title: Decreased 11β-Hydroxysteroid Dehydrogenase 1 Level and Activity in Murine Pancreatic Islets Caused by Insulin-Like Growth Factor I Overexpression.
abstract: We have reported a high expression of IGF-I in pancreatic islet β-cells of transgenic mice under the metallothionein promoter. cDNA microarray analysis of the islets revealed that the expression of 82 genes was significantly altered compared to wild-type mice. Of these, 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1), which is responsible for the conversion of inert cortisone (11-dehydrocorticosterone, DHC in rodents) to active cortisol (corticosterone) in the liver and adipose tissues, has not been identified previously as an IGF-I target in pancreatic islets. We characterized the changes in its protein level, enzyme activity and glucose-stimulated insulin secretion. In freshly isolated islets, the level of 11β-HSD1 protein was significantly lower in MT-IGF mice. Using dual-labeled immunofluorescence, 11β-HSD1 was observed exclusively in glucagon-producing, islet α-cells but at a lower level in transgenic vs. wild-type animals. MT-IGF islets also exhibited reduced enzymatic activities. Dexamethasone (DEX) and DHC inhibited glucose-stimulated insulin secretion from freshly isolated islets of wild-type mice. In the islets of MT-IGF mice, 48-h pre-incubation of DEX caused a significant decrease in insulin release, while the effect of DHC was largely blunted consistent with diminished 11β-HSD1 activity. In order to establish the function of intracrine glucocorticoids, we overexpressed 11β-HSD1 cDNA in MIN6 insulinoma cells, which together with DHC caused apoptosis and a significant decrease in proliferation. Both effects were abolished with the treatment of an 11β-HSD1 inhibitor. Our results demonstrate an inhibitory effect of IGF-I on 11β-HSD1 expression and activity within the pancreatic islets, which may mediate part of the IGF-I effects on cell proliferation, survival and insulin secretion.
authors: Fraser Laboratories for Diabetes Research, Department of Medicine, the Research Institute of McGill University Health Centre, Montreal, Canada.
authors: Subrata
authors: S
authors: Chowdhury
authors: Fraser Laboratories for Diabetes Research, Department of Medicine, the Research Institute of McGill University Health Centre, Montreal, Canada.
authors: Larson
authors: L
authors: Grimm
authors: Fraser Laboratories for Diabetes Research, Department of Medicine, the Research Institute of McGill University Health Centre, Montreal, Canada.
authors: Ying Jia Kate
authors: YJ
authors: Gong
authors: Fraser Laboratories for Diabetes Research, Department of Medicine, the Research Institute of McGill University Health Centre, Montreal, Canada.
authors: Beixi
authors: B
authors: Wang
authors: Fraser Laboratories for Diabetes Research, Department of Medicine, the Research Institute of McGill University Health Centre, Montreal, Canada.
authors: Bing
authors: B
authors: Li
authors: Fraser Laboratories for Diabetes Research, Department of Medicine, the Research Institute of McGill University Health Centre, Montreal, Canada.
authors: Coimbatore B
authors: CB
authors: Srikant
authors: Department of Pathology, the Research Institute of McGill University Health Centre, Montreal, Canada.
authors: Zu-hua
authors: ZH
authors: Gao
authors: Fraser Laboratories for Diabetes Research, Department of Medicine, the Research Institute of McGill University Health Centre, Montreal, Canada; Montreal Diabetes Research Centre, Montreal, Canada.
authors: Jun-Li
authors: JL
authors: Liu
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D049109:Cell Proliferation; D003345:Corticosterone / Q000031:analogs & derivatives* / Q000378:metabolism; D003907:Dexamethasone / Q000008:administration & dosage; D005934:Glucagon / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000235:genetics; D007515:Islets of Langerhans / Q000201:enzymology / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D007328:Insulin; D007334:Insulin-Like Growth Factor I; D003907:Dexamethasone; D005934:Glucagon; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C003552:11-dehydrocorticosterone; D005947:Glucose; D003345:Corticosterone