Regulation of islet beta-cell pyruvate metabolism: interactions of prolactin, glucose, and dexamethasone.
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.
Arumugam
Ramamani
R
Pediatric Endocrinology, Duke University Medical Center, Box 102820, Duke University Medical Center, Durham, NC 27710, USA. arumu001@mc.duke.edu
Horowitz
Eric
E
Noland
Robert C
RC
Lu
Danhong
D
Fleenor
Donald
D
Freemark
Michael
M
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
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