Abstract
The apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. We examined changes in the apelinergic system during normal mouse pregnancy and in pregnancies complicated by glucose intolerance with reduced BCM. Expression of Aplnr, Apelin and Apela was quantified in Ins+Glut2LO cells isolated from mouse pancreata and found to be significantly higher than in mature β-cells by DNA microarray and qPCR. Apelin was localized to most β-cells by immunohistochemistry although Aplnr was predominantly associated with Ins+Glut2LO cells. Aplnr-staining cells increased three- to four-fold during pregnancy being maximal at gestational days (GD) 9–12 but were significantly reduced in glucose intolerant mice. Apelin-13 increased β-cell proliferation in isolated mouse islets and INS1E cells, but not glucose-stimulated insulin secretion. Glucose intolerant pregnant mice had significantly elevated serum Apelin levels at GD 9 associated with an increased presence of placental IL-6. Placental expression of the apelinergic axis remained unaltered, however. Results show that the apelinergic system is highly expressed in pancreatic β-cell progenitors and may contribute to β-cell proliferation in pregnancy.
Highlights
The apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control
The findings from DNA microarray with respect to the apelinergic axis were validated using Quantitative polymerase chain reaction (qPCR) quantification of mRNA in fractions of Ins+Glut2LO vs. Ins+Glut2HI cells isolated from 7-day old mouse pancreata, relative to the expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and cyclophilin A
Levels of Apelin, Aplnr and Apela, were all expressed at significantly higher levels in Ins+Glut2LO cells (Fig. 1A)
Summary
The apelin receptor (Aplnr) and its ligands, Apelin and Apela, contribute to metabolic control. The insulin resistance associated with pregnancy is accommodated by an expansion of pancreatic β-cell mass (BCM) and increased insulin secretion, involving the proliferation of insulin-expressing, glucose transporter 2-low (Ins+Glut2LO) progenitor cells. A separate type of multi-lineage progenitor has been identified in mouse and human pancreata throughout life, both within islets and in the small, extra-islet endocrine c lusters[17] This progenitor cell fraction expresses some insulin, but glucose-stimulated insulin secretion (GSIS) is poor due to low expression of glucose transporter 2 ( Ins+Glut2LO cells)[18], . In a mouse model of gestational glucose intolerance characterized by a sub-optimal increase in BCM the number of proliferating Ins+Glut2LO cells was significantly lower[21]. Apelin is released by the placental syncytiotrophoblast into the maternal circulation with concentrations increasing throughout pregnancy in both humans and r odents[29,30]
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