A decade of experience with genetically tailored pig models for diabetes and metabolic research

Abstract

The global prevalence of diabetes mellitus and other metabolic diseases is rapidly increasing. Animal models play pivotal roles in unravelling disease mechanisms and developing and testing therapeutic strategies. Rodents are the most widely used animal models but may have limitations in their resemblance to human disease mechanisms and phenotypes. Findings in rodent models are consequently often difficult to extrapolate to human clinical trials. To overcome this 'translational gap', we and other groups are developing porcine disease models. Pigs share many anatomical and physiological traits with humans and thus hold great promise as translational animal models. Importantly, the toolbox for genetic engineering of pigs is rapidly expanding. Human disease mechanisms and targets can therefore be reproduced in pigs on a molecular level, resulting in precise and predictive porcine (PPP) models. In this short review, we summarize our work on the development of genetically (pre)diabetic pig models and how they have been used to study disease mechanisms and test therapeutic strategies. This includes the generation of reporter pigs for studying beta-cell maturation and physiology. Furthermore, genetically engineered pigs are promising donors of pancreatic islets for xenotransplantation. In summary, genetically tailored pig models have become an important link in the chain of translational diabetes and metabolic research.

The genome of the naturally evolved obesity-prone Ossabaw miniature pig

“…This makes the Ossabaw pig genome highly interesting in the search for molecular clues to predisposition to obesity and its comorbidities, including the obesity-associated increased risk of adverse outcomes during viral respiratory disease such as influenza and COVID-19 ( Heegaard et al., 2020 ; Popkin et al., 2020 ). The high quality Ossabaw pig genome presented here adds a highly human relevant obesity prone genome to the porcine genetic engineering toolbox increasingly used for diabetes and metabolic research ( Zettler et al., 2020 ). This allows new, relevant gene targets to be defined and provides precise information for designing genetic modifications for probing gene functions.…”

“…In this respect, the pig has emerged as highly promising ( Bellinger et al., 2006 ; Kleinert et al., 2018 ; Spurlock and Gabler, 2008 ; Zhang and Lerman, 2016 ). Generally for complex and systemic diseases, pigs are superior to rodent models, as they are much more similar to humans with respect to e.g., the cardiovascular system, inflammation phenotypes and mechanisms, and organ sizes ( Zettler et al., 2020 ). Moreover, certain types of pigs have a phenomenal propensity to obesity and this is especially the case for the Ossabaw pig, which is an outstanding human translatable obesity model ( Sturek et al., 2020 ).…”

Generation of a genetically modified pig model with CREBRFR457Q variant

“…Therefore, currently reported orthologous mouse CREBRF R458Q variant gene knock‐in mouse models do not effectively mimic these phenotypes. Compared with those of rodents, the anatomy, physiology, organ size, and life expectancy of pigs are more similar to those of humans 29,30 . The circadian rhythm (diurnal), eating behavior (discontinuously during the day), fat composition and deposition, gastrointestinal structure, islet structure, beta cell mass, insulin, and endocrine cell type proportion of pigs were similar to those of humans, 31‐39 indicating that pigs may be more suitable animal models for studying the relationship between obesity and T2D among different genotypes 40 …”

Developmental Effects of (Pre-)Gestational Diabetes on Offspring: Systematic Screening Using Omics Approaches

“…Non-human primate models have been used to study the developmental programming of diabetes and obesity [ 33 ]. Pigs are also attractive animal models due to their similarities with humans in anatomy and metabolism [ 34 ]. For diabetes, specific characteristics are particularly relevant (e.g., size and distribution of β cells, similarity in insulin structure) that make the pig a valuable model for human glucose metabolism [ 35 , 36 ].…”