CSIRO Publishing blank image blank image blank image blank imageBooksblank image blank image blank image blank imageJournalsblank image blank image blank image blank imageAbout Usblank image blank image blank image blank imageShopping Cartblank image blank image blank image You are here: Journals > Reproduction, Fertility and Development   
Reproduction, Fertility and Development
  Vertebrate reproductive science and technology
blank image Search
blank image blank image
blank image
  Advanced Search

Journal Home
About the Journal
Editorial Structure
Online Early
Current Issue
Just Accepted
All Issues
Special Issues
Research Fronts
Virtual Issues
Sample Issue
For Authors
General Information
Submit Article
Author Instructions
Open Access
Awards and Prizes
For Referees
Referee Guidelines
Review an Article
Annual Referee Index
For Subscribers
Subscription Prices
Customer Service
Print Publication Dates
Library Recommendation

blue arrow e-Alerts
blank image
Subscribe to our email Early Alert or RSS feeds for the latest journal papers.

red arrow Connect with us
blank image
facebook twitter logo LinkedIn

red arrow Connect with SRB
blank image
facebook TwitterIcon

Affiliated Societies

RFD is the official journal of the International Embryo Transfer Society and the Society for Reproductive Biology.

Article << Previous     |     Next >>   Contents Vol 22(1)


C. Fehlings A, S. Renner A, N. Herbach B, B. Kessler A, A. Hoffmann C, R. Wanke B, B. Goeke D, A. Pfeifer C and E. Wolf A

A Chair for Molecular Animal Breeding and Biotechnology, Gene Center, LMU Munich, Munich, Germany;
B Institute of Veterinary Pathology, LMU Munich, Munich, Germany;
C Institute of Pharmacology and Toxicology, University of Bonn, Bonn, Germany;
D Medical Clinic II, Klinikum Grosshadern, LMU Munich, Munich, Germany

Export Citation


The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted in response to nutrients and enhance glucose-induced insulin secretion. The insulinotropic action of GIP is impaired in type 2 diabetes (T2D) whereas that of GLP-1 is preserved. To evaluate the role of an impaired GIP function in the pathogenesis of T2D in a large animal model, we generated transgenic pigs expressing a dominant-negative GIP receptor (GIPRdn) in the pancreatic islets. GIPRdn transgenic pigs were generated using lentiviral transgenesis. Metabolic tests and quantitative stereological analyses of the pancreas were performed in 3 different age groups to investigate the effects of an impaired insulinotropic action of GIP on glucose metabolism and pancreas morphology. The insulinotropic action of GIP was significantly reduced, whereas insulin secretion in response to the GLP-1 receptor agonist exendin-4 was enhanced in 11-week-old GIPRdn transgenic pigs compared with control pigs. Eleven-week-old GIPRdn transgenic pigs (n = 5) exhibited significantly reduced oral glucose tolerance (P < 0.05) with a delay in insulin secretion compared with controls (n = 5). The area under the insulin curve (AUC) during the first 45 min following glucose load was 31% smaller (P < 0.05) in transgenic pigs compared with controls. The total insulin secretion capacity was not different between the 2 groups indicating that GIPRdn expression initially only interferes with the incretin effect. This was supported by the fact that intravenous glucose tolerance and insulin secretion in transgenic pigs were not different from controls. Five-month-old GIPRdn transgenic pigs revealed markedly reduced insulin secretion in response to oral glucose challenge (P < 0.01), resulting in significantly elevated glucose levels (P < 0.05). Also, intravenous glucose tolerance and insulin secretion were diminished in 11-month-old transgenic pigs. To determine the reason for the alterations in glucose metabolism, quantitative-stereological analyses of the pancreas were performed. In 11-week-old pigs, transgenic and control groups showed similar β-cell mass (n = 5 in each group). However, pancreatic β-cell mass was reduced by almost 40% (P < 0.05) in 5-month-old pigs and by 60% (P < 0.01) in adult (1 to 1.4 years) GIPRdn transgenic pigs compared with controls. To investigate the reason for the progressive reduction of pancreatic β-cell mass in GIPRdn transgenic pigs, β-cell proliferation rate was determined performing a double-immunohistochemistry for insulin and the proliferation marker Ki67. Eleven-week-old GIPRdn transgenic pigs showed significantly fewer Ki67-positive cell nuclei compared with controls (P < 0.05). In conclusion, GIPRdn transgenic pigs exhibit a comparable situation to T2D, such as impaired insulinotropic action of GIP, disturbed oral and intravenous glucose tolerance, and progressive reduction of β-cell mass. These alterations are at least partly attributable to diminished proliferation of β-cells.

Grant support: Deutsche Forschungsgemeinschaft (GRK 1029), Bayerische Forschungsstiftung (492/02).

Reproduction, Fertility and Development 22(5305) 369–369   http://dx.doi.org/10.1071/RDv22n1Ab424
Published online: 08 December 2009

Top  Email this page

Legal & Privacy | Contact Us | Help


© CSIRO 1996-2016