Glucose-dependent insulinotropic polypeptide receptor null mice exhibit compensatory changes in the enteroinsular axis

Nathalie Pamir, Francis C. Lynn, Alison M.J. Buchan, Jan Ehses, Simon A. Hinke, J. Andrew Pospisilik, Kazumasa Miyawaki, Yuichiro Yamada, Yutaka Seino, Christopher H.S. McIntosh, Raymond A. Pederson

Research output: Contribution to journalArticle

86 Scopus citations

Abstract

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 receptor 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, GIPR-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 wild-type (GIPR+/+) mice. Furthermore, GLP-1-induced cAMP production was also elevated twofold in the islets of the knockout animals. Pancreatic insulin content and gene expression were reduced in GIPR-/- mice compared with GIPR+/+ mice. Paradoxically, immunocytochemical studies showed a significant increase in β-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.

Original languageEnglish (US)
Pages (from-to)E931-E939
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume284
Issue number5 47-5
DOIs
StatePublished - May 1 2003

Keywords

  • CAMP
  • GLP-1
  • Incretin
  • Insulin
  • Pancreas perfusion

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology
  • Physiology (medical)

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    Pamir, N., Lynn, F. C., Buchan, A. M. J., Ehses, J., Hinke, S. A., Pospisilik, J. A., Miyawaki, K., Yamada, Y., Seino, Y., McIntosh, C. H. S., & Pederson, R. A. (2003). Glucose-dependent insulinotropic polypeptide receptor null mice exhibit compensatory changes in the enteroinsular axis. American Journal of Physiology - Endocrinology and Metabolism, 284(5 47-5), E931-E939. https://doi.org/10.1152/ajpendo.00270.2002