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UBC Theses and Dissertations

A characterization of glucose-induced downregulation of the glucose dependent insulinotropic polypeptide receptor (GIPR) Olver, Amy Virginia

Abstract

The primary role of the incretin hormone, glucose-dependent insulinotropic polypeptide (GIP) is to potentiate the secretion of insulin in a glucose-dependent manner. In humans and rat models with type 2 diabetes, however, this action is impaired as a result of attenuated GIP receptor (GIPR) expression in the pancreatic β-cell. It has been previously reported that glucose strongly downregulates GIPR mRNA expression in rat insulinoma FNS-1 (832/13) cells and rat islets in a concentration-dependent manner. Since chronic hyperglycemia was proposed to be a primary cause for GIP resistance one objective of my studies was to attempt reversal of this process by pharmacologically lowering blood glucose. However, treatment studies on the effects of the dipeptidyl peptidase (DPIV) inhibitor P32/98 and a DPIV-resistant analogue D-Ala²-GIP on VDF and ZDF rats respectively, showed only moderate improvements in glucose homeostasis, and therefore were not appropriate models for determining the potential reversal effects of lowering blood glucose on islet GIPR expression. The mechanism for the glucose-induced GIPR downregulation is not clear; however it has been previously reported that peroxisome proliferated activated receptor a (PPARa), an important transcription factor involved in fatty acid metabolism, plays an important role. The second objective of this study therefore, was to investigate the effects of a PPARa overexpression system on GIPR expression in INS-1 (832/13) cells. Unexpectedly PPARa did not significantly upregulate our gene of interest; however these studies and others suggest that stimulation of PPARa alone is not sufficient for regulation, and thus also requires an increase in availability of PPARa's co-activator retinoid X receptor (RXR). The third objective of this thesis was to examine the regulation of GIPR in adipose tissue and to determine whether GIPR is differentially expressed in fat and pancreatic islet. Glucose concentration-dependent studies on INS-1 (832/13) β-cell lines and 3T3L1-adipocytes as well as an in vivo characterization study of lean (Fa/?) versus fatty (fa/fa) VDF rat models, collectively demonstrated a tissue-specific pattern of GIPR expression. In all, the findings of this thesis therefore prompt new questions and provide a basis for future experimentation.

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