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Title: Modulatory effects of IGFBP-1 on insulin sensitivity & glucose regulation
Author: Haywood, Natalie Jayne
ISNI:       0000 0004 5371 4023
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2015
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Obesity is a key factor in the development of insulin resistance. Insulin resistance plays a central role in the initiation and progression of type 2 diabetes mellitus and atherosclerosis. Developing novel therapeutic strategies to prevent and treat insulin resistance is therefore important. In humans, the circulating concentration of IGFBP-1 (Insulin like growth factor binding protein-1) has been proposed as a marker of insulin sensitivity. IGFBP-1 can impact on cellular functions via an RGD (α5β1 integrin binding) motif independent of IGF binding. However, whether IGFBP-1 is causally implicated in glucose regulation and could be exploited therapeutically, remained unexplored. In this series of studies, complementary in vitro and in vivo approaches were used to explore the effect and mechanism of IGFBP-1 on metabolic homeostasis. Metabolically relevant cell lines were used to investigate the effects of rIGFBP-1 and an RGD synthetic hexapeptide (which binds α5β1 integrin) on glucose uptake, the insulin signalling pathway and insulin secretion. Metabolic profiling of genetically modified mice over-expressing hIGFBP-1 was also performed. Finally, two different in vivo models of insulin resistance were used to investigate the potential of an RGD synthetic hexapeptide as a novel treatment for insulin resistance. Promisingly, in vitro, rIGFBP-1 increases glucose uptake and insulin sensitivity through integrin engagement and focal adhesion kinase activation. rIGFBP-1, through its RGD domain and integrin linked kinase also improves glucose-stimulated insulin secretion from pancreatic β-cells. Encouragingly, in vivo, both acute and chronic RGD treatments appear to improve glucose clearance and enhance insulin sensitivity. Therefore, the RGD domain of IGFBP-1 represents a promising potential new therapeutic target, that both enhances insulin sensitivity and insulin secretion, in the field of type 2 diabetes mellitus.
Supervisor: Wheatcroft, Stephen B. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available