Current therapies for diabetes mellitus are insufficient to prevent the devastating complications associated with this disease. A novel approach for the treatment of diabetes is the restoration of an insulin-producing beta-cell mass through the stimulation of endogenous progenitor cells. Thus, the aim of this thesis was to determine if pharmacological initiation of islet neogenesis and subsequent beta-cell mass expansion will lead to the reversal of hyperglycaemia in a response that is under homeostatic regulation and has efficacy in humans. / A pentadecapeptide fragment of Islet Neogenesis Associated Protein (INGAP 104-108), was administered to normoglycaemic hamsters and was found to result in an expanded beta-cell mass as measured by immunohistochemical morphometric analysis. This expansion was shown to occur through the transformation of duct- and acinar-associated progenitors. In order to determine if this therapeutic approach would be effective in mammals other than hamsters, INGAP 104-108 was administered to normoglycaemic mice, dogs and monkeys, hyperglycaemic mice, and to human pancreatic tissue cultures. / INGAP104-108 administration led to a dose-dependent increase of beta-cell mass in mice, with similar trends observed in dogs. Similarly, administration of INGAP104-108 to normoglycaemic monkeys for 90 days resulted in profound areas of islet neogenesis. Administration of INGAP104-108 to diabetic mice resulted in restoration of euglycaemia and a dramatic increase in beta-cell mass. Furthermore, INGAP104-108 administration to cultured human acinar tissue, led to the formation of insulin-producing islet-like structures. These results suggest that INGAP 104-108 therapy has the ability to reverse a diabetic state and could be effective in humans. However, it was necessary to determine whether the continual stimulation of islet neogenesis through INGAP 104-108 administration is a safe therapeutic approach. / The beta-cell mass dynamics of euglycaemic mice administered INGAP 104-108 at various doses for 31 or 90 days were determined. beta-cell mass was greatly increased at 31 days of therapy, though by 90 days of therapy there was no difference in total beta cell mass between all treatment groups. However, there were marked instances of islet neogenesis in mice treated with INGAP104-108 for 90 days. This elevation in islet neogenesis was tempered by decreased beta-cell replication and increased beta-cell apoptosis, resulting in no overall difference in total beta-cell mass. These results suggest that inherent homeostatic regulation persisted to maintain a net beta-cell mass that matched the physiological need, even in the setting of continual induction of islet neogenesis. / INGAP104-108 therapy has been shown to expand the insulin-producing beta-cell mass in a safe homeostatic manner and reverse diabetic hyperglycaemia. These findings suggest that a novel pharmacological agent for the successful stimulation of beta-cell mass expansion is within reach, enabling new therapeutic modalities for the treatment of diabetes.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.103170 |
| Date | January 2006 |
| Creators | Lipsett, Mark Andrew. |
| 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 Surgical Research.) |
| Rights | © Mark Andrew Lipsett, 2006 |
| Relation | alephsysno: 002584393, proquestno: AAINR32369, Theses scanned by UMI/ProQuest. |
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