Permanent Neonatal Diabetes inINSC94Y Transgenic Pigs

Abstract

Mutations in the insulin (INS) gene may cause permanent neonatal diabetes mellitus (PNDM). Ins2 mutant mouse models provided important insights into the disease mechanisms of PNDM but have limitations for translational research. To establish a large animal model of PNDM, we generated INSC94Y transgenic pigs. A line expressing high levels of INSC94Y mRNA (70–86% of wild-type INS transcripts) exhibited elevated blood glucose soon after birth but unaltered β-cell mass at the age of 8 days. At 4.5 months, INSC94Y transgenic pigs exhibited 41% reduced body weight, 72% decreased β-cell mass (−53% relative to body weight), and 60% lower fasting insulin levels compared with littermate controls. β-cells of INSC94Y transgenic pigs showed a marked reduction of insulin secretory granules and severe dilation of the endoplasmic reticulum. Cataract development was already visible in 8-day-old INSC94Y transgenic pigs and became more severe with increasing age. Diabetes-associated pathological alterations of kidney and nervous tissue were not detected during the observation period of 1 year. The stable diabetic phenotype and its rescue by insulin treatment make the INSC94Y transgenic pig an attractive model for insulin supplementation and islet transplantation trials, and for studying developmental consequences of maternal diabetes mellitus.

Comparative aspects of rodent and nonrodent animal models for mechanistic and translational diabetes research

“…In contrast to pigs, non-invasive imaging techniques in rodents still have resolution limitations because of their small size and even ultrasonography requires anesthesia [38]. Moreover, non-invasive imaging approaches for the quantification of islet/beta-cell mass (reviewed in [39]) can be reliably tested in human-sized pig models, for example, reduced beta-cell mass [40,41] or diet-induced obesity [42], and subsequently be validated by quantitative stereological analyses of the pancreas [41]. The large blood volume of pigs (Table 1) enables the reliable performance of metabolic tests, for example, glucose/insulin tolerance tests and clamp studies, with frequent recovery of blood samples large enough to perform complex hormone and metabolite profiling in each sample.…”

39 Factors Influencing the Efficiency of Generating Genetically Engineered Pigs by Nuclear Transfer: Multi-Factorial Analysis of a Large Data Set

“…Genetically tailored pig models have already been developed to investigate cystic fibrosis [12], diabetes mellitus [13][14][15][16], and neurodegenerative diseases [17] (reviewed in [18]). Multiple lines of genetically modified pigs have also been generated for xenotransplantation (reviewed in [19]), most notably α1,3-galactosyl transferase knockout pigs lacking α1,3-Gal, the major xeno-antigen [5].…”

Somatic Cell Nuclear Transfer and the Creation of Transgenic Large Animal Models

“…Most of these piglets did not survive past weaning, with only four piglets living up to 1-6 months of age (Umeyama et al 2009). Renner and colleagues have also been developing models of insulin-independent diabetes (Renner et al 2010) as well as permanent neonatal diabetes (Renner et al 2013). A suitable model for type II diabetes remains to be developed and the ongoing effort into the creation of models for this particular disease will be indispensable due to the increasing incidence of this disorder worldwide.…”