title: Prolactin, progesterone, and dexamethasone coordinately and adversely regulate glucokinase and cAMP/PDE cascades in MIN6 beta-cells.
abstract: Islet cells undergo major changes in structure and function to meet the demand for increased insulin secretion during pregnancy, but the nature of the hormonal interactions and signaling events is incompletely understood. Here, we used the glucose-responsive MIN6 beta-cell line treated with prolactin (PRL), progesterone (PRG), and dexamethasone (DEX, a synthetic glucocorticoid), all elevated during late pregnancy, to study their effects on mechanisms of insulin secretion. DEX alone or combined with PRL and PRG inhibited insulin secretion in response to 16 mM glucose-stimulating concentrations. However, in the basal state (3 mM glucose), the insulin levels in response to DEX treatment were unchanged, and the three hormones together maintained higher insulin release. There were no changes of protein levels of GLUT2 or glucokinase (GK), but PRL or PRG treatment increased GK activity, whereas DEX had an inhibitory effect on GK activity. alpha-Ketoisocaproate (alpha-KIC)-stimulated insulin secretion was also reduced by DEX alone or combined with PRL and PRG, suggesting that DEX may inhibit distal steps in the insulin-exocytotic process. PRL treatment increased the concentration of intracellular cAMP in response to 16 mM glucose, suggesting a role for cAMP in potentiation of insulin secretion, whereas DEX alone or combined with PRL and PRG reduced cAMP levels by increasing phosphodiesterase (PDE) activity. These data provide evidence that PRL and to a lesser extent PRG, which increase in early pregnancy, enhance basal and glucose-stimulated insulin secretion in part by increasing GK activity and amplifying cAMP levels. Glucocorticoid, which increases throughout gestation, counteracts only glucose-stimulated insulin secretion under high glucose concentrations by dominantly inhibiting GK activity and increasing PDE activity to reduce cAMP levels. These adaptations in the beta-cell may play an important role in maintaining the basal hyperinsulinemia of pregnancy while limiting the capacity of PRL and PRG to promote glucose-stimulated insulin secretion during late gestation.
authors.affiliation: Department of Pediatrics, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. Jianhua.Shao@UCHSC.edu
authors.forename: Jianhua
authors.initials: J
authors.lastname: Shao
authors.forename: Liping
authors.initials: L
authors.lastname: Qiao
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Friedman
mesh_terms: D000818:Animals; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism*; D003907:Dexamethasone / Q000378:metabolism* / Q000494:pharmacology; D004357:Drug Synergism; D005938:Glucocorticoids / Q000494:pharmacology; D005941:Glucokinase / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D007329:Insulin Antagonists / Q000494:pharmacology; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007651:Keto Acids / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011374:Progesterone / Q000494:pharmacology / Q000502:physiology*; D011388:Prolactin / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D005938:Glucocorticoids; D007328:Insulin; D007329:Insulin Antagonists; D007651:Keto Acids; D011374:Progesterone; D003907:Dexamethasone; C013082:alpha-ketoisocaproic acid; D011388:Prolactin; D000242:Cyclic AMP; D005941:Glucokinase; D010727:Phosphoric Diester Hydrolases; D005947:Glucose