Signal transducer and activator of transcription 3-regulated sarcoendoplasmic reticulum Ca2+-ATPase 2 expression by prolactin and glucocorticoids is involved in the adaptation of insulin secretory response during the peripartum period

Abstract

During pregnancy, the maternal endocrine pancreas undergoes, as a consequence of placental lactogens and prolactin (PRL) action, functional changes that are characterized by increased glucose-induced insulin secretion. After delivery, the maternal endocrine pancreas rapidly returns to nonpregnant state, which is mainly attributed to the increased serum levels of glucocorticoids (GCs). Although GCs are known to decrease insulin secretion and counteract PRL action, the mechanisms for these effects are poorly understood. We have previously demonstrated that signal transducer and activator of transcription 3 (STAT3) is increased in islets treated with PRL. In the present study, we show that STAT3 expression and serine phosphorylation are increased in pancreatic islets at the end of pregnancy (P19). STAT3 serine phosphorylation rapidly returned to basal levels 3 days after delivery (L3). The expression of the sarcoendoplasmic reticulum Ca 2C -ATPase 2 (SERCA2), a crucial protein involved in the regulation of calcium handling in b-cells, was also increased in P19, returning to basal levels at L3. PRL increased SERCA2 and STAT3 expressions and STAT3 serine phosphorylation in RINm5F cells. The upregulation of SERCA2 by PRL was abolished after STAT3 knockdown. Moreover, PRL-induced STAT3 serine phosphorylation and SERCA2 expression were inhibited by dexamethasone (DEX). Insulin secretion from islets of P19 rats pre-incubated with thapsigargin and L3 rats showed a dramatic suppression of first phase of insulin release. The present results indicate that PRL regulates SERCA2 expression by a STAT3-dependent mechanism. PRL effect is counteracted by DEX and might contribute to the adaptation of maternal endocrine pancreas during the peripartum period.

UPR-mediated TRIB3 expression correlates with reduced AKT phosphorylation and inability of interleukin 6 to overcome palmitate-induced apoptosis in RINm5F cells

“…We have found that phosphorylation of both STAT3 and AKT was activated by IL6, but only that of AKT was impaired by PA. In pancreatic b-cells, downregulation of STAT3 activity is mainly involved in the modulation of insulin secretion (Gorogawa et al 2004, Anhê et al 2007). On the other hand, it is well documented that the phosphatidylinositol 3-kinase (PI3K)/AKT signaling is a critical pathway regulating b-cell survival (Elghazi et al 2007), which is impaired by FFAs (Wrede et al 2002, Kharroubi et al 2004.…”

“…1 mM glucose and 10% FBS) as described previously (Anhê et al 2007). For the time-course and doseresponse experiments, the cells were incubated for 30 min at 37 8C with Krebs-bicarbonate buffer (KBB) containing 0 .…”

MKP-1 mediates glucocorticoid-induced ERK1/2 dephosphorylation and reduction in pancreatic β-cell proliferation in islets from early lactating mothers

“…The contribution of gestational hormones on ␤-cell adaptation to pregnancy is highlighted by the demonstration that, even when the increased demand for insulin is compensated by exogenous insulin, changes in islet function characteristic of gestation still occur (36). However, the increases in both insulin secretion and ␤-cell proliferation are time-limited events that resume the nonpregnant features just after the delivery (5,38). It is likely that the reduction of intracellular calcium stores and SERCA2 expression in pancreatic islets mediate the decrease of maternal insulin secretion just after delivery (5,25).…”

“…However, the increases in both insulin secretion and ␤-cell proliferation are time-limited events that resume the nonpregnant features just after the delivery (5,38). It is likely that the reduction of intracellular calcium stores and SERCA2 expression in pancreatic islets mediate the decrease of maternal insulin secretion just after delivery (5,25). However, the precise mechanism by which the pancreatic ␤-cell switches from a high to a low proliferative status is much less comprehended.…”

“…Isolated islets and cultured cells were homogenized in 100 l of solubilization buffer and processed for protein extraction and Western blot, as described previously (5). After centrifugation, equal amounts of protein were resolved in SDS-PAGE and transferred to nitrocellulose membranes.…”