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

S. Renner; D. C. Kress; B. Kessler; N. Herbach; R. Wanke; A. Hofmann; A. Pfeifer; E. Wolf

doi:10.1055/s-2007-972214

Experimental and Clinical Endocrinology & Diabetes, Inhaltsverzeichnis

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

Abstract

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 (GIPR^dn) were established. While GIPR^-/- mice show only relatively mild changes in glucose homeostasis, GIPR^dn 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 GIPR^dn under the control of the rat Ins2 promoter (RIP). RIP-GIPR^dn 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-GIPR^dn 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-GIPR^dn transgenic pigs (n=5) than in their non-transgenic littermate controls (n=5). These findings demonstrate that expression of a GIPR^dn, 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-GIPR^dn transgenic pigs is disturbed like in the mouse model.

This study was supported by the DFG (GRK1029).