Glucose intolerance and reduced proliferation of pancreatic beta-cells in transgenic pigs with impaired glucose-dependent insulinotropic polypeptide function.
Glucose intolerance and reduced proliferation of pancreatic beta-cells in transgenic pigs with impaired glucose-dependent insulinotropic polypeptide function.
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作者：
Renner S;Fehlings C;Herbach N;Hofmann A;von Waldthausen DC;Kessler B;Ulrichs K;Chodnevskaja I;Moskalenko V;Amselgruber W;Göke B;Pfeifer A;Wanke R;Wolf E
肠促胰岛素葡萄糖依赖性促胰岛素多肽（GIP）的促胰岛素作用在2型糖尿病中受损，而胰高血糖素样肽-1（GLP-1）的作用得以保留。为了评估受损的GIP功能在葡萄糖稳态和内分泌胰腺的发育中的作用，在大型动物模型中，我们产生了在胰岛中表达显性阴性GIP受体（GIPRdn）的转基因猪。使用慢病毒转基因产生GIPRdn转基因猪。对不同内分泌胰岛细胞群进行代谢试验和定量体视学分析，并对β细胞增殖和凋亡进行定量，以表征这种新型动物模型。由于胰岛素分泌延迟，11周龄的GIPRdn转基因猪表现出显著降低的口服葡萄糖耐量，而静脉内葡萄糖耐量和胰腺β细胞质量与对照组没有差异。GIP的促胰岛素作用显著降低，而响应GLP-1受体激动剂exendin-4的胰岛素分泌在GIPRdn转基因猪中与对照猪相比增强。随着年龄的增长，GIPRdn转基因猪的葡萄糖控制恶化，如由于胰岛素分泌受损导致的口服和静脉内葡萄糖耐量降低所示。重要的是，与年龄匹配的对照组相比，11周龄GIPRdn转基因猪的β细胞增殖减少了60%，导致5月龄和1至1.4岁转基因猪的β细胞质量分别减少了35%和58%。第一个肠降血糖素功能受损的大型动物模型证明了GIP对胰岛素分泌、β细胞增殖和β细胞群的生理性扩增的重要作用。
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 (GIPRdn) in pancreatic islets. GIPRdn 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. Eleven-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. The 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.
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