Exp Clin Endocrinol Diabetes 2007; 115 - OR02_6
DOI: 10.1055/s-2007-972214

GIPRdn transgenic pigs – a novel model for studying consequences of impaired incretin hormone function

S Renner 1, DC Kress 1, B Kessler 1, N Herbach 2, R Wanke 2, A Hofmann 3, A Pfeifer 3, E Wolf 1
  • 1Institut für Molekulare Tierzucht und Biotechnologie, Genzentrum der LMU München, München, Germany
  • 2Institut für Tierpathologie, LMU München, München, Germany
  • 3Institut für Pharmakologie und Toxikologie, Universität Bonn, Bonn, Germany

The incretin effect delineates the phenomenon that an oral glucose load elicits a higher insulin response than does an intravenous glucose load. Responsible for this effect are two hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). In patients with type 2 diabetes mellitus the overall incretin effect is reduced. This fact is mostly put down to an obviously lowered insulinotropic effect of GIP, while the effect of GLP-1 is vastly preserved. In order to better understand the consequences of impaired function of GIP, knockout mice lacking a functional GIP receptor (GIPR-/-) as well as transgenic mice expressing a dominant negative GIPR (GIPRdn) were established. While GIPR-/- mice show only relatively mild changes in glucose homeostasis, GIPRdn mice develop severe diabetes mellitus due to disturbed development of the endocrine pancreas. To further clarify the underlying mechanisms we generated transgenic pigs expressing a GIPRdn under the control of the rat Ins2 promoter (RIP). RIP-GIPRdn transgenic pigs develop normally and do not develop diabetes mellitus up to at least one year of age. However, similar as observed in GIPR-/- mice, RIP-GIPRdn transgenic pigs exhibited reduced insulin release and higher glucose levels in an oral glucose tolerance test than non-transgenic littermate controls. The area under the curve (AUC) for insulin was 49% smaller (p<0.01), the AUC for glucose 26% larger (p<0.05) in RIP-GIPRdn transgenic pigs (n=5) than in their non-transgenic littermate controls (n=5). These findings demonstrate that expression of a GIPRdn, which was shown by RT-PCR in isolated pancreatic islets, disturbs the function of GIP in transgenic pigs. Thus we have created a novel animal model, which is more similar to the human than the mouse physiology, for studying the roles of the GIP/GIPR system. Quantitative morphological studies of the pancreas are being performed to clarify whether islet development of RIP-GIPRdn transgenic pigs is disturbed like in the mouse model.

This study was supported by the DFG (GRK1029).