title: Regulation of islet beta-cell pyruvate metabolism: interactions of prolactin, glucose, and dexamethasone.
abstract: Prolactin (PRL) induces beta-cell proliferation and glucose-stimulated insulin secretion (GSIS) and counteracts the effects of glucocorticoids on insulin production. The mechanisms by which PRL up-regulates GSIS are unknown. We used rat islets and insulinoma (INS-1) cells to explore the interactions of PRL, glucose, and dexamethasone (DEX) in the regulation of beta-cell pyruvate carboxylase (PC), pyruvate dehydrogenase (PDH), and the pyruvate dehydrogenase kinases (PDKs), which catalyze the phosphorylation and inactivation of PDH. PRL increased GSIS by 37% (P < 0.001) in rat islets. Glucose at supraphysiological concentrations (11 mm) increased PC mRNA in islets; in contrast, PRL suppressed PC mRNA levels in islets and INS-1 cells, whereas DEX was without effect. Neither PRL nor DEX altered PC protein or activity levels. In INS-1 cells, PRL increased PDH activity 1.4- to 2-fold (P < 0.05-0.001) at glucose concentrations ranging from 2.5-11 mm. DEX reduced PDH activity; this effect was reversed by PRL. PDK1, -2, -3, and -4 mRNAs were detected in both islets and insulinoma cells, but the latter expressed trivial amounts of PDK4. PRL reduced PDK2 mRNA and protein levels in rat islets and INS-1 cells and PDK4 mRNA in islets; DEX increased PDK2 mRNA in islets and INS-1 cells; this effect was reversed by PRL. Our findings suggest that PRL induction of GSIS is mediated by increases in beta-cell PDH activity; this is facilitated by suppression of PDKs. PRL counteracts the effects of DEX on PDH and PDK expression, suggesting novel roles for the lactogens in the defense against diabetes.
authors.affiliation: Pediatric Endocrinology, Duke University Medical Center, Box 102820, Duke University Medical Center, Durham, NC 27710, USA. arumu001@mc.duke.edu
authors.forename: Ramamani
authors.initials: R
authors.lastname: Arumugam
authors.forename: Eric
authors.initials: E
authors.lastname: Horowitz
authors.forename: Robert C
authors.initials: RC
authors.lastname: Noland
authors.forename: Danhong
authors.initials: D
authors.lastname: Lu
authors.forename: Donald
authors.initials: D
authors.lastname: Fleenor
authors.forename: Michael
authors.initials: M
authors.lastname: Freemark
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D066298:In Vitro Techniques; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011388:Prolactin / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011766:Pyruvate Carboxylase / Q000235:genetics; D011767:Pyruvate Decarboxylase / Q000235:genetics; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C000631434:Pdk1 protein, rat; C000631436:Pdk2 protein, rat; C000631440:Pdk4 protein, rat; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D003907:Dexamethasone; D011388:Prolactin; D017346:Protein Serine-Threonine Kinases; D011767:Pyruvate Decarboxylase; D011766:Pyruvate Carboxylase; D005947:Glucose