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J. Biol. Chem., Vol. 275, Issue 45, 34841-34844, November 10, 2000
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From the Metabolic transformation of glucocorticoid
hormones constitutes a determinant of their cell-specific effects. The
most important reaction for this class of steroids is the reversible
C11 keto/
ACCELERATED PUBLICATION
Type 1 11
-Hydroxysteroid Dehydrogenase Mediates Glucocorticoid
Activation and Insulin Release in Pancreatic Islets*
§,,,
Department of Molecular Medicine, Karolinska
Hospital, S 171 76 Stockholm, Sweden, the § Department of
Medical Nutrition, University Hospital, NOVUM, S 141 86 Huddinge,
Sweden, and the ¶ Department of Medical Biochemistry and
Biophysics, Karolinska Institutet, S 171 77 Stockholm, Sweden
-hydroxyl conversion between receptor-binding 11-OH
steroids and the nonbinding 11-oxo compounds, carried out by
11-hydroxysteroid dehydrogenases (11-HSDs). In this study, we
determined the role of glucocorticoid conversion by 11-HSD in
pancreatic islets and its function in the regulation of insulin
release. Pancreatic islets isolated from ob/ob mice display type
1 11-hydroxysteroid dehydrogenase activity, i.e. in
intact cells the reductive reaction prevails, leading from
dehydrocorticosterone to corticosterone. Expression of type 1 11-HSD
mRNA was detected by reverse transcriptase-polymerase chain
reaction in islets isolated from ob/ob mice and also from human tissue.
Incubation of -cells in the presence of 11-dehydrocorticosterone leads to a dose-dependent inhibition of insulin release,
indicating cellular activation of 11-dehydrocorticosterone to the
receptor ligand, further confirmed by reporter gene assays. Inhibition of 11-HSD activity by carbenoxolone reverses inhibition of insulin release. The presence of 11-HSD in islets supports the concept that
reactivation of inert circulating hormone precursors in a cell-specific
manner plays a major role in glucocorticoid physiology in rodents and man.
*
This study was supported by grants from the European
Community (BIO4CT97-2123), Swedish Medical Research Council (13X-3532, 4X-3766, 72X-00034, and 13X-2819), Novo Nordisk Fonden, Denmark, the
Nordic Insulin Foundation committee, Karolinska Institutet, and
Pharmacia Corporation (to U. C. T. O.), Sweden.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.:
46 8 728 76 80; Fax: 46 8 33 74 62; E-mail:
Udo.Oppermann@mbb.ki.se.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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