Pro-glucagon derived peptides, namely glucagon like peptide-l (GLP- I), oxyntomodulin, glucagon and the structurally related peptide, glucose dependent insulinotropic polypeptide (GIP) work to maintain glucose homeostasis, energy balance and body weight. In diabetes the action of GIP is attenuated and the secretion of GLP-I is reduced. Glucagon release aggravates the hyperglycaemic state and promotes progression to type 2 diabetes; being assisted by insulin resistance caused by obesity. Peptide mimetic development is impeded by degradation with dipeptidyl peptidases as well as endopeptidases and subsequently renal clearance. To date no peptide mimetic has exhibited stringent control of glycaemia in addition to providing effective weight loss. This thesis investigates the efficacy of various hybrid combinations of pro-glucagon derived and structurally related peptides in counteracting the deleterious effects of obesity-diabetes. Glucagon analogues with strategic amino acid substitutions to promote GIP function, GIP-Oxyntomodulin hybrids with anorectic and insulinotropic abilities and various GLP-I, GIP and glucagon hybrid peptide combinations were tested for in vitro and in vivo activity. Importantly, all hybrid peptides tested were completely stable to the actions ofDPPIV up to and beyond 8 hours and stimulated an enhancement of insulin secretion in BRIN-BDII cells. Furthermore, selected peptides exhibited acute insulin-releasing and glucose-lowering properties in lean mice. Modified glucagon analogues displayed long-term glycaemic control without exerting any changes in body weight. A GIP-Oxyntomodulin hybrid acutely and sub-chronically improved glycaemic state while lowering circulating levels of glucose and increasing levels of insulin and presented with lowered body weight independent of food intake. This was also accompanied by improved insulin sensitivity. [DA2]GLP-I/GCG acutely improved glucose control reflected by enhanced insulin release. This effect was persistent even at 8 hours post-administration. In models of insulin resistance (oblob mice), [DA2]GLP-lIGCG lowered glucose and improved insulin secretion possibly through a mode of peripheral glucagon-induced gluconeogenic inhibition. In HFF mice, long-term administration of [DA2]GLP-lIGCG improved glucose control with higher circulating levels of insulin and ameliorated insulin sensitivity. Glucose tolerance was enhanced with significant weight loss.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:669694 |
| Date | January 2014 |
| Creators | Bhat, Kattathila Vikas |
| Publisher | Ulster University |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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