Elucidating the role of prolactin receptor during β cell adaptation to metabolic stressors
Date
2024-05-06
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Abstract
The role of prolactin receptor (PRLR) during β cell adaptation to pregnancy has been extensively studied. Human epidemiological studies have revealed a potential role of prolactin outside pregnancy in maintaining glucose homeostasis. In this study, we discovered that the absence of PRLR in pancreatic β cells leads to impaired glucose tolerance in multiparous mice challenged with a high-fat diet (HFD). Unlike during pregnancy, where PRLR regulates β cell mass expansion, we observed that PRLR had a smaller role in regulating β cell mass in this model. Pancreatic islets from our knockout mice had a similar insulin secretory capacity as the wild-type mice in vitro, suggesting that an in vivo factor was responsible for the difference in glucose homeostasis. Interestingly, a difference in in vivo insulin secretion was observed when mice were challenged with oral but not intraperitoneal glucose, suggesting a defect in the incretin effect. The incretin effect, where oral glucose administration elicits a greater insulin secretory response compared to intravenous administration, is mediated by incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). We found a reduction in mRNA expressions of both incretin hormone receptors, GIP receptor (Gipr) and GLP-1 receptor (Glp-1r), in the pancreatic islets of our islet-specific PRLR knockout mice in comparison to wild-type controls after 12 weeks of HFD. Additionally, the mRNA expression of transcription factors, E2F transcription factor 1 (E2f1) and peroxisome proliferator-activated receptor-γ (Pparg), which have been shown to regulate the expressions of Gipr and Glp-1r and are downstream of PRLR, were downregulated. Together, these results suggest PRLR may have a role in the maintaining incretin effect during metabolic stress outside of pregnancy. Our findings contribute to our understanding of the complexity of PRLR in maintaining glucose homeostasis outside of pregnancy.
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Keywords
Incretin effect, Diabetes
Citation
Lee, D. (2024). Elucidating the role of prolactin receptor during β cell adaptation to metabolic stressors (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.