Participation of prolactin receptors and phosphatidylinositol 3-kinase and MAP kinase pathways in the increase in pancreatic islet mass and sensitivity to glucose during pregnancy

Abstract

Prolactin (PRL) exerts its biological effects mainly by activating the Janus kinase/signal transducer and activator of transcription 5 (JAK/STAT5) signaling pathway. We have recently demonstrated that PRL also stimulates the insulin receptor substrates/phosphatidylinositol 3-kinase (IRSs/PI3K) and SH2-plekstrin homology domain (SHC)/ERK pathways in islets of neonatal rats. In the present study, we investigated the involvement of the PI3K and MAP kinase (MAPK) cascades in islet development and growth in pregnant rats. The protein expression of AKT1, p70 S6K and SHC was higher in islets from pregnant compared with control rats. Higher basal levels of tyrosine phosphorylation were found in classic transducers of insulin cell signaling (IRS1, IRS2 and SHC). Increased levels of threonine/tyrosine phosphorylation of ERK1/2 and serine phosphorylation of AKT and p70 S6K were also detected. To assess the participation of PRL in these phenomena, pregnant and control rats were treated with an antisense oligonucleotide to reduce the expression of the PRL receptor (PRLR). Phosphorylation of AKT was reduced in islets from pregnant and control rats, whereas p70 S6K protein levels were reduced only in islets from treated pregnant rats. Finally, glucose-induced insulin secretion was reduced in islets from pregnant but not from control rats treated with the PRLR antisense oligonucleotide. In conclusion, downstream proteins of the PI3K (AKT and p70 S6K) and MAPK (SHC and ERK1/2) cascades are regulated by PRL signaling in islets from pregnant rats. These findings indicate that these pathways participate in the increase in islet mass and the sensitivity to glucose during pregnancy.

Inhibition of c-jun N terminal kinase (JNK) improves functional beta cell mass in human islets and leads to AKT and glycogen synthase kinase-3 (GSK-3) phosphorylation

“…Since the integrity of the insulin signalling cascade in beta cells is responsible for preservation of beta cell mass and for insulin secretion [43], and since JNK inhibition affects IRS-1/AKT in peripheral tissues [13][14][15], we tested the effect of L-JNKI in human islet insulin pathway with our main focus on AKT and its substrates. Among those substrates, GSK-3B and p70S6K participate in the regeneration of beta cell mass via increased mitogenesis [44,45], while PRAS40 is also activated by insulin in peripheral tissues and is implicated in protection of neurons against ischaemic injury [46,47]. We found that JNK inhibition in human islets treated with either L-JNKI or SP600125 specifically stimulated the phosphorylation of AKT and GSK-3B (Fig.…”

Reproductive factors and pancreatic cancer risk: a Norwegian cohort study

“…Almost all women in our cohort were born too early to have used oral contraceptives or hormone replacement therapy, although these apparently do not affect risk (Teras et al, 2005). Alternatively, the breastfeeding effect may reflect the raised prolactin levels maintained at these times (Freeman et al, 2000) since prolactin causes a change in islet mass (Amaral et al, 2004). Although most tumours occur in the exocrine pancreas, the islets seem to play a role in carcinogenesis and may even harbour precursor cells (Hennig et al, 2004).…”

Fever suppression in near-term pregnant rats is dissociated from LPS-activated signaling pathways

“…There are several potential candidates for ERK1/2 and STAT5 activation in an immuneindependent fashion. For example, prolactin can activate both ERK1/2 and STAT5 pathways (1,11,27,73), and both prolactin plasma levels and hypothalamic prolactin receptor expression are high during pregnancy (2,25,26). Another candidate for the constitutive activation of the ERK1/2 and STAT5 pathways is leptin (30,31), whose circulating levels are increased during pregnancy (38,64).…”