The Interplay of Prolactin and the Glucocorticoids in the Regulation of β-Cell Gene Expression, Fatty Acid Oxidation, and Glucose-Stimulated Insulin Secretion: Implications for Carbohydrate Metabolism in Pregnancy

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-1 alpha (PGC-1 alpha), PPAR alpha,and carnitine palmitoyltransferase 1 (CPT-1) mRNAs and increased Glut-2mRNA and GSIS; conversely, dexamethasone (DEX) upregulated FoxO1, PGC1 alpha, PPAR alpha, 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, PPAR alpha, and CPT-1 mRNAs, whereas DEX increased FoxO1, PGC1 alpha, 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, PGC1 alpha, PPAR alpha, 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. (Endocrinology 149: 5401-5414, 2008)