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.Arts, Faculty ofPsychology, Department ofGraduat