Actions of anti-diabetic drugs on hippocampal dependent cognitive function in obesity and type 2 diabetes

Abstract

The rate of cognitive decline is accelerated in patients with type 2 diabetes (T2DM), which is now a recognised as a risk factor for Alzheimer’s disease (AD). This connection is well established however the underlying mechanisms are yet to be elucidated. The prevalence of T2DM and AD is increasing making it imperative these mechanisms and effective treatment options are investigated. This thesis has evaluated the effects of novel and established anti-diabetic drugs on hippocampal-dependent memory alongside metabolic effects in high-fat fed mice. This diet-induced model of T2DM was employed to investigate the underlying mechanisms affecting cognitive performance and possible treatment with pharmacological agents. A novel glucagon-like peptide-1 (GLP-1) receptor agonist, (Val8)GLP-1GluPAL, was developed and its efficacy evaluated. Chronic administration of (Val8)GLP-1GluPAL (25 nmol/kg) improved glycaemic control, cognitive performance and synaptic plasticity. In addition, (Val8)GLP-1GluPAL enhanced hippocampal neurogenesis and expression of genes involved in memory and learning processes whilst reducing hippocampal oxidative stress. However, when combined with metformin (300 mg/kg), effects were not further enhanced. Lixisenatide (50 nmol/kg) reduced plasma glucose and increased insulin and glucose. Assessment of memory and learning parameters revealed enhanced recognition memory and hippocampal neurogenesis with up-regulation of key genes. Positively, lixisenatide showed no signs of pancreatic inflammation. Other studies demonstrated that administration of the dipeptidylpeptidase-IV (DPP-IV) inhibitor sitagliptin (50 mg/kg) resulted in marked anti-hyperglycaemic effects. Treatment also markedly improved recognition memory accompanied by reduced oxidative stress and increased hippocampal neurogenesis. Expression of fundamental hippocampal genes was also up-regulated following sitagliptin treatment. In conclusion, this thesis has demonstrated that the beneficial actions of GLP-1 receptor agonists and DPP-IV inhibitors improve memory, impaired insulin signalling, inflammation and oxidative stress levels in models of T2DM with cognitive dysfunction. This provides evidence for the potential use of these agents in the treatment of cognitive decline in T2DM and neurodegenerative disorders.

Date of Award	Nov 2014
Original language	English
Supervisor	Victor Gault (Supervisor) & Peter Flatt (Supervisor)