Constitutively active PDX1 induced efficient insulin production in adult murine liver.
To generate insulin-producing cells in the liver, recombinant adenovirus containing a constitutively active mutant of PDX1 (PDX1-VP16), designed to activate target genes without the need for protein partners, was prepared and administered intravenously to streptozotocin (STZ)-treated diabetic mice. The effects were compared with those of administering wild-type PDX1 (wt-PDX1) adenovirus. Administration of these adenoviruses at 2x10(8)pfu induced similar levels of PDX1 protein expression in the liver. While wt-PDX1 expression exerted small effects on blood glucose levels, treatment with PDX1-VP16 adenovirus efficiently induced insulin production in hepatocytes, resulting in reversal of STZ-induced hyperglycemia. The effects were sustained through day 40 when exogenous PDX1-VP16 protein expression was undetectable in the liver. Endogenous PDX1 protein came to be expressed in the liver, which is likely to be the mechanism underlying the sustained effects. On the other hand, albumin and transferrin expressions were observed in insulin-producing cells in the liver, suggesting preservation of hepatocytic functions. Thus, transient expression of an active mutant of PDX1 in the liver induced sustained PDX1 and insulin expressions without loss of hepatocytic function.
Imai
Junta
J
Division of Molecular Metabolism and Diabetes, Tohoku University Graduate School of Medicine, Japan.
Katagiri
Hideki
H
Yamada
Tetsuya
T
Ishigaki
Yasushi
Y
Ogihara
Takehide
T
Uno
Kenji
K
Hasegawa
Yutaka
Y
Gao
Junhong
J
Ishihara
Hisamitsu
H
Sasano
Hironobu
H
Mizuguchi
Hiroyuki
H
Asano
Tomoichiro
T
Oka
Yoshitomo
Y
D000256:Adenoviridae / Q000235:genetics; D000375:Aging / Q000502:physiology*; D000418:Albumins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000139:chemically induced / Q000235:genetics / Q000473:pathology / Q000628:therapy; D015316:Genetic Therapy / Q000379:methods*; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D007328:Insulin / Q000096:biosynthesis* / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism*; D014168:Transferrin / Q000235:genetics / Q000378:metabolism
D000418:Albumins; D001786:Blood Glucose; D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; D014168:Transferrin; C084010:pancreatic and duodenal homeobox 1 protein