The role of insulin-like growth factor I (IGF-I) in pancreatic islet cell growth and development has been debated in recent years. The dogma that IGF-I stimulates pancreatic islet growth has been challenged by combinational targeting of IGF or IGF-IR genes, as well as beta-cell-specific IGF-IR gene deficiency. In order to assess the physiological role of locally produced IGF-I, we have developed pancreatic-specific IGF-I gene deficiency (PID) by crossing Pdx1-Cre and IGF-I/loxP mice. PID mice were normal except for decreased blood glucose level and a 2.3-fold enlarged islet cell mass. When challenged with low doses of streptozotocin, control mice developed hyperglycemia after 6 days that was maintained at high levels for at least 2 months. In contrast, PID mice only exhibited marginal hyperglycemia after 12 days, maintained throughout the experiment. Furthermore, streptozotocin-induced beta-cell apoptosis (TUNEL assay) was significantly prevented in PID mice. PID mice also exhibited a delayed onset of type 2 diabetes induced by a high-fat diet, accompanied by super enlarged pancreatic islets and preserved sensitivity to insulin. As the phenotype is unlikely a direct consequence of IGF-I deficiency, we used oligonucleotide DNA microarray to explore possible activation of pro-islet genes in PID mice, which revealed upregulation of multiple new members of the Reg family genes (Reg2, 3alpha and 3beta) in the pancreas. The results were subsequently confirmed by Northern blot and/or realtime PCR, which exhibited 2 to 8 fold increases in the level of their mRNAs. Moreover, these Reg family genes were also activated following streptozotocin-induced beta-cell damage and diabetes. Our results reveal a possible mechanism of islet growth and protection in PID mice, thus serving a potential strategy in combating diabetes.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.111827 |
| Date | January 2006 |
| Creators | Lu, Yarong, 1971- |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Experimental Medicine.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 002330136, proquestno: AAINR25198, Theses scanned by UMI/ProQuest. |
Page generated in 0.0016 seconds