Pancreatic prolactin receptor signaling regulates maternal glucose homeostasis

Nteeba, Jackson; Kubota, Kaiyu; Wang, Wenfang; Zhu, Hao; Vivian, Jay L.; Dai, Guoli; Soares, Michael J.

doi:10.1530/joe-18-0518

Cited by 24 publications

(26 citation statements)

References 67 publications

(82 reference statements)

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“…RIP-Cre) and the other using the Pdx1 promoter controlled Cre (i.e. Pdx1-Cre) (3,20,24). Similar to our findings in Prlr +/mice, β-cell specific Prlrdeletion caused gestational diabetes, accompanied by a reduction in β-cell proliferation and a blunted glucose-stimulated insulin secretion.…”

Section: Introductionsupporting

confidence: 84%

Regulation of islet function and gene expression by prolactin during pregnancy

Shrivastava

Lee²,

Pretorius³

et al. 2019

Preprint

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Pancreatic islets adapt to insulin resistance of pregnancy by up regulating β-cell proliferation and increase insulin secretion. Previously, we found that prolactin receptor (Prlr) signaling is important for this process, as heterozygous prolactin receptor-null (Prlr +/-) mice are glucose intolerant, had a lower number of β cells and lower serum insulin levels than wild type mice during pregnancy. However, since Prlr expression is ubiquitous, to determine its β-cell specific effects, we generated a transgenic mouse with a floxed Prlr allele under the control of an inducible promoter, allowing conditional deletion of Prlr from β cells in adult mice. In this study, we found that β-cell-specific Prlr reduction resulted in elevated blood glucose during pregnancy. Similar to our previous finding in mouse with global Prlr reduction, β-cell-specific Prlr loss led to a lower β-cell mass and a lower in vivo insulin level during pregnancy. However, these islets do not have an intrinsic insulin secretion defect when tested in vitro. Interestingly, when we compared the islet gene expression profile, using islets isolated from mice with global versus β-cell-specific Prlr reduction, we found some important differences in genes that regulate apoptosis and insulin secretion. This suggests that Prlr has both cell-autonomous and non-cell-autonomous effect on β cells, beyond its regulation of pro-proliferative genes.are expressed during embryonic development and they causes a defect in β-cell mass at birth, we generated an inducible conditional Prlr knockout mouse to circumvent this developmental defect.Furthermore, since prolactin receptor is ubiquitously expressed, Prlr may have non-cell autonomous effect on β cells. Our objective is to determine the cell autonomous effect of Prlr during pregnancy, and to explore the non-cell autonomous effect of Prlr by comparing islet gene expression using mice with global and β-cell-specific prolactin receptor deletion. Methods Ethical approval.All experimental procedures were approved by the Animal Use Review Committee at the University of Calgary in accordance with standards of the Canadian Council on Animal Care. Mice.Heterozygous prolactin receptor null mice (Prlr +/-) on a C57BL/6 background were purchased from Jackson Laboratory and a working stock was generated by crossing Prlr +/mice with wild type Prlr +/+ mice. The pups were genotyped as previously described (4). Generation of the conditional prolactin-receptor null mice.A promoter-driven targeting cassette for the generation of a knockout-first allele with potential for conditional knockout was obtained from EUCOMM (The European Conditional Mouse Mutagenesis Program)(27). The vector was linearized at AsiSI-site and electroporated into mouse ES cells. Neomycin resistant cells were isolated and selected by Southern analysis. ES cells that contain the correctly recombined genome and correct karyotype were then injected into 8-cell CD1E wild type mouse embryos to generate chimeras. The male chimeric mice were then crossed to albino C57B...

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Section: Introductionsupporting

confidence: 84%

Regulation of islet function and gene expression by prolactin during pregnancy

Shrivastava

Lee²,

Pretorius³

et al. 2019

Preprint

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“…Blood glucose levels were measured from the tail vein using the OneTouch Ultra Smart blood glucose monitoring system (LifeScan, Milpitas, California, USA). 13…”

Section: Blood Glucose Measurementsmentioning

confidence: 99%

Poorly controlled diabetes mellitus alters placental structure, efficiency, and plasticity

Nteeba

Varberg

Scott

et al. 2020

BMJ Open Diab Res Care

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IntroductionThe hemochorial placenta provides a critical barrier at the maternal–fetal interface to modulate maternal immune tolerance and enable gas and nutrient exchange between mother and conceptus. Pregnancy outcomes are adversely affected by diabetes mellitus; however, the effects of poorly controlled diabetes on placental formation, and subsequently fetal development, are not fully understood.Research design and methodsStreptozotocin was used to induce hyperglycemia in pregnant rats for the purpose of investigating the impact of poorly controlled diabetes on placental formation and fetal development. The experimental paradigm of hypoxia exposure in the pregnant rat was also used to assess properties of placental plasticity. Euglycemic and hyperglycemic rats were exposed to ambient conditions (~21% oxygen) or hypoxia (10.5% oxygen) beginning on gestation day (gd) 6.5 and sacrificed on gd 13.5. To determine whether the interaction of hyperglycemia and hypoxia was directly altering trophoblast lineage development, rat trophoblast stem (TS) cells were cultured in high glucose (25 mM) and/or exposed to low oxygen (0.5% to 1.5%).ResultsDiabetes caused placentomegaly and placental malformation, decreasing placental efficiency and fetal size. Elevated glucose disrupted rat TS cell differentiation in vitro. Evidence of altered trophoblast differentiation was also observed in vivo, as hyperglycemia affected the junctional zone transcriptome and interfered with intrauterine trophoblast invasion and uterine spiral artery remodeling. When exposed to hypoxia, hyperglycemic rats showed decreased proliferation and ectoplacental cone development on gd 9.5 and complete pregnancy loss by gd 13.5. Furthermore, elevated glucose concentrations inhibited TS cell responses to hypoxia in vitro.ConclusionsOverall, these results indicate that alterations in placental development, efficiency, and plasticity could contribute to the suboptimal fetal outcomes in offspring from pregnancies complicated by poorly controlled diabetes.

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“…The global Prlr null mouse (on a 129svJ background) has reduced islet size and density, decreased β-cell mass, and lowered production and secretion of insulin in response to glucose treatment ( 7 ). Also, mice lacking the PRLR in the pancreas ( 8 ) and specifically in β-cells, develop gestational diabetes ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Global Deletion of the Prolactin Receptor Aggravates Streptozotocin-Induced Diabetes in Mice

et al. 2021

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Prolactin (PRL) levels are reduced in the circulation of rats with diabetes or obesity, and lower circulating levels of PRL correlate with increased prevalence of diabetes and a higher risk of metabolic alterations in the clinic. Furthermore, PRL stimulates β-cell proliferation, survival, and insulin production and pregnant mice lacking PRL receptors in β-cells develop gestational diabetes. To investigate the protective effect of endogenous PRL against diabetes outside pregnancy, we compared the number of cases and severity of streptozotocin (STZ)-induced hyperglycemia between C57BL/6 mice null for the PRL receptor gene (Prlr-/-) and wild-type mice (Prlr+/+). STZ-treated diabetic Prlr-/- mice showed a higher number of cases and later recovery from hyperglycemia, exacerbated glucose levels, and glucose intolerance compared to the Prlr+/+ mice counterparts. Consistent with the worsening of hyperglycemia, pancreatic islet density, β-cell number, proliferation, and survival, as well as circulating insulin levels were reduced, whereas α-cell number and pancreatic inflammation were increased in the absence of PRL signaling. Deletion of the PRL receptor did not alter the metabolic parameters in vehicle-treated animals. We conclude that PRL protects whole body glucose homeostasis by reducing β-cell loss and pancreatic inflammation in STZ-induced diabetes. Medications elevating PRL circulating levels may prove to be beneficial in diabetes.

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Pancreatic prolactin receptor signaling regulates maternal glucose homeostasis

Cited by 24 publications

References 67 publications

Regulation of islet function and gene expression by prolactin during pregnancy

Regulation of islet function and gene expression by prolactin during pregnancy

Poorly controlled diabetes mellitus alters placental structure, efficiency, and plasticity

Global Deletion of the Prolactin Receptor Aggravates Streptozotocin-Induced Diabetes in Mice

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