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Title: Investigating the Desensitization and Internalization of Incretin
Authors: Ghina Mohammad Shaaban 
Supervisor: Dr. Suleiman Al-­‐Sabah
Keywords: GLP-1;GIB;Incretin
Issue Date: 2015
Publisher:  Kuwait university - college of graduate studies
Abstract: Oral food ingestion stimulates the release of two incretin hormones known as glucagon-­‐like peptide 1 (GLP-­‐1) and glucose insulinotropic peptide (GIP). Binding of these hormones to their respective receptors; GLP-­‐1R and GIPR on pancreatic β-­‐cells results in elevation of cAMP levels and amplification of insulin release. The aim of this study was to compare the desensitization and internalization of GIPR and GLP-­‐1R expressed in HEK 293 cells. To achieve this, a myc-­‐tag was introduced at the N-­‐terminal region of both receptors downstream of their signal peptide by a sequential overlapping polymerase chain reaction. The myc-­‐tag didn’t affect function of either receptor when assessed by creluc assays. Desensitization experiments were carried out by stimulating the transfected receptors in HEK 293 cells with agonist following a 2 hr prestimulation with the same agonist. GIPR was found to desensitize faster than GLP-­‐1R at a rate that can’t be reliably calculated, and both receptors continued to signal after washout of the first stimulation with a greater signal observed with GIPR. In terms of internalization, stimulation of the transfected cells with the agonist for up to 2 hours caused GLP-­‐1R to internalize at a rate that was comparable to its rate of desensitization, while GIPR’s internalization couldn’t be observed. Measurement of surface receptor expression revealed that GIPR had a low ratio of surface to total number of receptors that suggests that a high percentage of GIPR is already internalized. Furthermore, both receptors were found to signal after agonist washout which suggests that GLP-­‐1R continue to signal following internalization. In conclusion, GLP-­‐1R desensitizes and internalizes at a similar rate. GIPR on the other hand desensitizes faster than GLP-­‐1R, but no internalization could be observed over 2 hours of agonist exposure. Future studies should further investigate these two receptors in order to better understand their molecular signaling properties and preferably when these receptors are expressed in human β-­‐cells.
Appears in Programs:0550 Pharmacology (M.Sc.)

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