Permanent Neonatal Diabetes in INSC94Y Transgenic Pigs
- Simone Renner1,
- Christina Braun-Reichhart1,
- Andreas Blutke3,
- Nadja Herbach3,
- Daniela Emrich3,
- Elisabeth Streckel1,
- Annegret Wünsch1,
- Barbara Kessler1,
- Mayuko Kurome1,5,
- Andrea Bähr1,
- Nikolai Klymiuk1,
- Stefan Krebs2,
- Oliver Puk4,
- Hiroshi Nagashima5,
- Jochen Graw4,
- Helmut Blum2,
- Ruediger Wanke3 and
- Eckhard Wolf1,2,5
- 1Chair for Molecular Animal Breeding and Biotechnology, Ludwig Maximilian University Munich, Munich, Germany
- 2Laboratory for Functional Genome Analysis, Gene Center, Ludwig Maximilian University Munich, Munich, Germany
- 3Institute of Veterinary Pathology at the Centre for Clinical Veterinary Medicine, Ludwig Maximilian University Munich, Munich, Germany
- 4Helmholtz Center Munich-German Research Center for Environmental Health, Institute of Developmental Genetics, Neuherberg, Germany
- 5Meiji University, International Institute for Bio-Resource Research, Kawasaki, Japan
- Corresponding author: Eckhard Wolf,
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.
- Received August 7, 2012.
- Accepted November 7, 2012.
- © 2013 by the American Diabetes Association.
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