Pro-glucagon derived peptide therapies for type 2 diabetes and obesity

Abstract

Pro-glucagon derived peptides, namely glucagon like peptide-1 (GLP-1),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-1 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-1, 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 of DPP-IV up to and beyond 8 hours and stimulated an enhancement of insulin secretion in BRIN-BD11 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-1/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 (ob/ob mice),[DA²]GLP-1/GCG 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-1/GCG improved glucose control with higher circulating levels of insulin and ameliorated insulin sensitivity. Glucose tolerance was enhanced with significant weight loss.

To conclude, this thesis shows chemical modification of native peptides and their combinations within a molecule can offset enzymatic degradation and renal clearance as well as improve efficacy. The uses of such peptides have demonstrated their ability to suit a dual purpose of glycaemic control and weight loss with no adverse effects. Hopefully this thesis and study will be the first among mixed pro-glucagon peptide hybrid combination therapies and will act as a catalyst for further development of novel peptide combinations for treatment of obesity-diabetes.

Date of Award	May 2014
Original language	English
Sponsors	Vice Chancellor's Research Scholarship (VCRS)
Supervisor	Victor Gault (Supervisor) & Peter Flatt (Supervisor)