Browsing by Author "Huang, Carol"

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    Cortisol regulates skeletal muscle glucose uptake during stress in zebrafish
    (2021-12-20) Antomagesh, Femilarani; Vijayan, Matt (Mathilakath); Hansen, David Donald; Huang, Carol; Habibi, Hamid H; Storey, Douglas Gordan
    The circulating glucocorticoid (GC) levels elevate in response to stress, and this response is conserved in vertebrates. GCs play an important role in mobilizing glucose to meet the increased energy demand associated with stress. GCs have also been shown to restrict skeletal muscle glucose uptake during stress, but the mechanisms are far from clear. In this thesis, the overriding hypothesis tested was that the glucocorticoid receptor (GR) activation by GCs restricts insulin-stimulated skeletal muscle glucose uptake using zebrafish as a model. The chronic elevation of cortisol resulted in an impairment in plasma glucose clearance when subjected to a glucose tolerance test but did not modify whole-body insulin levels. Cortisol treated fish also showed decreased skeletal muscle glucose uptake and a lower glycogen content, while the transcript abundance of genes encoding enzymes involved in muscle glycogen synthesis and glycolysis were upregulated. When we tested the insulin response in the cortisol treated zebrafish, insulin-stimulated blood glucose clearance and muscle glycogen storage was affected but not the glucose uptake. Interestingly, cortisol group showed an increased insulin-induced phosphorylation of AKT in the skeletal muscle, but the phosphorylation of S6 kinase, a downstream target of AKT, was reduced. Moreover, the transcript abundance of glut1b, the most abundant GLUT identified in the zebrafish skeletal muscle, was upregulated with insulin treatment only in the cortisol treated group. Using ubiquitous GR knockout zebrafish, the results revealed that the absence of GR improved glucose tolerance with increased skeletal muscle glucose uptake. In summary, my study shows that cortisol-GR signalling restricts skeletal muscle glucose uptake and metabolism, and this may involve disrupted insulin signalling downstream of AKT activation in zebrafish.
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    Elucidating the role of prolactin receptor during β cell adaptation to metabolic stressors
    (2024-05-06) Lee, Daniel; Huang, Carol; Hemberger, Myriam; Shemanko, Carrie
    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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    Prolactin as an Adjunct to Anti-CD3 Type I Diabetes Therapy
    (2014-10-09) Hyslop, Colin; Huang, Carol
    Type I diabetes is caused by autoimmune destruction of ß-cells. While immune therapy halts autoimmune attack on ß-cells, the residual ß-cell number is often insufficient for euglycemia. We hypothesize that addition of a growth factor to increase β-cell number will be more effective at reversing hyperglycemia than immune therapy alone. We chose prolactin because it stimulates ß-cell proliferation and insulin synthesis in vivo. In this study, we found that diabetic NOD mice treated with anti-CD3 and prolactin achieved a higher diabetes remission rate in comparison to those treated with anti-CD3 alone. Mice treated with anti-CD3 and prolactin had higher pancreatic insulin content and secreted more insulin during a glucose tolerance test. They had higher ß-cell mass and number due to a higher ß-cell proliferation rate. Furthermore, the anti-CD3 and prolactin treated group had a higher proportion of insulitis-free islets. We found no evidence of ß-cell neogenesis and even the addition of exendin-4, a growth factor analagoue thought to be able to induce β-cell neogenesis, failed to induce β-cell neogenesis. Therefore, this study suggests that the paradigm of using a growth factor to stimulate ß-cell proliferation and expand ß-cell number in conjunction with immune therapy is potentially an effective strategy to treat type 1 diabetes.
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    Prolactin Receptor Is Required for Normal Glucose Homeostasis and Modulation of β-Cell Mass during Pregnancy
    (The Endocrine Society, 2009-04) Huang, Carol; Snider, Francis; Cross, James C.
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    The Role of Prolactin Receptors in Regulation of Pancreatic Beta Cell Mass and Function
    (2016) Shrivastava, Vipul; Huang, Carol; Cross, James; Slater, Donna
    During pregnancy, pancreatic β-cells adapt to the increase in maternal insulin resistance by up-regulating β-cell mass, insulin synthesis, and lowering glucose-stimulated insulin secretion threshold. Signaling through prolactin receptor (PrlR) is critical for these adaptive responses. We hypothesize that PrlR present on β-cells are the primary determinant of β-cell adaptation to pregnancy. We found that β-cell specific deletion of PrlR in mice leads to higher fasted blood glucose and impaired glucose tolerance in comparison with wild type mice. Furthermore, we identified Lrrc55 (leucine rich repeat containing 55), an auxiliary subunit of BK channels as one of the potentially novel targets of PrlR. Results suggest that Lrrc55 overexpression protected INS-1 cells from H2O2, high glucose, palmitate, and high glucose+palmitate-induced apoptosis by attenuating ER stress and intrinsic apoptosis pathways and also maintaining healthy ER calcium reserves. Taken together, this study helps unravel components of PrlR signaling as possible therapeutic strategy to treat diabetes.