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UBC Theses and Dissertations
Modulation of insulinotropic hormone bioactivity with a focus on clucose-dependent insulinotropic polipeptide (GIP) and its receptor Hinke, Simon Amadeus
Abstract
Insulin secretory responses to oral glucose are compromised in type 2 diabetes. GIP receptor desensitization and internalization were studied as possible mechanisms for the blunted responsiveness to GIP in the human disease, employing in vitro cellular models. Using clonal insulin producing tumour cells (βTC-3) and rat GIP receptor transfected CHO-K1 cells, it was possible to characterize important aspects of receptor regulation. GIP receptor desensitization appeared to be slower than for other related receptors, and the rate appeared to parallel receptor internalization. Phosphorylation of receptor carboxyl terminal serine residues was implicated in both processes. Using co-transfection techniques and pharmacological agents, it was possible to partially delineate cellular proteins involved in GIP receptor desensitization and internalization. Dipeptidyl peptidase IV cleaves dipeptides from the N-termini of GIP, GLP-1 and glucagon, all of which are insulinotropic peptides involved in glucose homeostasis. Using cells transfected with the cognate receptors for these hormones, it was possible to demonstrate the importance of this enzyme in the modulation of hormone bioactivity. Structure-activity relationships for the peptides were designed to characterize the N-terminally truncated peptides, as well as design enzyme resistant molecules predicted to have superagonist activity in vivo. Such analogues with enhanced bioactivity may have a use in the treatment of diabetic states (GIP and GLP-1) or cardiovascular complications (glucagon). In vivo bioassay of these peptides confirmed their increased potency and highlighted their therapeutic potential. Additionally, fragment analysis was performed on GIP in an attempt to minimize the bioactive domain of the molecule, thus generating small molecular weight GIP receptor agonists.
Item Metadata
Title |
Modulation of insulinotropic hormone bioactivity with a focus on clucose-dependent insulinotropic polipeptide (GIP) and its receptor
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Creator | |
Publisher |
University of British Columbia
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Date Issued |
2002
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Description |
Insulin secretory responses to oral glucose are compromised in type 2 diabetes. GIP receptor desensitization and internalization were studied as possible mechanisms for the blunted responsiveness to GIP in the human disease, employing in vitro cellular models. Using clonal insulin producing tumour cells (βTC-3) and rat GIP receptor transfected CHO-K1 cells, it was possible to characterize important aspects of receptor regulation. GIP receptor desensitization appeared to be slower than for other related receptors, and the rate appeared to parallel receptor internalization. Phosphorylation of receptor carboxyl terminal serine residues was implicated in both processes. Using co-transfection techniques and pharmacological agents, it was possible to partially delineate cellular proteins involved in GIP receptor desensitization and internalization. Dipeptidyl peptidase IV cleaves dipeptides from the N-termini of GIP, GLP-1 and glucagon, all of which are insulinotropic peptides involved in glucose homeostasis. Using cells transfected with the cognate receptors for these hormones, it was possible to demonstrate the importance of this enzyme in the modulation of hormone bioactivity. Structure-activity relationships for the peptides were designed to characterize the N-terminally truncated peptides, as well as design enzyme resistant molecules predicted to have superagonist activity in vivo. Such analogues with enhanced bioactivity may have a use in the treatment of diabetic states (GIP and GLP-1) or cardiovascular complications (glucagon). In vivo bioassay of these peptides confirmed their increased potency and highlighted their therapeutic potential. Additionally, fragment analysis was performed on GIP in an attempt to minimize the bioactive domain of the molecule, thus generating small molecular weight GIP receptor agonists.
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Extent |
12235793 bytes
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Genre | |
Type | |
File Format |
application/pdf
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Language |
eng
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Date Available |
2009-11-13
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Provider |
Vancouver : University of British Columbia Library
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Rights |
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.
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DOI |
10.14288/1.0091443
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URI | |
Degree | |
Program | |
Affiliation | |
Degree Grantor |
University of British Columbia
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Graduation Date |
2002-11
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Campus | |
Scholarly Level |
Graduate
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Aggregated Source Repository |
DSpace
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Item Media
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Rights
For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.