Item – Theses Canada

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OCLC number
505270127
Link(s) to full text
LAC copy
LAC copy
Author
Lipsett, Mark Andrew,1974-
Title
Pharmacological induction of islet neogenesis and subsequent beta-cell mass expansion.
Degree
Ph. D. -- McGill University, 2007
Publisher
Ottawa : Library and Archives Canada = Bibliothèque et Archives Canada, [2008]
Description
3 microfiches
Notes
Includes bibliographical references.
Abstract
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.
ISBN
9780494323694
0494323698