title: Transgenic expression of human INS gene in Ins1/Ins2 double knockout mice leads to insulin underproduction and diabetes in some male mice.
abstract: We have generated transgenic mouse lines expressing exclusively a human INS transgene on an Ins1/Ins2 double knockout (mIKO) background. The transgene expression was driven by either a 4000 bp or a 353 bp promoter. These transgenic lines, designated mIKO:INS4000 and mIKO:INS353, were viable and fertile. Determination of the amounts of insulin transcripts and total pancreatic insulin content revealed relative insulin underproduction in both lines, from birth to adulthood. Total pancreatic insulin stores in mIKO:INS4000 and mIKO:INS353 mice represented only about 50% and 27%, respectively, as compared to wild-type mice. Morphometric analysis of pancreas did not show any compensatory beta-cell hyperplasia. The majority of animals in both lines remained normoglycemic throughout their lives. Nevertheless, glucose tolerance tests revealed glucose intolerance in nearly half of mIKO:INS4000 male mice, likely due to impaired insulin secretion detected in those animals. In addition, a small fraction (2-4%) of male mice in both lines spontaneously developed diabetes with very distinct pathophysiological features. Diabetes was never seen in female animals. The diabetes developed by mIKO:INS353 mice was rapidly lethal, accompanied by a dramatic depletion of pancreatic insulin stores whereas the mIKO:INS4000 diabetic animals could live for several months. This suggests a possible link between the structure of the human INS gene promoter and the type of diabetes developed in these lines.
authors.affiliation: Department of Genetics and Development, Institut Cochin, INSERM U567, CNRS UMR 8104, Université René Descartes Paris 5, 24 rue du Faubourg Saint-Jacques, 75014 Paris, France.
authors.forename: Melis
authors.initials: M
authors.lastname: Karaca
authors.forename: Béatrice
authors.initials: B
authors.lastname: Durel
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Languille
authors.forename: Luciane
authors.initials: L
authors.lastname: Lamotte
authors.forename: Cécile
authors.initials: C
authors.lastname: Tourrel-Cuzin
authors.forename: Loïc
authors.initials: L
authors.lastname: Leroux
authors.forename: Gretta
authors.initials: G
authors.lastname: Abou Sleymane
authors.forename: Susan
authors.initials: S
authors.lastname: Saint-Just
authors.forename: Danielle
authors.initials: D
authors.lastname: Bucchini
authors.forename: Alain
authors.initials: A
authors.lastname: Ktorza
authors.forename: Rajiv L
authors.initials: RL
authors.lastname: Joshi
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001786:Blood Glucose / Q000032:analysis; D003920:Diabetes Mellitus / Q000097:blood / Q000235:genetics* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D018149:Glucose Intolerance / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000096:biosynthesis / Q000097:blood / Q000235:genetics*; D008297:Male; D051379:Mice; D010179:Pancreas / Q000473:pathology
chemical_list: D001786:Blood Glucose; C514817:Ins1 protein, mouse; D007328:Insulin