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葡萄糖耐量受损和胰腺β细胞增殖减少的转基因猪，其葡萄糖依赖性胰岛素分泌多肽功能受损。

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

机构信息

Chair for Molecular Animal Breeding and Biotechnology and Laboratory for Functional Genome Analysis, Gene Center, Ludwig Maximilians University (LMU) Munich, Munich, Germany.

出版信息

Diabetes. 2010 May;59(5):1228-38. doi: 10.2337/db09-0519. Epub 2010 Feb 25.

DOI:10.2337/db09-0519
PMID:20185813
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2857903/
Abstract

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(dn)) in pancreatic islets.

RESEARCH DESIGN AND METHODS

GIPR(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(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(dn) transgenic versus control pigs. With increasing age, glucose control deteriorated in GIPR(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(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.

摘要

目的

在 2 型糖尿病中，肠促胰岛素葡萄糖依赖性胰岛素释放多肽（GIP）的促胰岛素作用受损，而胰高血糖素样肽-1（GLP-1）的作用则得以保留。为了评估在大型动物模型中受损的 GIP 功能对葡萄糖稳态和内分泌胰腺发育的作用，我们生成了在胰岛中表达显性负性 GIP 受体（GIPR(dn)）的转基因猪。

研究设计和方法

使用慢病毒转基因生成 GIPR(dn)转基因猪。进行代谢测试和不同内分泌胰岛细胞群体的定量体视学分析，并定量分析β细胞增殖和凋亡，以表征这种新型动物模型。

结果

11 周龄的 GIPR(dn)转基因猪表现出明显的口服葡萄糖耐量受损，原因是胰岛素分泌延迟，而静脉葡萄糖耐量和胰腺β细胞质量与对照相比没有差异。GIP 的促胰岛素作用显著降低，而 GIPR(dn)转基因猪对 GLP-1 受体激动剂 exendin-4 的胰岛素分泌反应增强。随着年龄的增长，GIPR(dn)转基因猪的葡萄糖控制恶化，表现为由于胰岛素分泌受损导致口服和静脉葡萄糖耐量降低。重要的是，11 周龄的 GIPR(dn)转基因猪的β细胞增殖减少了 60%，导致 5 月龄和 1 至 1.4 岁的转基因猪的β细胞质量分别减少了 35%和 58%，与年龄匹配的对照相比。

结论

第一个具有受损肠促胰岛素功能的大型动物模型表明 GIP 对于胰岛素分泌、β 细胞增殖和β 细胞质量的生理扩张具有重要作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12a2/2857903/afa2ca3d6fb2/zdb0051061170007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12a2/2857903/ce6087070473/zdb0051061170001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12a2/2857903/6ea58d747a88/zdb0051061170002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12a2/2857903/d651443f177d/zdb0051061170003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12a2/2857903/57eb4c270ded/zdb0051061170004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12a2/2857903/7489dd2474ba/zdb0051061170005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12a2/2857903/0548de053275/zdb0051061170006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12a2/2857903/afa2ca3d6fb2/zdb0051061170007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12a2/2857903/ce6087070473/zdb0051061170001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12a2/2857903/6ea58d747a88/zdb0051061170002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12a2/2857903/d651443f177d/zdb0051061170003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12a2/2857903/57eb4c270ded/zdb0051061170004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12a2/2857903/7489dd2474ba/zdb0051061170005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12a2/2857903/0548de053275/zdb0051061170006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/12a2/2857903/afa2ca3d6fb2/zdb0051061170007.jpg

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