The Role of Glucagon-like Peptides in Experimental Type 1 Diabetes
Type 1 diabetes mellitus (T1D) is an autoimmune disorder that targets the insulin-producing β-cells. The gut may play a role in the pathogenesis of T1D, as genetically-susceptible individuals and animal models of T1D exhibit increased intestinal permeability and improving gut barrier function can in...
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ndltd-LACETR-oai-collectionscanada.gc.ca-OTU.1807-247632013-11-02T03:42:23ZThe Role of Glucagon-like Peptides in Experimental Type 1 DiabetesHadjiyianni, Irene Ioannadiabetesglucagon-like peptidesGLP-1RGLP-2GLP-1NOD mouseType 1 diabetes mellitus (T1D) is an autoimmune disorder that targets the insulin-producing β-cells. The gut may play a role in the pathogenesis of T1D, as genetically-susceptible individuals and animal models of T1D exhibit increased intestinal permeability and improving gut barrier function can interfere with the onset of diabetes. Moreover gut-derived peptides are capable of modifying barrier function and regulate β-cell mass via effects on proliferation and apoptosis. I tested whether chronic administration of glucagon-like peptide-2 (GLP-2), a peptide which potently improves gut barrier function, modifies diabetes onset in a mouse model of T1D, the non obese diabetic (NOD) mouse. Although chronic treatment with a long-acting GLP-2 analogue was associated with improved intestinal barrier function, it failed to delay the onset of T1D. Once the autoimmune attack is initiated, pathogenic T-cells infiltrate the islets and trigger the death of β-cells. Studies in animal models have revealed that β-cells exhibit a compensatory response in the initial stages of the immune attack, which eventually fails, resulting in β-cell mass deficiency and onset of T1D. Glucagon-like peptide-1 (GLP-1) exerts both proliferative and anti-apoptotic actions on β-cells. I hypothesized that chronic activation of the GLP-1 receptor (GLP-1R) would delay or prevent the loss of functional β-cell mass in the NOD mouse. I have shown that chronic administration of the GLP-1R agonist exendin-4 significantly delayed the onset of diabetes and enhanced β-cell mass. Furthermore, GLP-1R activation was associated with a reduction of islet-infiltrating immune cells, as well as changes in lymphocyte subpopulations. Consequently, I addressed whether the GLP-1R has a role in the immune system of NOD and C57Bl/6 mice. GLP-1R mRNA transcripts were detectable in several immune subpopulations, and GLP-1R activation was associated with cAMP production in primary splenocytes and thymocytes. Furthermore I demonstrated that GLP-1R signaling controls proliferation of thymocytes and lymphocytes, and is required for maintaining peripheral regulatory T-cells. In summary, these studies establish that while GLP-2R activation is not sufficient to modify disease onset in a murine model of T1D, GLP-1R activation reduces the extent of diabetes development by exerting actions on β-cells and the immune system.Drucker, Daniel J.2010-062010-08-13T13:48:40ZNO_RESTRICTION2010-08-13T13:48:40Z2010-08-13T13:48:40ZThesishttp://hdl.handle.net/1807/24763en_ca |
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diabetes glucagon-like peptides GLP-1R GLP-2 GLP-1 NOD mouse |
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diabetes glucagon-like peptides GLP-1R GLP-2 GLP-1 NOD mouse Hadjiyianni, Irene Ioanna The Role of Glucagon-like Peptides in Experimental Type 1 Diabetes |
description |
Type 1 diabetes mellitus (T1D) is an autoimmune disorder that targets the insulin-producing β-cells. The gut may play a role in the pathogenesis of T1D, as genetically-susceptible individuals and animal models of T1D exhibit increased intestinal permeability and improving gut barrier function can interfere with the onset of diabetes. Moreover gut-derived peptides are capable of modifying barrier function and regulate β-cell mass via effects on proliferation and apoptosis. I tested whether chronic administration of glucagon-like peptide-2 (GLP-2), a peptide which potently improves gut barrier function, modifies diabetes onset in a mouse model of T1D, the non obese diabetic (NOD) mouse. Although chronic treatment with a long-acting GLP-2 analogue was associated with improved intestinal barrier function, it failed to delay the onset of T1D.
Once the autoimmune attack is initiated, pathogenic T-cells infiltrate the islets and trigger the death of β-cells. Studies in animal models have revealed that β-cells exhibit a compensatory response in the initial stages of the immune attack, which eventually fails, resulting in β-cell mass deficiency and onset of T1D. Glucagon-like peptide-1 (GLP-1) exerts both proliferative and anti-apoptotic actions on β-cells. I hypothesized that chronic activation of the GLP-1 receptor (GLP-1R) would delay or prevent the loss of functional β-cell mass in the NOD mouse. I have shown that chronic administration of the GLP-1R agonist exendin-4 significantly delayed the onset of diabetes and enhanced β-cell mass. Furthermore, GLP-1R activation was associated with a reduction of islet-infiltrating immune cells, as well as changes in lymphocyte subpopulations. Consequently, I addressed whether the GLP-1R has a role in the immune system of NOD and C57Bl/6 mice. GLP-1R mRNA transcripts were detectable in several immune subpopulations, and GLP-1R activation was associated with cAMP production in primary splenocytes and thymocytes. Furthermore I demonstrated that GLP-1R signaling controls proliferation of thymocytes and lymphocytes, and is required for maintaining peripheral regulatory T-cells.
In summary, these studies establish that while GLP-2R activation is not sufficient to modify disease onset in a murine model of T1D, GLP-1R activation reduces the extent of diabetes development by exerting actions on β-cells and the immune system. |
author2 |
Drucker, Daniel J. |
author_facet |
Drucker, Daniel J. Hadjiyianni, Irene Ioanna |
author |
Hadjiyianni, Irene Ioanna |
author_sort |
Hadjiyianni, Irene Ioanna |
title |
The Role of Glucagon-like Peptides in Experimental Type 1 Diabetes |
title_short |
The Role of Glucagon-like Peptides in Experimental Type 1 Diabetes |
title_full |
The Role of Glucagon-like Peptides in Experimental Type 1 Diabetes |
title_fullStr |
The Role of Glucagon-like Peptides in Experimental Type 1 Diabetes |
title_full_unstemmed |
The Role of Glucagon-like Peptides in Experimental Type 1 Diabetes |
title_sort |
role of glucagon-like peptides in experimental type 1 diabetes |
publishDate |
2010 |
url |
http://hdl.handle.net/1807/24763 |
work_keys_str_mv |
AT hadjiyianniireneioanna theroleofglucagonlikepeptidesinexperimentaltype1diabetes AT hadjiyianniireneioanna roleofglucagonlikepeptidesinexperimentaltype1diabetes |
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1716612327536590848 |