title: Diabetic phenotype of transgenic pigs introduced by dominant-negative mutant hepatocyte nuclear factor 1α.
abstract: OBJECTIVE
  The present study aimed to identify the characteristics of genetically modified pigs carrying a mutant human gene as a research model for diabetes and its complications.
  
  
  METHODS
  We developed a transgenic cloned pig (founder, male) carrying a mutant gene, i.e., human HNF-1α (P291fsinsC), which is responsible for maturity-onset diabetes of the young type 3. Transgenic progeny obtained via the artificial insemination of wild type (WT) sows with the cryopreserved sperm derived from the founder pig was pathologically examined.
  
  
  RESULTS
  The transgenic progeny maintained a high blood glucose level (>200mg/dL). Additionally, the oral glucose tolerance test results showed that the recovery of blood glucose levels in the transgenic progeny was significantly delayed compared with that in the WT semi-siblings. Hypoplasia of the islets of Langerhans was confirmed by the histopathological image of the pancreas, based on the hyperglycemia noted in the progeny being ascribed to decreased insulin secretion. Retinal hemorrhage and cotton-wool spots, i.e., findings consistent with non-proliferative diabetic retinopathy, were detected, and these progressed over time. The histopathological image of the renal glomeruli showed a nodular lesion that is characteristic of diabetic nephropathy in humans.
  
  
  CONCLUSIONS
  These data demonstrated that the genetically modified pig that we developed is a promising model for research on diabetes and its complications.
authors.affiliation: Meiji University International Institute for Bio-Resource Research, 1-1-1 Higashimita, Tama-ku, Kawasaki 214-8571, Japan; Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki 214-8571, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Umeyama
authors.affiliation: Department of Ophthalmology, Nihon University School of Medicine, 30-1 Oyaguchi, Kamicho, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Nakajima
authors.affiliation: Division of Nephrology and Hypertension, Department of Internal Medicine, The Jikei University School of Medicine, 3-25-8 Nishishinbashi, Minato-ku, Tokyo 105-8461, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokoo
authors.affiliation: Meiji University International Institute for Bio-Resource Research, 1-1-1 Higashimita, Tama-ku, Kawasaki 214-8571, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Nagaya
authors.affiliation: Meiji University International Institute for Bio-Resource Research, 1-1-1 Higashimita, Tama-ku, Kawasaki 214-8571, Japan; Laboratory of Developmental Engineering, Department of Life Sciences, School of Agriculture, Meiji University, 1-1-1 Higashimita, Tama-ku, Kawasaki 214-8571, Japan. Electronic address: hnagas@meiji.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagashima
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001786:Blood Glucose / Q000032:analysis; D019976:Cloning, Organism; D015925:Cryopreservation / Q000662:veterinary; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology; D003930:Diabetic Retinopathy / Q000473:pathology / Q000503:physiopathology; D018450:Disease Progression; D005799:Genes, Dominant; D005951:Glucose Tolerance Test / Q000662:veterinary; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007315:Insemination, Artificial / Q000662:veterinary; D007515:Islets of Langerhans / Q000473:pathology*; D007678:Kidney Glomerulus / Q000473:pathology / Q000503:physiopathology; D016254:Mutagenesis, Insertional; D009154:Mutation; D051437:Renal Insufficiency / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D012166:Retinal Hemorrhage / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D012662:Semen Preservation / Q000662:veterinary; D012720:Severity of Illness Index; D034421:Sus scrofa / Q000235:genetics*
chemical_list: D001786:Blood Glucose; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha
keywords: Diabetic nephropathy; Diabetic retinopathy; Dominant-negative mutant; HNF1α (hepatocyte nuclear factor 1α); MODY3 (maturity-onset diabetes of the young type 3); Transgenic pig