Molecular mechanisms regulating physiological adaptions in pancreatic [Beta]- cells
- Kartik Viswanathan.
- June 2011.
- Physical description
- online resource (xii, 135 pages) : illustrations (some color)
- Viswanathan, Kartik.
- Giaccia, Amato J. thesis advisor.
- Kim, Seung (Seung K.) thesis advisor (primary).
- Kuo, Calvin Jay. thesis advisor.
- Wysocka, Joanna, Ph. D. thesis advisor.
- Stanford University. Committee on Graduate Studies. degree grantor.
- Stanford University. Program in Cancer Biology.
- Includes bibliographical references (p. 120-135).
- Pancreatic [Beta]-cells secrete insulin to maintain systemic glucose balance. In response to physiological or pathological stresses that increase insulin demand, [Beta]-cells proliferate and enhance insulin secretion to increase insulin output. However, the mechanisms that govern these facultative changes are unclear. In this thesis, I investigate two potential factors in achieving these essential adaptive changes -- hypoxia inducible factor 1 alpha (Hif1a) and prolactin receptor (Prlr). During pregnancy, a common acquire state with increased insulin demand, Hif1a and Hif1a target gene expression, including Vegfa, Glut1, Gck were increased in maternal islets. Using mouse genetics, conditional deletion of Hif1a in [Beta]-cells ([Beta]Hif1a KO) resulted in glucose intolerance in pregnant, but not virgin, mice. Pregnant [Beta]Hif1a KO mice had impaired target gene expression, defective islet insulin secretion, and reduced vascularity. Pregnant mice develop transient hyperlipidemia, and recapitulation of the hyperlipidemia with fat-challenge or lipid treament induced Hif1a, Vegfa, and Pgk1 expression. Similar to pregnant [Beta]Hif1a KO mice, fat-challenged [Beta]Hif1a KO developed hyperglycemia, hypoinsulinemia, and glucose intolerance. All three hyperlipidemic states show ER stress, and treatment of unstressed mouse or human islets with thapsigargin was sufficient to increase Hif1a and downstream targets. To assess the significance of prolactin signaling in [Beta]-cell function and proliferation in adaptive settings, I created a novel conditional Prlr mouse model. In non-pregnant mice with [Beta]-cell-specific deletion of Prlr ([Beta]Prlr KO), glucose homeostasis is normal. However, pregnant [Beta]Prlr KO mice developed significant glucose intolerance. Given the widespread effects of lactogens on [Beta]-cell physiology, I anticipate altered [Beta]-cell proliferation and secretion in [Beta]Prlr KO islets, and current studies are underway to address this hypothesis. Collectively, our work has revealed that in settings of insulin resistance, both Hif1a and Prlr signaling play important roles in regulating the physiological changes required for proper [Beta]-cell function.
- Publication date
- Title Variation
- Molecular mechanisms regulating physiological adaptions in pancreatic β-cells
- Submitted to the Program in Cancer Biology and the Committee on Graduate Studies of Stanford University.
- Thesis (Ph.D.)--Stanford University, 2011.