Decreased 11?-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 ?-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, 11?-hydroxysteroid dehydrogenase 1 (11?-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 11?-HSD1 protein was significantly lower in MT-IGF mice. Using dual-labeled immunofluorescence, 11?-HSD1 was observed exclusively in glucagon-producing, islet ?-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 11?-HSD1 activity. In order to establish the function of intracrine glucocorticoids, we overexpressed 11?-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 11?-HSD1 inhibitor. Our results demonstrate an inhibitory effect of IGF-I on 11?-HSD1 expression and activity within the pancreatic islets, which may mediate part of the IGF-I effects on cell proliferation, survival and insulin secretion.

SUBMITTER: Chowdhury S 

PROVIDER: S-EPMC4549276 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature