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Vertebrate reproductive science and technology
RESEARCH ARTICLE

4 IMPAIRED INCRETIN EFFECT IN TRANSGENIC PIGS EXPRESSING A DOMINANT NEGATIVE RECEPTOR FOR GLUCOSE-DEPENDENT INSULINOTROPIC POLYPEPTIDE IN THE PANCREATIC ISLETS

S. Renner, B. Keßler, N. Herbach, D. C. von Waldthausen, R. Wanke, A. Hofmann, A. Pfeifer and E. Wolf

Reproduction, Fertility and Development 20(1) 82 - 82
Published: 12 December 2007

Abstract

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted by specific cell types in the intestine and are responsible for the so-called incretin effect, the phenomenon that an oral glucose load elicits a higher insulin response than does an intravenous glucose load. In patients with type 2 diabetes mellitus the overall incretin effect is reduced. This fact is mostly attributed to a lowered insulinotropic effect of GIP, while the effect of GLP-1 is 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 display a distinct diabetic phenotype due to disturbed development of the endocrine pancreas (Herbach et al. 2005 Regul. Pept. 125, 103–117). To further clarify the underlying mechanisms, we used a novel, highly efficient gene transfer technology based on lentiviral vectors (Hofmann et al. 2003 EMBO Rep. 4, 1054–1060; Hofmann et al. 2006 Mol. Ther. 13, 59–66) to generate transgenic pigs expressing a GIPRdn under the control of the rat Ins2 promoter (RIP). RIP-GIPRdn transgenic pigs develop normally and do not display diabetes mellitus up to at least one year of age. Weekly measured fasting blood glucose levels in transgenic animals did not show a significant difference compared to control pigs. The same was true for monthly determined fructosamine levels. However, RIP-GIPRdn transgenic pigs exhibited reduced insulin release and higher glucose levels than non-transgenic littermate controls in an oral glucose tolerance test. The area under the curve (AUC) for insulin was 49% smaller (P < 0.01) and 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, clinically relevant animal model for studying the roles of the GIP/GIPR system. Quantitative morphological studies of the pancreas are being performed to clarify whether GIPR function is essential for pancreatic islet development and maintenance.

https://doi.org/10.1071/RDv20n1Ab4

© CSIRO 2007

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