Glucose Intolerance and Reduced Proliferation of Pancreatic β-Cells in Transgenic Pigs With Impaired Glucose-Dependent Insulinotropic Polypeptide Function

Abstract

OBJECTIVEThe 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 (GIPRdn) in pancreatic islets.RESEARCH DESIGN AND METHODSGIPRdn transgenic pigs were generated using lentiviral transgenesis. Metabolic tests and quantitative stereological analyses of the different endocrine islet cell populations were performed, and β-cell proliferation and apoptosis were quantified to characterize this novel animal model.RESULTSEleven-week-old GIPRdn transgenic pigs exhibited significantly reduced oral glucose tolerance due to delayed insulin secretion, whereas intravenous glucose tolerance and pancreatic β-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 GIPRdn transgenic versus control pigs. With increasing age, glucose control deteriorated in GIPRdn transgenic pigs, as shown by reduced oral and intravenous glucose tolerance due to impaired insulin secretion. Importantly, β-cell proliferation was reduced by 60% in 11-week-old GIPRdn transgenic pigs, leading to a reduction of β-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.CONCLUSIONSThe first large animal model with impaired incretin function demonstrates an essential role of GIP for insulin secretion, proliferation of β-cells, and physiological expansion of β-cell mass.

Chronic Reduction of GIP Secretion Alleviates Obesity and Insulin Resistance Under High-Fat Diet Conditions

“…Apart from its role in the inhibition of gastric acid secretion (4), GIP exhibits potent glucose-dependent insulinotropic action (5,6), and, therefore, it is classified as an incretin (3). In addition to its insulinotropic effect, in the absence of which glucose intolerance develops (7), GIP stimulates islet growth (8) and proliferation of b-cells (9), and reduces b-cell apoptosis (10,11). Studies of GIP receptor (GIPR) knock-out (GIPRKO) mice (7) describe GIP as an obesitypromoting factor in high-fat diet (HFD) conditions, and show that deletion of GIPR signaling causes resistance to obesity (12) but leads to osteoporosis (13), revealing an important role of GIP in bone metabolism.…”

Dual-Monoclonal, Sandwich Immunoassay Specific for Glucose-Dependent Insulinotropic Peptide1-42, the Active Form of the Incretin Hormone

“…Renner and coworkers created a transgenic pig with a dominant negative GIP receptor (GIPR) and demonstrated that this animal model showed a normal response to an IV glucose tolerance test, but an impaired response to an oral glucose tolerance test (27 ). These observations were particularly interesting in light of previous studies, suggesting that an impaired response to an oral glucose tolerance test (OGTT) is associated with increased risk of developing type 2 diabetes and increased cardiovascular events (28 ).…”

Tissue Sampling Guides for Porcine Biomedical Models

“…The respective protocols are designed to fit the demands of the industrial standards of the pharmaceutical industry and toxicologic pathology. They have been developed based on extensive experiences in pig toxicopathology, in pathomorphological characterization of numerous genetically modified pig models, and in porcine animal model biobanking (Abbott 2015;Aigner et al 2010;Kemter et al 2012;Klymiuk et al 2013;Klymiuk et al 2012a;Klymiuk et al 2012b;Klymiuk et al 2012c;Renner et al 2010Renner et al , 2012Renner et al , 2013Streckel et al 2015;Wuensch et al 2014). The proposed sampling protocols are intended as general guidelines but not as requirements for the sampling of tissues in any porcine model.…”