Participation of Akt, menin, and p21 in pregnancy-induced beta-cell proliferation.
β-Cell mass increases during pregnancy to accommodate for insulin resistance. This increase is mainly due to β-cell proliferation, a process that requires intact prolactin receptor (Prlr) signaling. Signaling molecules that are known to regulate β-cell proliferation include Jak2, Akt, the tumor suppressor menin, and cell cycle proteins. Whether these pathways are involved in prolactin-mediated β-cell proliferation is unknown. Using the heterozygous prolactin receptor-null (Prlr(+/-)) mice, we isolated pancreatic islets from both Prlr(+/+) and Prlr(+/-) mice on d 0 and 15 of pregnancy and examined the expression levels of these signaling molecules. In the wild-type mice (Prlr(+/+)), both phospho-Jak2 and phospho-Akt expression in pancreatic islets increased during pregnancy, which were attenuated in the pregnant Prlr(+/-) mice. During pregnancy, menin expression was reduced by 50 and 20% in the Prlr(+/+) and the Prlr(+/-) mice, respectively, and the pregnant Prlr(+/-) mice had higher islet p18 levels than the Prlr(+/+) mice. Interestingly, between d 0 and 15 of pregnancy, expression of cyclin inhibitory protein p21(cip) was increased in the Prlr(+/+) mice, but this increase was blunted in the Prlr(+/-) mice. Lastly, we did not find any difference in the expression levels of cyclins D1, D2, and inhibitory kinases between the pregnant Prlr(+/+) and Prlr(+/-) mice. Therefore, we conclude that during pregnancy, placental hormones act through the prolactin receptor to increase β-cell mass by up regulating β-cell proliferation by engaging Jak2, Akt, menin/p18, and p21. Future studies will determine the relative contribution of these molecules in maintaining normal glucose homeostasis during pregnancy.
University of Calgary, Faculty of Medicine, Department of Pediatrics, Calgary, Alberta, Canada T2N 4N1.
Elizabeth
E
Hughes
Carol
C
Huang
D000818:Animals; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000502:physiology*; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D054778:NM23 Nucleoside Diphosphate Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D011388:Prolactin / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011981:Receptors, Prolactin / Q000235:genetics / Q000378:metabolism
D050759:Cyclin-Dependent Kinase Inhibitor p21; D055504:Insulin Receptor Substrate Proteins; C526298:Irs2 protein, mouse; C484898:Men1 protein, mouse; D054778:NM23 Nucleoside Diphosphate Kinases; D011518:Proto-Oncogene Proteins; D011981:Receptors, Prolactin; D011388:Prolactin; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D051057:Proto-Oncogene Proteins c-akt; C517941:Nme2 protein, mouse