Antisense inhibition of 11betahydroxysteroid dehydrogenase type 1 improves diabetes in a novel cortisone-induced diabetic KK mouse model.
The inhibition of 11betahydroxysteroid dehydrogenase 1 (11betaHSD1), an enzyme that catalyzes the conversion of inactive cortisone to active cortisol, is an attractive target to treat diabetes by suppressing hepatic gluconeogenesis. To test this hypothesis, we developed a novel glucocorticoid-induced diabetic KK mouse model and used 11betaHSD1 antisense oligonucleotide (ASO) as an inhibitory tool. KK mice were treated with 25 or 50mg/kg/day of 11betaHSD1 ASO for 28 days. On day 25, cortisone pellets were surgically implanted to induce diabetes. In the ASO-treated mice, plasma blood glucose levels were significantly reduced by up to 54%. In parallel, cortisol and other diabetes endpoints were also significantly reduced. Hepatic 11betaHSD1 mRNA was suppressed by up to 84% with a concomitant respective decrease of up to 49% in the expression of PEPCK. The results suggest that inhibition of 11betaHSD1 activity reduces the availability of cortisol to activate the glucocorticoid receptor, down regulates gluconeogenesis and thus reduces plasma glucose levels in cortisone-induced diabetic KK mice.
Bhat
B Ganesh
BG
Diabetes Biology, Pfizer Global Research and Development, La Jolla Laboratories, La Jolla, CA, USA.
Younis
Husam
H
Herrera
Jocelyn
J
Palacio
Kimbie
K
Pascual
Bernadette
B
Hur
George
G
Jessen
Bart
B
Ogilvie
Kathleen M
KM
Rejto
Paul A
PA
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics*; D000818:Animals; D003348:Cortisone; D003920:Diabetes Mellitus / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D020868:Gene Silencing; D018390:Gene Targeting; D015316:Genetic Therapy / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*; D016896:Treatment Outcome
D016376:Oligonucleotides, Antisense; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003348:Cortisone