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UBC Theses and Dissertations

The enteroinsular axis in glucose dependent insulinotropic polypeptide receptor knockout (GIPR-/-) miee Pamir, Nathalie


The incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide-1 (GLP-1), are gut hormones that act via the enteroinsular axis to potentiate insulin secretion from the pancreas in a glucose-dependent manner. Both GLP-1 and GIP receptor knockout mice (GLP-1 R-/- and GIPR-/- respectively) have been generated to investigate the physiological importance of this axis. Studies in this thesis were carried out on GIP receptor knockout mice (GIPR-/-). Although reduced GIP action is a component of type 2 diabetes, GIP receptor-deficient mice exhibit only moderately impaired glucose tolerance. Thus, the present thesis was directed at investigating possible compensatory mechanisms that take place within the enteroinsular axis in the absence of GIP action. Fasting and 20t h minute OGTT serum GIP levels as well as duodenojejunal GIP content were altered in GIPR-/- mice. Total serum GLP-1 levels and serum DPIV activity in GIPR knockout mice were not significantly different from those in control animals, either before or during a glucose tolerance test. However, insulin responses to GLP-1 in pancreas perfusions and static islet incubations were significantly greater in GIPR -/- than in +/+ mice (P<0.05), and GLP-1 induced cAMP production was also elevated in the pancreatic islets of the knockout animals (P<0.05). Additionally, pancreatic insulin content and insulin gene expression were reduced in GIPR-/- mice compared to wild type (+/+) mice (P< 0.05). There was, however, no discernible difference in GLP-1 receptor mRNA levels. Immunohistochemistry studies revealed a normal distribution and localization of endocrine cells within the pancreatic islets of GIPR-/- mice. Surprisingly, these studies showed an increase in islet area, when compared to total pancreatic area, in the -/- mice (P<0.05) with less intense staining for insulin. In conclusion, the GIPR-/- mouse exhibits increased islet size and (3 cell sensitivity to GLP-1 despite a decrease in pancreatic insulin protein content and gene expression. These findings suggest a critical role for GIP in normal islet and (3 cell function and development.

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