the therapeutic efficacy of novel and stable proglucagon derivedanalogues that are dual receptor acting namely, (DS2)Oxm[K-γ-glu-Pal], (DS2)Oxm), (D-Ser2)glucagon-exe and N-ac(ᴅ-Ala2)GIP/GLP-1-exe). Furthermore, we have also identified thetherapeutic competence of a combination regimen of an established GLP-1 analogue,exendin 4 along with green tea derived epigallocatechin-3-gallate (EGCG). When tested indiet 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/kgbw) reduced non fasting blood glucose, body fat, body weight, improved glucosetolerance and enhanced insulin sensitivity. Therapeutic intervention with (DS2)Oxm[K-γ-glu-Pal], (DS2)Oxm), induced an increases the gene expression of markers involved in thememory processing and insulin action in the hippocampus whilst enhancing synapticplasticity, neurogenesis and reducing oxidative stress. Also, four week treatment with Nac(ᴅ-Ala2)GIP/GLP-1-exe and a combination regimen of exendin 4 and EGCG markedlyreduced hippocampal oxidative stress, enhanced synaptic plasticity and increasedneurogenesis of progenitor neuronal cells. Assessment of learning and memoryparameters revealed enhanced recognition memory and learning ability in treated mice.Notably, the observed biological parameters were superior with combined treatmentscompared with individual therapies. In conclusion, this thesis has demonstrated thatnovel proglucagon derived peptides can not only provide metabolic protection under type2 diabetes but also hold the potential to counter the underlying hippocampal associatedcognitive decline.

Thesis is embargoed until 30th November 2018

Date of Award	Nov 2016
Original language	English
Sponsors	Vice Chancellor's Research Scholarship (VCRS)
Supervisor	Victor Gault (Supervisor) & Peter Flatt (Supervisor)