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 [Endocrinology] Journal article

Carbohydrate metabolism in pregnancy reflects the balance between counter-regulatory 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 (INS-1) cells, rat PRL caused 30-50% (p<0.001) reductions in FoxO1, PGC1alpha, PPARalpha, and CPT-1 mRNAs and increased Glut-2 mRNA and GSIS; conversely, Dexamethasone (DEX) upregulated FoxO1, PGC1alpha, PPARalpha, CPT-1, and UCP-2 mRNAs in INS-1 cells and inhibited GSIS. Hydrocortisone had similar effects. The effects of DEX were attenuated by co-incubation of cells with PRL. In primary rat islets PRL reduced FoxO1, PPARalpha and CPT-1 mRNAs while DEX increased FoxO1, PGC1alpha, and UCP-2 mRNAs. The effects of PRL on gene expression were mimicked by constitutive over-expression of STAT5b. PRL induced STAT5 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 (FAO) and reduced FA 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.

Endocrinology [Endocrinology]