Glucocorticoids suppress beta-cell development and induce hepatic metaplasia in embryonic pancreas.
Elevated glucocorticoids are associated with low birth weight and fetal 'programming' of hypertension and glucose intolerance. In the present paper, we show that treatment of fetal rats with dexamethasone during the last week of gestation reduces the insulin content of their pancreatic beta-cells. We reproduce this effect of dexamethasone in vitro using organ cultures of mouse embryonic pancreas, and show that it is associated with an elevation of expression of the transcription factor C/EBPbeta (CCAAT/enhancer-binding protein beta) and a reduction of the transcription factor Pdx-1 (pancreatic duodenal homeobox-1). Dexamethasone also induces the appearance of hepatocyte-like cells in organ cultures of pancreas, based on the expression of liver markers, albumin, alpha1-antitrypsin and transthyretin. Evidence that C/EBPbeta is responsible for compromising the differentiation and later function of beta-cells is obtained from its effects on the beta-cell-like cell line RIN-5F. Transfection with a constitutive form of C/EBPb suppresses insulin formation, whereas introduction of a dominant-negative inhibitor of C/EBPb has no effect. We conclude that dexamethasone inhibits insulin expression in pancreatic beta-cells via a mechanism involving down-regulation of Pdx-1 and induction of C/EBPbeta. This mechanism may operate in combination with other changes during fetal programming, leading to type 2 diabetes in later life.
D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D018398:Homeodomain Proteins; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000473:pathology; D008679:Metaplasia; D051379:Mice; D009924:Organ Culture Techniques; D010179:Pancreas / Q000187:drug effects* / Q000196:embryology* / Q000473:pathology; D051381:Rats; D015534:Trans-Activators / Q000378:metabolism
D022782:CCAAT-Enhancer-Binding Protein-beta; D005938:Glucocorticoids; D018398:Homeodomain Proteins; D007328:Insulin; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein; D003907:Dexamethasone