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Am J Physiol Endocrinol Metab (January 21, 2003). doi:10.1152/ajpendo.00270.2002
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Submitted on June 19, 2002
Accepted on January 18, 2003

Glucose-dependent Insulinotropic Polypeptide Receptor Null Mice (GIPR-/-) Exhibit Compensatory Changes in the Enteroinsular Axis

Nathalie Pamir1, Francis C. Lynn1, Alison M. J. Buchan1, Jan Ehses1, Simon A. Hinke1, J. Andrew Pospisilik1, Kazumasa Miyawaki2, Yuichiro Yamada2, Yutaka Seino2, Christopher H. S. McIntosh1, and Raymond A. Pederson1*

1 Department of Physiology, University of British Columbia, Vancouver, BC, Canada
2 Department of Metabolism and Clinical Nutrition, Kyoto University, Kyoto, Japan

* To whom correspondence should be addressed. E-mail: pederson{at}interchange.ubc.ca.

The incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like 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-1R-/- and GIPR-/- respectively) have been generated to investigate the physiological importance of this axis. Although reduced GIP action is a component of type 2 diabetes, GIP receptor-deficient mice exhibit only moderately impaired glucose tolerance. The present study was directed at investigating possible compensatory mechanisms that take place within the enteroinsular axis in the absence of GIP action. Although, serum total GLP-1 levels in GIPR knockout mice were unaltered, insulin responses to GLP-1 from pancreas perfusions and static islet incubations were significantly greater (40-60%) in GIPR-/- than in GIPR+/+ mice. Furthermore, GLP-1 induced cAMP production was also elevated two-fold in the islets of the knockout animals. Pancreatic insulin content and gene expression were reduced in GIPR-/- mice compared to wild type (GIPR+/+) mice. Paradoxically, immunocytochemical studies showed a significant increase in beta cell area in the GIPR null mice, but with less intense staining for insulin. In conclusion, GIPR-/- mice exhibit altered islet structure and topography, and increased islet sensitivity to GLP-1 despite a decrease in pancreatic insulin content and gene expression.




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