title: Permanent neonatal diabetes in INS(C94Y) 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 INS(C94Y) transgenic pigs. A line expressing high levels of INS(C94Y) 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, INS(C94Y) 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 INS(C94Y) 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 INS(C94Y) 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 INS(C94Y) transgenic pig an attractive model for insulin supplementation and islet transplantation trials, and for studying developmental consequences of maternal diabetes mellitus.
authors.affiliation: Chair for Molecular Animal Breeding and Biotechnology, Ludwig Maximilian University Munich, Munich, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Renner
authors.forename: Christina
authors.initials: C
authors.lastname: Braun-Reichhart
authors.forename: Andreas
authors.initials: A
authors.lastname: Blutke
authors.forename: Nadja
authors.initials: N
authors.lastname: Herbach
authors.forename: Daniela
authors.initials: D
authors.lastname: Emrich
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Streckel
authors.forename: Annegret
authors.initials: A
authors.lastname: Wünsch
authors.forename: Barbara
authors.initials: B
authors.lastname: Kessler
authors.forename: Mayuko
authors.initials: M
authors.lastname: Kurome
authors.forename: Andrea
authors.initials: A
authors.lastname: Bähr
authors.forename: Nikolai
authors.initials: N
authors.lastname: Klymiuk
authors.forename: Stefan
authors.initials: S
authors.lastname: Krebs
authors.forename: Oliver
authors.initials: O
authors.lastname: Puk
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagashima
authors.forename: Jochen
authors.initials: J
authors.lastname: Graw
authors.forename: Helmut
authors.initials: H
authors.lastname: Blum
authors.forename: Ruediger
authors.initials: R
authors.lastname: Wanke
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D030801:Animals, Genetically Modified; D002386:Cataract / Q000150:complications / Q000473:pathology / Q000503:physiopathology; D048909:Diabetes Complications / Q000473:pathology* / Q000503:physiopathology; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000473:pathology / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism / Q000648:ultrastructure; D005786:Gene Expression Regulation; D006943:Hyperglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000648:ultrastructure; D009154:Mutation; D012333:RNA, Messenger / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism / Q000648:ultrastructure; D012720:Severity of Illness Index; D034421:Sus scrofa
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D012333:RNA, Messenger