Effect of a “Metabolic Challenge” of feeding a low-carbohydrate diet on insulin sensitivity in the GIPRdn transgenic pig model for Diabetes mellitus

糖尿病及其前驱代谢综合征是一种发病率极高且具有社会经济相关性的代谢性疾病。我们的目标是通过低碳水化合物，高脂肪（LCHF）饮食挑战野生型和GIPRdn转基因猪，建立人类2型糖尿病（Dm2）的转化模型。由于解剖、生理和代谢方面的相似性，猪已被确立为翻译研究的优秀模式物种。基因修饰菌株，如GIPRdn转基因猪，表达显性阴性的GIP（不依赖葡萄糖的胰岛素多肽）受体，在模拟人类Dm2的发病机制方面是有价值的，这在猪身上并不自然发生。与对照动物相比，转基因GIPRdn猪出现代谢综合征，葡萄糖耐量降低，胰岛素分泌减少，β细胞质量降低。我们项目的目的是通过营养代谢挑战诱导转化为Dm2。我们预计，LCHF饮食将诱导野生型猪酮症和胰岛素抵抗，更明显的是，在giprdn转基因猪中。在LCHF挑战后，猪将被切换到含有碳水化合物的对照日粮。预计这将导致糖尿病代谢状态伴有高血糖。通过密切监测这一转变期间和之后的几周，我们的目标是发现这一糖尿病期是持续的还是短暂的——这取决于由酮症和内质网应激（ER应激）引起的胰腺β细胞凋亡形式的损伤是否是永久性的。该项目的总体目标是通过对野生型和GIPRdn转基因猪进行营养代谢挑战，从而产生胰岛素抵抗并表现出Dm2，从而产生并表征人类Dm2的转化模型。这将是一项重大成就，使我们能够进一步了解代谢综合征和dm2患者的发病机制、长期并发症的发展以及预防和治疗干预措施。代谢组学生物标志物作为早期诊断工具具有很高的潜力。

Diabetes and its precursor, the Metabolic Syndrome, are metabolicdiseases of exceptionally high prevalence and socioeconomicrelevance. We aim to create a translational model for human diabetesmellitus type 2 (Dm2) by challenging wild-type and GIPRdn transgenicpigs with a low-carbohydrate, high fat (LCHF) diet. Pigs have beenestablished to be an excellent model species for translationalresearch because of anatomic, physiologic and metabolic similarities.Genetically modified strains such as the GIPRdn transgenic pig,which expresses a dominant-negative GIP (glucose-independentinsulinotropic polypeptide) receptor, are valuable in mimicking thepathogenesis of human Dm2, which does not naturally occur in pigs.GIPRdn transgenic pigs develop the Metabolic Syndrome withreduced glucose tolerance, reduced insulin secretion and a lowerbeta-cell mass than control animals. The aim of our project is toinduce the conversion into Dm2 by the nutritive Metabolic Challenge.We expect that the LCHF diet will induce ketosis and insulinresistance in the wild type and, more pronounced, in the GIPRdntransgenic pigs. After the LCHF challenge, the pigs will be switched toa control diet containing carbohydrates. This is expected to cause adiabetic metabolic status with hyperglycaemia. By close monitoringduring this transition and the weeks afterwards, we aim to find outwhether this diabetic period is persistent or transient - depending onwhether the damage in form of pancreatic beta-cell apoptosis causedby ketosis and endoplasmic reticulum stress (ER stress) ispermanent. The overall aim of the project is to generate andcharacterise a translational model for human Dm2 by putting wild-typeand GIPRdn transgenic pigs through a nutritive Metabolic Challenge,resulting in insulin resistance and manifest Dm2. This woud be amajor accomplishment, enabling further insights into pathogenesis,development of long-term complications and preventive as well astherapeutic interventions for patients with the metabolic syndrome andDm2. Metabolomic biomarkers hold a high potential as early-stage diagnostic tools.