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.
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).
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