Hypoplasia of endocrine and exocrine pancreas in homozygous transgenic TGF-beta1.
We generated the homozygous transgenic mice with expression of the active form of TGF-beta1 by the glucagon promoter (homozygous NOD-TGF-beta1). The homozygous NOD-TGF-beta1 showed severe diabetes in 84.6%, impaired glucose tolerance, and low serum insulin levels. The final size of endocrine and whole pancreas decreased, respectively, to 6 and 34%, compared to wild-type mice. The homozygous N(2) backcross to C57BL/6 (B6-TGF-beta1) showed no diabetes, but impaired glucose tolerance and low serum insulin levels. In homozygous NOD-TGF-beta1, the expression of p15(INK4b) was induced by 3.4-fold in pancreatic islets than that in wild-type mice. Based on these, we conclude first that excessive paracrine TGF-beta1 signaling in islets results in endocrine and exocrine pancreatic hypoplasia, second that TGF-beta1decrease the final size of endocrine and exocrine pancreas presumably through regulating cell cycle via p15(INK4b) at least in endocrine pancreas, and third that hypoplastic action of TGF-beta1 of pancreatic islets is independent of the genetic background.
Moritani
Maki
M
Institute for Genome Research, Division of Genetic Information, The University of Tokushima, Tokushima 770-8503, Japan.
Yamasaki
Seiji
S
Kagami
Mitsuhiro
M
Suzuki
Takao
T
Yamaoka
Takashi
T
Sano
Toshiaki
T
Hata
Jun-Ichi
J
Itakura
Mitsuo
M
D000818:Animals; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D003433:Crosses, Genetic; D050762:Cyclin-Dependent Kinase Inhibitor p15; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology; D005260:Female; D005934:Glucagon / Q000235:genetics; D005951:Glucose Tolerance Test; D006720:Homozygote; D006943:Hyperglycemia / Q000209:etiology; D007328:Insulin / Q000097:blood; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D046790:Pancreas, Exocrine / Q000378:metabolism / Q000473:pathology*; D011401:Promoter Regions, Genetic; D013552:Swine / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins / Q000378:metabolism
C493968:Cdkn2b protein, mouse; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D007328:Insulin; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; D005934:Glucagon