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

低碳水化合物饮食的“代谢挑战”对 GIPRdn 转基因猪糖尿病模型中胰岛素敏感性的影响

• 批准号: 442341976
• 负责人: Dr. Linda Böswald
• 金额: --
• 依托单位: Forschungsbereich Physiologische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/442341976?language=en
• 关键词: Effect; Metabolic; Challenge; feeding; low

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.

糖尿病及其前身代谢综合征是一种发病率极高且与社会经济相关的代谢性疾病。我们的目标是通过用低碳水化合物、高脂肪（LCHF）饮食挑战野生型和GIPRdn转基因猪来建立人2型糖尿病（Dm 2）的转化模型。猪由于解剖、生理和代谢的相似性，已被确立为预防研究的优良模式物种。（葡萄糖非依赖性促胰岛素多肽）受体，在模拟人Dm 2的发病机制中是有价值的，与对照动物相比，GIPRdn转基因猪发展出葡萄糖耐量降低、胰岛素分泌减少和β细胞质量降低的代谢综合征。我们的项目的目的是通过营养代谢挑战诱导转化为Dm 2。我们预计LCHF饮食将在野生型猪中诱导酮症和胰岛素抵抗，更明显的是，在GIPRdn转基因猪中。LCHF激发后，将猪转换为含碳水化合物的对照饮食。预计这会导致代谢紊乱伴高血糖。通过在这个过渡期和之后的几周内进行密切监测，我们的目标是发现这个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细胞凋亡形式的损害是否是永久性的。该项目的总体目标是通过将野生型和GIPRdn转基因猪通过营养代谢挑战，导致胰岛素抵抗和表现出Dm 2，来产生和验证人Dm 2的翻译模型。这将是一个重大成就，使进一步了解发病机制，长期并发症的发展和预防以及代谢综合征和Dm 2患者的治疗干预。代谢组学生物标志物作为早期诊断工具具有很高的潜力。