AbstractResearch presented in this thesis has revealed exciting possibilities for exploiting normal physiological mechanisms triggered by incretin and other gut hormones for treatment of diabetes. A major theme has been the design of different families of enzyme resistant forms of GIP, GLP-1, CCK and oxyntomodulin by modification or substitution of amino acids at strategic sites. Further extension of bioactivity was achieved by acylation or mini- PEGylation. Stable forms of these peptides alone or in combination were shown to represent a novel and highly effective means of treating of obesity-diabetes. Such effects
were mediated through a variety of mechanisms including stimulation of insulin secretion, promotion of beta cell function and, with exception of GIP agonists, inhibition of feeding and body weight loss. Remarkably, novel GIP receptor antagonists also ameliorated diabetes but by alleviation of insulin resistance and promotion of beta cell rest. These effects were secondary to inhibition of GIP-mediated lipogenesis and depletion of tissue triglycerides. Novel analogues of oxyntomodulin exhibited antidiabetic effects at both islet and extrapancreatic sites by dual agonism of GLP-1 and glucagon receptors. This discovery
prompted work leading to development and characterisation of a series of unique unimolecular di- or tri-agonist peptides capable of activating receptors for GLP-1, glucagon and GIP. Such agents ameliorated diabetes, restored beta cell function and improved both lipid profile and body weight loss. Stable analogues also countered defects in cognition and bone quality revealing hitherto unappreciated actions of incretins. Alpha cell production of GLP-1 and GIP, driven by changes in relative expression of pro-convertases PC2 and PC1/3, were shown to be instrumental in the beta cell compensatory responses to pregnancy and metabolic stress. This research substantially advances knowledge on incretin and related gut hormones, revealing considerable potential of their stable peptide analogues and activation pathways for the effective treatment of diabetes in man.
|Date of Award||Mar 2018|