Characterization of the molecular mechanisms involved in the increased insulin secretion in rats with acute liver failure.
To investigate the mechanism of hyperinsulinaemia in rats with acute liver failure induced by the administration of d-galactosamine (GalN), we focused on the role of polyprimidine tract-binding protein (PTB) in islet insulin synthesis. Recent reports indicate that PTB binds and stabilizes mRNA encoding insulin and insulin secretory granule proteins, including islet cell autoantigen 512 (ICA512), prohormone convertase 1/3 (PC1/3), and PC2. In the present study, glucose-stimulated insulin secretion was significantly increased in GalN-treated rats compared to controls. Levels of mRNA encoding insulin 1, ICA512, and PC1/3 were increased in the pancreatic islets of GalN-treated rats. This mRNA level elevation was not prevented by pretreatment with actinomycin D. When the PTB-binding site in insulin 1 mRNA was incubated with the islet cytosolic fraction, the RNA-protein complex level was increased in the cytosolic fraction obtained from GalN-treated rats compared to the level in control rats. The cytosolic fraction obtained from pancreatic islets obtained from GalN-treated rats had an increased PTB level compared to the levels obtained from the pancreatic islets of control rats. These findings suggest that, in rats with acute liver failure, cytosolic PTB binds and stabilizes mRNA encoding insulin and its secretory granule proteins.
Kuwahata
Masashi
M
Department of Molecular Nutrition, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan. kuwahata@nutr.med.tokushima-u.ac.jp
Tomoe
Yuka
Y
Harada
Nagakatsu
N
Amano
Saki
S
Segawa
Hiroko
H
Tatsumi
Sawako
S
Ito
Mikiko
M
Oka
Tatsuzo
T
Miyamoto
Ken-ichi
K
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001786:Blood Glucose; D004195:Disease Models, Animal; D005688:Galactosamine; D006946:Hyperinsulinism / Q000097:blood / Q000139:chemically induced / Q000378:metabolism*; D007328:Insulin / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D009929:Organ Size / Q000187:drug effects; D038941:Polypyrimidine Tract-Binding Protein / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation
D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; D038941:Polypyrimidine Tract-Binding Protein; D005688:Galactosamine; D000410:Alanine Transaminase