Mild maternal hyperglycemia in <i>INS</i>C93S transgenic pigs causes impaired glucose tolerance and metabolic alterations in neonatal offspring

Martins, Ana Sofia; Streckel, Elisabeth; Braun-Reichhart, Christina; Backman, Mattias; Prehn, Cornelia; Klymiuk, Nikolai; Bähr, Andrea; Blutke, Andreas; Landbrecht-Schessl, Christina; Wünsch, Annegret; Keßler, Barbara; Kurome, Mayuko; Hinrichs, Arne; Koopmans, S.J.; Krebs, Stefan; Kemter, Elisabeth; Rathkolb, Birgit; Nagashima, Hiroshi; Blum, Helmut; Ritzmann, Mathias; Wanke, Rüdiger; Aigner, Bernhard; Adamski, Jerzy; Angelis, Martin Hrabé de; Wolf, Eckhard

doi:10.1242/dmm.039156

Cited by 12 publications

(12 citation statements)

References 43 publications

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“…INS C93S transgenic pigs showed impaired glucose tolerance due to reduced insulin secretion and mild fasting hyperglycemia. The milder phenotype of INS C93S vs. INS C94Y transgenic pigs is in line with lower expression of the mutant INS transgene (Renner et al, 2019). During pregnancy, insulin sensitivity decreased in both INS C93S transgenic and WT sows, but only the WT sows were able to compensate for the increased insulin demand with sufficiently increased insulin production to maintain normoglycemia.…”

Section: Ins C93s Transgenic Pigs Developing a Milder Diabetic Phenotypementioning

confidence: 88%

“…Compared to offspring from WT sows, neonatal WT offspring from INS C93S transgenic sows revealed impaired glucose tolerance and insulin resistance with females being more severely affected than males. In addition, distinct changes in amino acid and lipid metabolism were observed, indicating that even mild maternal hyperglycemia can have significant metabolic programming effects in neonatal offspring (Renner et al, 2019).…”

Section: Ins C93s Transgenic Pigs Developing a Milder Diabetic Phenotypementioning

confidence: 99%

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

Zettler

Kemter

Hinrichs³

et al. 2020

Anim. Reprod.

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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.

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Section: Ins C93s Transgenic Pigs Developing a Milder Diabetic Phenotypementioning

confidence: 88%

Section: Ins C93s Transgenic Pigs Developing a Milder Diabetic Phenotypementioning

confidence: 99%

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

Zettler

Kemter

Hinrichs³

et al. 2020

Anim. Reprod.

Self Cite

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“…2c), mild fasting hyperglycemia and hypoinsulinemia (Fig. 2d, e), reduced glucose tolerance and very subtle beta cell loss (Renner et al 2019). Ren et al 2017 GT gene transfer, SCNT somatic cell nuclear transfer, KO knockout, KI knockin, HFHC high-fat high-cholesterol, NHEJ non-homologous end-joining, HDR homology-directed repair, HR homologous recombination, TC total cholesterol, NIBS Nippon Institute for Biological Sciences Different lines of INS knockout pigs have been generated using the CRISPR/Cas9 system exhibiting absolute insulin deficiency due to bi-allelic nucleotide deletions or insertions (Cho et al 2018).…”

Section: Expression Of Mutant Insulin Transgenes/modifications Of the Insulin Genementioning

confidence: 94%

“…Two different pig models for permanent neonatal diabetes were established-transgenic pigs expressing the mutant insulin C94Y or C93S (Renner et al 2019) (Fig. 2a).…”

Section: Expression Of Mutant Insulin Transgenes/modifications Of the Insulin Genementioning

confidence: 99%

Porcine models for studying complications and organ crosstalk in diabetes mellitus

Renner¹,

Blutke

Clauß

et al. 2020

Cell Tissue Res

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The worldwide prevalence of diabetes mellitus and obesity is rapidly increasing not only in adults but also in children and adolescents. Diabetes is associated with macrovascular complications increasing the risk for cardiovascular disease and stroke, as well as microvascular complications leading to diabetic nephropathy, retinopathy and neuropathy. Animal models are essential for studying disease mechanisms and for developing and testing diagnostic procedures and therapeutic strategies. Rodent models are most widely used but have limitations in translational research. Porcine models have the potential to bridge the gap between basic studies and clinical trials in human patients. This article provides an overview of concepts for the development of porcine models for diabetes and obesity research, with a focus on genetically engineered models. Diabetes-associated ocular, cardiovascular and renal alterations observed in diabetic pig models are summarized and their similarities with complications in diabetic patients are discussed. Systematic multi-organ biobanking of porcine models of diabetes and obesity and molecular profiling of representative tissue samples on different levels, e.g., on the transcriptome, proteome, or metabolome level, is proposed as a strategy for discovering tissue-specific pathomechanisms and their molecular key drivers using systems biology tools. This is exemplified by a recent study providing multi-omics insights into functional changes of the liver in a transgenic pig model for insulin-deficient diabetes mellitus. Collectively, these approaches will provide a better understanding of organ crosstalk in diabetes mellitus and eventually reveal new molecular targets for the prevention, early diagnosis and treatment of diabetes mellitus and its associated complications.

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“…Several murine models of NF1 have already been developed; however, mice are too small for the relevant medical imaging systems to be used in detection and monitoring the progression of NF1's phenotypes [19][20][21]24 . Minipigs have proven to be successful models in a range of human diseases including Huntington's disease, ataxia-telangiectasia, cystic fibrosis, and cancer [25][26][27][28][29][30][31][32][33] . The similarities between the minipig and humans with regards to anatomy, physiology, and size allows them to be studied using the same imaging systems that are used clinically for human patients.…”

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confidence: 99%

Longitudinal phenotype development in a minipig model of neurofibromatosis type 1

Uthoff

Larson

Sato

et al. 2020

Sci Rep

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Neurofibromatosis type 1 (NF1) is a rare, autosomal dominant disease with variable clinical presentations. Large animal models are useful to help dissect molecular mechanisms, determine relevant biomarkers, and develop effective therapeutics. Here, we studied a NF1 minipig model (NF1 +/ex42del ) for the first 12 months of life to evaluate phenotype development, track disease progression, and provide a comparison to human subjects. Through systematic evaluation, we have shown that compared to littermate controls, the NF1 model develops phenotypic characteristics of human NF1: [1] café-au-lait macules, [2] axillary/inguinal freckling, [3] shortened stature, [4] tibial bone curvature, and [5] neurofibroma. At 4 months, full body computed tomography imaging detected significantly smaller long bones in NF1 +/ex42del minipigs compared to controls, indicative of shorter stature. We found quantitative evidence of tibial bowing in a subpopulation of NF1 minipigs. By 8 months, an NF1 +/ex42del boar developed a large diffuse shoulder neurofibroma, visualized on magnetic resonance imaging, which subsequently grew in size and depth as the animal aged up to 20 months. the NF1 +/ex42del minipig model progressively demonstrates signature attributes that parallel clinical manifestations seen in humans and provides a viable tool for future translational NF1 research.Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with nearly 100% penetrance and an incidence of approximately 1 in every 3,000 births worldwide 1 . The clinical manifestations of the disorder are highly variable, even among individuals with the same mutation in NF1 1,2 . The most common phenotypic presentations of NF1 include café-au-lait macules (CALMs), axillary and inguinal freckling, optic pathway gliomas, pilocytic astrocytoma, and the presence of neurofibromas and plexiform neurofibromas (PNs) that have the potential to develop into malignant peripheral nerve sheath tumors (MPNSTs) 1-3 . Some individuals with NF1 may exhibit learning disabilities, increased pain, short stature, or macrocephaly at birth 3,4 . Although uncommon, they may also be born with or develop tibial bowing and sphenoid wing dysplasia 4 . Those affected by NF1 are also at increased risk of developing a number of different cancers including glioblastoma, breast cancer, and leukemia 1 . Because of the heterogeneity, impact on quality of life, and significant morbidity associated with NF1, there is a considerable need for research into its underlying pathology and noninvasive monitoring of its progression.Systematic study of NF1 in human subjects is a major challenge as the variability in disease presentation between individuals makes it difficult to create an effective longitudinal cohort. Medical imaging is used in the NF1 population to detect and monitor disease phenotypes including optic-pathway glioma 5-7 , plexiform neurofibroma and MPNST, spinal neurofibroma, tibial bowing and scoliosis. Retrospectively collected imaging studies have assessed prevalence and NF1 findings i...

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Mild maternal hyperglycemia in INSC93S transgenic pigs causes impaired glucose tolerance and metabolic alterations in neonatal offspring

Cited by 12 publications

References 43 publications

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

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

Porcine models for studying complications and organ crosstalk in diabetes mellitus

Longitudinal phenotype development in a minipig model of neurofibromatosis type 1

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