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dc.contributor.advisorGrattan, Dave
dc.contributor.authorBurnett, Tristan Bruce
dc.date.available2015-07-09T04:29:42Z
dc.date.copyright2015
dc.identifier.citationBurnett, T. B. (2015). Prolactin’s Site of Action and its Role for the Regulation of Glucose Homeostasis During Pregnancy (Thesis, Bachelor of Medical Science with Honours). University of Otago. Retrieved from http://hdl.handle.net/10523/5790en
dc.identifier.urihttp://hdl.handle.net/10523/5790
dc.description.abstractDuring pregnancy, the mother’s capacity for glucose homeostasis must change to permit the optimal nutritional environment for the development of her offspring. The hormone prolactin is a primary mediator of this glycaemic change. This natural phenomenon is believed to counteract the mother’s necessary peripheral insulin resistance, which develops during pregnancy. This study examined the full effect of prolactin’s glycaemic role in pregnancy by conditionally deleting its receptor from the β-cells of the mouse pancreas (Cre- recombinase technology). Prolactin’s receptor was also removed from certain areas of the forebrain to investigate whether this pregnancy adaptation is initiated directly through the hormonal action of prolactin or via its action on the central nervous system. With the unique ability to conditionally delete prolactin receptors, this study compared the effect of prolactin on glucose homeostasis across genotype and across pregnancy states. Comparative analyses was achieved through two main experiments; 1) the proportion of insulin producing tissue in the pancreas - β- cell fraction and 2) an intra-peritoneal glucose tolerance test - IPGTT. 1. Mouse pancreatic tissue was retrieved and processed then analysed by primarily assessing the proportion of pancreatic tissue devoted to insulin production. This method reaffirmed the significant upregulation of insulin- producing tissue in pregnancy - Control (Cre-negative) animals showed a 56.5% increase in β-cell fraction of pregnant animals compared to non-pregnant (P<0.05). The study concurrently determined that deletion of prolactin receptors either from the pancreas or from the forebrain significantly reduced β-cell expansion during pregnancy. This was particularly evident in the animals missing the prolactin receptor in the pancreas (RIP-Cre pregnant mice had no difference in β-cell fraction from their respective non-pregnant group, and 47.6% less β-cell fraction than the control (Cre-negative) pregnant animals – P<0.05). The forebrain knockout animals (CamK-Cre mice) also experienced a deleterious effect on their β-cell fraction in pregnancy although not statistically significant (22% less than pregnant Cre-Negatives). This result however, was difficult to interpret given the resultant hyperprolactinaemia experienced by these animals due to their brain-specific loss of prolactin receptors. These results collectively, suggest a mix of both neural and hormonal (indirect and direct) influences upon the β-cells by prolactin. However, it did appear that the predominant, and more significant pathway for this pregnancy adaptation was the direct signalling of serum prolactin on pancreatic β-cells. 2. Before tissue removal, experimental mice were also subject to an Intra- Peritoneal Glucose Tolerance Test (IPGTT). This aimed to reveal whether functional glucose homeostasis was affected by the knockout genotypes and pregnancy states. Analysis for the Areas Under the Curve (AUC) of the GTT profiles were taken as an indication of glucose tolerance. Pregnant control animals showed a more ‘flattened’ curve, suggestive of typical pregnant glucose handling (increased insulin resistance and increase basal insulin) despite the overall glucose tolerance showing no significant difference between pregnant and non-pregnant states. The RIP-Cre animals (those lacking prolactin’s effect in the pancreatic β-cells), irrespective of pregnancy had an absolute AUC that was higher (22.5% - non-pregnant), than the Cre-Negative control group. This suggests a role for prolactin in glucose homeostasis outside of pregnancy and that RIP-Cre pancreata were essentially blind to preganancy’s effect on glucose handling. Also the CamK-Cre group appeared to show a trend suggestive of ‘not- coping’ with pregnant conditions - exhibiting prengancy’s insulin resistance (elevated AUC – 19.7%) but unable to counter-manage with an increase in insulin production. These results confirm the significance of prolactin as an important mediator of blood sugar control during pregnancy and also suggest it has influence outside of the pregnant state. This study determined how much of an effect the lactogens influence the maintenance of glucose homeostasis during pregnancy. It also attempted to reveal on the somatic pathway by which prolactin initiates this change. Thus highlighting avenues for further study on how prolactin could be used not only as a therapy for individuals at risk of gestational diabetes, but other forms of malfunctioning glucose control.
dc.language.isoen
dc.publisherUniversity of Otago
dc.rightsAll items in OUR Archive are provided for private study and research purposes and are protected by copyright with all rights reserved unless otherwise indicated.
dc.subjectProlactin
dc.subjectPregnancy
dc.subjectGlucose-Homeostasis
dc.subjectblood-sugar
dc.subjecttissue-specific
dc.subjectRIP-Cre
dc.subjectCamK-Cre
dc.subjectIPGTT
dc.subjectIsletsofLangerhans
dc.subjectBeta-cells
dc.subjectInsulin
dc.subjectInsulin-resistance
dc.titleProlactin’s Site of Action and its Role for the Regulation of Glucose Homeostasis During Pregnancy
dc.typeThesis
dc.date.updated2015-07-09T04:06:04Z
dc.language.rfc3066en
thesis.degree.disciplineDepartment of Anatomy
thesis.degree.nameBachelor of Medical Science with Honours
thesis.degree.grantorUniversity of Otago
thesis.degree.levelHonours
otago.interloanno
otago.openaccessAbstract Only
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