Antisense inhibition of 11betahydroxysteroid dehydrogenase type 1 improves diabetes in a novel cortisone-induced diabetic KK mouse model |
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Authors: | Bhat B Ganesh Younis Husam Herrera Jocelyn Palacio Kimbie Pascual Bernadette Hur George Jessen Bart Ogilvie Kathleen M Rejto Paul A |
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Affiliation: | a Diabetes Biology, Pfizer Global Research and Development, La Jolla Laboratories, La Jolla, CA, USA b Drug Safety Research & Development, Pfizer Global Research and Development, La Jolla Laboratories, La Jolla, CA, USA c Structural and Computational Biology, Pfizer Global Research and Development, La Jolla Laboratories, La Jolla, CA, USA |
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Abstract: | The inhibition of 11βhydroxysteroid dehydrogenase 1 (11βHSD1), 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 11βHSD1 antisense oligonucleotide (ASO) as an inhibitory tool. KK mice were treated with 25 or 50 mg/kg/day of 11βHSD1 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 11βHSD1 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 11βHSD1 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. |
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Keywords: | 11βhydroxysteroid dehydrogenase Cortisol Glucocorticoid Animal model Diabetes |
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