| First Author | Chowdhury S | Year | 2015 |
| Journal | PLoS One | Volume | 10 |
| Issue | 8 | Pages | e0136656 |
| PubMed ID | 26305481 | Mgi Jnum | J:243029 |
| Mgi Id | MGI:5907437 | Doi | 10.1371/journal.pone.0136656 |
| Citation | Chowdhury S, et al. (2015) Decreased 11beta-Hydroxysteroid Dehydrogenase 1 Level and Activity in Murine Pancreatic Islets Caused by Insulin-Like Growth Factor I Overexpression. PLoS One 10(8):e0136656 |
| abstractText | We have reported a high expression of IGF-I in pancreatic islet beta-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, 11beta-hydroxysteroid dehydrogenase 1 (11beta-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 11beta-HSD1 protein was significantly lower in MT-IGF mice. Using dual-labeled immunofluorescence, 11beta-HSD1 was observed exclusively in glucagon-producing, islet alpha-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 11beta-HSD1 activity. In order to establish the function of intracrine glucocorticoids, we overexpressed 11beta-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 11beta-HSD1 inhibitor. Our results demonstrate an inhibitory effect of IGF-I on 11beta-HSD1 expression and activity within the pancreatic islets, which may mediate part of the IGF-I effects on cell proliferation, survival and insulin secretion. |
