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

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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.