Details

Autor(en) / Beteiligte

• Renner, Simone
• Fehlings, Christiane
• Herbach, Nadja
• Hofmann, Andreas
• von Waldthausen, Dagmar C
• Kessler, Barbara
• Ulrichs, Karin
• Chodnevskaja, Irina
• Moskalenko, Vasiliy
• Amselgruber, Werner
• Goke, Burkhard
• Pfeifer, Alexander
• Wanke, Rudiger
• Wolf, Eckhard

Titel

Glucose intolerance and reduced proliferation of pancreatic [beta]-cells in transgenic pigs with impaired glucose-dependent insulinotropic polypeptide function

Ist Teil von

• Diabetes (New York, N.Y.), 2010-05, Vol.59 (5), p.1228

Ort / Verlag

New York: American Diabetes Association

Erscheinungsjahr

2010

Link zum Volltext

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• OBJECTIVE -- The insulinotropic action of the incretin glucose-dependent insulinotropic polypeptide (GIP) is impaired in type 2 diabetes, while the effect of glucagon-like peptide-1 (GLP-1) is preserved. To evaluate the role of impaired GIP function in glucose homeostasis and development of the endocrine pancreas in a large animal model, we generated transgenic pigs expressing a dominant-negative GIP receptor ([GIPR.sup.dn]) in pancreatic islets. RESEARCH DESIGN AND METHODS--[GIPR.sup.dn] transgenic pigs were generated using lentiviral transgenesis. Metabolic tests and quantitative stereological analyses of the different endocrine islet cell populations were performed, and [beta]-cell proliferation and apoptosis were quantified to characterize this novel animal model. RESULTS--Eleven-week-old [GIPR.sup.dn] transgenic pigs exhibited significantly reduced oral glucose tolerance due to delayed insulin secretion, whereas intravenous glucose tolerance and pancreatic [beta]-cell mass were not different from controls. The insulinotropic effect of GIP was significantly reduced, whereas insulin secretion in response to the GLP-1 receptor agonist exendin-4 was enhanced in [GIPR.sup.dn] transgenic versus control pigs. With increasing age, glucose control deteriorated in [GIPR.sup.dn] transgenic pigs, as shown by reduced oral and intravenous glucose tolerance due to impaired insulin secretion. Importantly, [beta]-cell proliferation was reduced by 60% in 11-week-old [GIPR.sup.dn] transgenic pigs, leading to a reduction of [beta]-cell mass by 35% and 58% in 5-month-old and 1- to 1.4-year-old transgenic pigs compared with age-matched controls, respectively. CONCLUSIONS--The first large animal model with impaired incretin function demonstrates an essential role of GIP for insulin secretion, proliferation of [beta]-cells, and physiological expansion of [beta]-cell mass. Diabetes 59:1228-1238, 2010