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The interplay of prolactin and the glucocorticoids in the regulation of beta-cell gene expression, fatty acid oxidation, and glucose-stimulated insulin secretion: implications for carbohydrate metabolism in pregnancy.

Publication ,  Journal Article
Arumugam, R; Horowitz, E; Lu, D; Collier, JJ; Ronnebaum, S; Fleenor, D; Freemark, M
Published in: Endocrinology
November 2008

Carbohydrate metabolism in pregnancy reflects the balance between counterregulatory hormones, which induce insulin resistance, and lactogenic hormones, which stimulate beta-cell proliferation and insulin production. Here we explored the interactions of prolactin (PRL) and glucocorticoids in the regulation of beta-cell gene expression, fatty acid oxidation, and glucose-stimulated insulin secretion (GSIS). In rat insulinoma cells, rat PRL caused 30-50% (P < 0.001) reductions in Forkhead box O (FoxO)-1, peroxisome proliferator activator receptor (PPAR)-gamma coactivator-1alpha (PGC-1alpha), PPARalpha, and carnitine palmitoyltransferase 1 (CPT-1) mRNAs and increased Glut-2 mRNA and GSIS; conversely, dexamethasone (DEX) up-regulated FoxO1, PGC1alpha, PPARalpha, CPT-1, and uncoupling protein 2 (UCP-2) mRNAs in insulinoma cells and inhibited GSIS. Hydrocortisone had similar effects. The effects of DEX were attenuated by coincubation of cells with PRL. In primary rat islets, PRL reduced FoxO1, PPARalpha, and CPT-1 mRNAs, whereas DEX increased FoxO1, PGC1alpha, and UCP-2 mRNAs. The effects of PRL on gene expression were mimicked by constitutive overexpression of signal transducer and activator of transcription-5b. PRL induced signal transducer and activator of transcription-5 binding to a consensus sequence in the rat FoxO1 promoter, reduced nuclear FoxO1 protein levels, and induced its phosphorylation and cytoplasmic redistribution. DEX increased beta-cell fatty acid oxidation and reduced fatty acid esterification; these effects were attenuated by PRL. Thus, lactogens and glucocorticoids have opposing effects on a number of beta-cell genes including FoxO1, PGC1alpha, PPARalpha, CPT-1, and UCP-2 and differentially regulate beta-cell Glut-2 expression, fatty acid oxidation, and GSIS. These observations suggest new mechanisms by which lactogens may preserve beta-cell mass and function and maternal glucose tolerance despite the doubling of maternal cortisol concentrations in late gestation.

Duke Scholars

Published In

Endocrinology

DOI

ISSN

0013-7227

Publication Date

November 2008

Volume

149

Issue

11

Start / End Page

5401 / 5414

Location

United States

Related Subject Headings

  • STAT5 Transcription Factor
  • Rats
  • Protein Binding
  • Promoter Regions, Genetic
  • Prolactin
  • Pregnancy
  • Oxidation-Reduction
  • Insulin-Secreting Cells
  • Insulin Secretion
  • Insulin
 

Citation

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Arumugam, R., Horowitz, E., Lu, D., Collier, J. J., Ronnebaum, S., Fleenor, D., & Freemark, M. (2008). The interplay of prolactin and the glucocorticoids in the regulation of beta-cell gene expression, fatty acid oxidation, and glucose-stimulated insulin secretion: implications for carbohydrate metabolism in pregnancy. Endocrinology, 149(11), 5401–5414. https://doi.org/10.1210/en.2008-0051
Arumugam, Ramamani, Eric Horowitz, Danhong Lu, J Jason Collier, Sarah Ronnebaum, Don Fleenor, and Michael Freemark. “The interplay of prolactin and the glucocorticoids in the regulation of beta-cell gene expression, fatty acid oxidation, and glucose-stimulated insulin secretion: implications for carbohydrate metabolism in pregnancy.Endocrinology 149, no. 11 (November 2008): 5401–14. https://doi.org/10.1210/en.2008-0051.
Journal cover image

Published In

Endocrinology

DOI

ISSN

0013-7227

Publication Date

November 2008

Volume

149

Issue

11

Start / End Page

5401 / 5414

Location

United States

Related Subject Headings

  • STAT5 Transcription Factor
  • Rats
  • Protein Binding
  • Promoter Regions, Genetic
  • Prolactin
  • Pregnancy
  • Oxidation-Reduction
  • Insulin-Secreting Cells
  • Insulin Secretion
  • Insulin