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Title: Therapeutic utility of xenin based hybrid peptides for the treatment of obesity-diabetes
Author: Hasib, Annie
ISNI:       0000 0004 7653 1166
Awarding Body: Ulster University
Current Institution: Ulster University
Date of Award: 2017
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Type 2 diabetes mellitus (T2DM) is characterised by an impaired incretin effect, related to reduced glucagon-like-peptide-1 (GLP-1) secretion and impaired glucose- dependent insulinotropic (GIP) action. The inherent reduction in GLP-1 secretion can be overcome by clinically approved GLP-1 mimetics, whereas there is still need to develop novel therapeutic approaches to restore the blunted insulinotropic effect of GIP. Xenin has been recently reported to potentiate the biological actions of GIP. To date, no peptide mimetic has been able to surpass the beneficial antidiabetic effects of bariatric surgeries. In relation to this, altered secretion of various gut hormones are linked to superior metabolic control associated with bariatric surgeries. This thesis characterised the biological activity and therapeutic applicability of xenin based hybrid peptides in obesity-diabetes. These hybrid peptides included (DAla2)GIP/xenin-8-Gln, exendin-4/xenin-8-Gln, exendin-4/gastrin/xenin-8-Gln and cxendin-4/gastrin/xenin-8-Gln-Lys27PAL. Importantly, all hybrid peptides were resistant to enzymatic degradation and enhanced insulin secretion in vitro. All selected hybrid peptides displayed glucose lowering, insulin secretory and satiety effects. Importantly, there was a clear augmentation of the biological action of native GIP in all hybrid peptide treated mice, suggestive of restored GIP effectiveness. Twice daily administration of (DAla2)GIP/xenin-8-Gln for 21 days improved glucose tolerance, insulin resistance and pancreatic islet morphology in high-fat fed mice. Similarly, twice daily treatment with exendin-4/gastrin/xenin-8-Gln and exendin-4/xenin-8-Gln significantly improved metabolic control in dietary-induced diabetes. The superior metabolic profile of exendin-4/gastrin/xenin-8-Gln prompted further development of its related fatty acid derivative analogues. The protracted response of exendin- 4/gastrin/xenin-8-Gln-Lys27PAL was evident for up to 12 hours. Furthermore, sub­chronic administration of both peptides offered enhanced biological potency in terms of glycaemic control, insulin secretory responsiveness, insulin sensitivity and potentiation of GIP action in ob/ob mice. Similarly, combination therapy of exendin- 4/gastrin and xenin-8-Gln enhanced biological response to native GIP, improved insulin sensitivity, glucose homeostasis, reduced food intake and body weight. Additionally, these beneficial metabolic effects persisted for 21 days after cessation of treatment. Overall, these findings provide strong encouragement for the development of xenin based hybrid peptides as a new class of multiple targeting peptides for alleviation of insulin resistance and beta cell dysfunction in T2DM.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available