{"id":{"repo_id":"ubc","oai_identifier":"oai:circle.library.ubc.ca:2429/222"},"canonical_url":"https://search.dev.ndltd.org/etd/ubc/oai:circle.library.ubc.ca:2429/222","repository":{"repo_id":"ubc","name":"University of British Columbia","base_url":"http://circle.library.ubc.ca/oai/request"},"display":{"title":"Manipulating proglucagon processing in the pancreatic alpha-cell for the treatment of diabetes","abstract":"Glucagon-like peptide-1 (GLP-1) has received much attention as a novel diabetes therapeutic due to its pleotropic blood glucose-lowering effects, including enhancement of glucose-stimulated insulin secretion, inhibition of gastric emptying and glucagon secretion, and promotion of beta-cell survival and proliferation. GLP-1 is produced in the intestinal L-cell via processing of the proglucagon precursor by prohormone convertase (PC) 1/3. Proglucagon is also expressed in the pancreatic alpha-cell; however, in this tissue PC2 is typically expressed instead of PC1/3, resulting in differential cleavage of proglucagon to yield glucagon as the major product. We hypothesized that expression of PC1/3 in the alpha-cell would induce GLP-1 production in this tissue, and that this intervention would improve islet function and survival. Initial studies in alpha-cell lines demonstrate that adenoviral delivery of PC1/3 to alpha-cells increases GLP-1 production. By encapsulating and transplanting either PC1/3- or PC2-expressing alpha-cells, the following studies show that while PC2-expressing alpha-cells increase fasting blood glucose and impair glucose tolerance, PC1/3-expressing alpha-cells decrease fasting blood glucose and dramatically improve glucose tolerance in normal mice and in mouse models of diabetes. We further show that transplantation of PC1/3-expressing alpha-cells prevents streptozotocin (STZ)- induced hyperglycemia. We also found that PC1/3-expressing alpha-cells also improve cold-induced thermogenesis in db/db mice, demonstrating a previously unappreciated effect of one or more of the PC1/3-derived proglucagon products. Studies in isolated mouse islets demonstrate that adenoviral delivery of PC1/3 to isolated islets increases islet GLP-1 secretion and improves glucose-stimulated insulin secretion and islet survival. Experiments with diabetic mice show that these GLP-1-producing islets are better able to restore normoglycemia in recipient mice following islet transplantation. Taken together, these studies demonstrate that the alpha-cell can be induced to process proglucagon into PC1/3-derived products, and that this shift redirects the alpha-cell from a hyperglycemia-promoting fate to a blood glucose-lowering one. This research opens up avenues for further investigating the therapeutic potential of inducing islet GLP-1 production in isolated human islets and in vivo in diabetes patients, and may represent a novel way to intervene in the progressive loss of beta-cells that characterizes diabetes.","abstract_html":"Glucagon-like peptide-1 (GLP-1) has received much attention as a novel diabetes therapeutic due to its pleotropic blood glucose-lowering effects, including enhancement of glucose-stimulated insulin secretion, inhibition of gastric emptying and glucagon secretion, and promotion of beta-cell survival and proliferation. GLP-1 is produced in the intestinal L-cell via processing of the proglucagon precursor by prohormone convertase (PC) 1/3. Proglucagon is also expressed in the pancreatic alpha-cell; however, in this tissue PC2 is typically expressed instead of PC1/3, resulting in differential cleavage of proglucagon to yield glucagon as the major product. We hypothesized that expression of PC1/3 in the alpha-cell would induce GLP-1 production in this tissue, and that this intervention would improve islet function and survival. Initial studies in alpha-cell lines demonstrate that adenoviral delivery of PC1/3 to alpha-cells increases GLP-1 production. By encapsulating and transplanting either PC1/3- or PC2-expressing alpha-cells, the following studies show that while PC2-expressing alpha-cells increase fasting blood glucose and impair glucose tolerance, PC1/3-expressing alpha-cells decrease fasting blood glucose and dramatically improve glucose tolerance in normal mice and in mouse models of diabetes. We further show that transplantation of PC1/3-expressing alpha-cells prevents streptozotocin (STZ)- induced hyperglycemia. We also found that PC1/3-expressing alpha-cells also improve cold-induced thermogenesis in db/db mice, demonstrating a previously unappreciated effect of one or more of the PC1/3-derived proglucagon products. Studies in isolated mouse islets demonstrate that adenoviral delivery of PC1/3 to isolated islets increases islet GLP-1 secretion and improves glucose-stimulated insulin secretion and islet survival. Experiments with diabetic mice show that these GLP-1-producing islets are better able to restore normoglycemia in recipient mice following islet transplantation. Taken together, these studies demonstrate that the alpha-cell can be induced to process proglucagon into PC1/3-derived products, and that this shift redirects the alpha-cell from a hyperglycemia-promoting fate to a blood glucose-lowering one. This research opens up avenues for further investigating the therapeutic potential of inducing islet GLP-1 production in isolated human islets and in vivo in diabetes patients, and may represent a novel way to intervene in the progressive loss of beta-cells that characterizes diabetes.","abstract_has_math":false,"creators":["Wideman, Rhonda D."],"institution":"University of British Columbia","degree_name":"Doctor of Philosophy - PhD","degree_level":"doctoral","degree_discipline":"Physiology","degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2007,"date_issued":"2007","date_published":"2007","updated_at":"2026-07-24T05:07:06Z","subjects":[],"languages":["eng"],"rights":["Attribution-NonCommercial-NoDerivatives 4.0 International"],"rights_urls":["http://creativecommons.org/licenses/by-nc-nd/4.0/"],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/2429/222","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Wideman, Rhonda D."]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2007"]},{"key":"dc:publisher","label":"Institution","values":["University of British Columbia"]},{"key":"dc:type","label":"Dc Type","values":["Text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Physiology"]},{"key":"thesis:degree_level","label":"Degree Level","values":["doctoral"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Doctor of Philosophy - PhD"]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of British Columbia"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["http://creativecommons.org/licenses/by-nc-nd/4.0/","Attribution-NonCommercial-NoDerivatives 4.0 International"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2429/222","http://circle.library.ubc.ca/bitstream/2429/222/1/ubc_2008_spring_wideman_rhonda.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Glucagon-like peptide-1 (GLP-1) has received much attention as a novel diabetes therapeutic due to its pleotropic blood glucose-lowering effects, including enhancement of glucose-stimulated insulin secretion, inhibition of gastric emptying and glucagon secretion, and promotion of beta-cell survival and proliferation. GLP-1 is produced in the intestinal L-cell via processing of the proglucagon precursor by prohormone convertase (PC) 1/3. Proglucagon is also expressed in the pancreatic alpha-cell; however, in this tissue PC2 is typically expressed instead of PC1/3, resulting in differential cleavage of proglucagon to yield glucagon as the major product. We hypothesized that expression of PC1/3 in the alpha-cell would induce GLP-1 production in this tissue, and that this intervention would improve islet function and survival. Initial studies in alpha-cell lines demonstrate that adenoviral delivery of PC1/3 to alpha-cells increases GLP-1 production. By encapsulating and transplanting either PC1/3- or PC2-expressing alpha-cells, the following studies show that while PC2-expressing alpha-cells increase fasting blood glucose and impair glucose tolerance, PC1/3-expressing alpha-cells decrease fasting blood glucose and dramatically improve glucose tolerance in normal mice and in mouse models of diabetes. We further show that transplantation of PC1/3-expressing alpha-cells prevents streptozotocin (STZ)- induced hyperglycemia. We also found that PC1/3-expressing alpha-cells also improve cold-induced thermogenesis in db/db mice, demonstrating a previously unappreciated effect of one or more of the PC1/3-derived proglucagon products. Studies in isolated mouse islets demonstrate that adenoviral delivery of PC1/3 to isolated islets increases islet GLP-1 secretion and improves glucose-stimulated insulin secretion and islet survival. Experiments with diabetic mice show that these GLP-1-producing islets are better able to restore normoglycemia in recipient mice following islet transplantation. Taken together, these studies demonstrate that the alpha-cell can be induced to process proglucagon into PC1/3-derived products, and that this shift redirects the alpha-cell from a hyperglycemia-promoting fate to a blood glucose-lowering one. This research opens up avenues for further investigating the therapeutic potential of inducing islet GLP-1 production in isolated human islets and in vivo in diabetes patients, and may represent a novel way to intervene in the progressive loss of beta-cells that characterizes diabetes."]},{"key":"dc:format","label":"Dc Format","values":["25388517","application/pdf"]},{"key":"dc:title","label":"Title","values":["Manipulating proglucagon processing in the pancreatic alpha-cell for the treatment of diabetes"]}]}],"canonical_facts":{"dc:creator":["Wideman, Rhonda D."],"dc:date":["2007"],"dc:description":["Glucagon-like peptide-1 (GLP-1) has received much attention as a novel diabetes therapeutic due to its pleotropic blood glucose-lowering effects, including enhancement of glucose-stimulated insulin secretion, inhibition of gastric emptying and glucagon secretion, and promotion of beta-cell survival and proliferation. GLP-1 is produced in the intestinal L-cell via processing of the proglucagon precursor by prohormone convertase (PC) 1/3. Proglucagon is also expressed in the pancreatic alpha-cell; however, in this tissue PC2 is typically expressed instead of PC1/3, resulting in differential cleavage of proglucagon to yield glucagon as the major product. We hypothesized that expression of PC1/3 in the alpha-cell would induce GLP-1 production in this tissue, and that this intervention would improve islet function and survival. Initial studies in alpha-cell lines demonstrate that adenoviral delivery of PC1/3 to alpha-cells increases GLP-1 production. By encapsulating and transplanting either PC1/3- or PC2-expressing alpha-cells, the following studies show that while PC2-expressing alpha-cells increase fasting blood glucose and impair glucose tolerance, PC1/3-expressing alpha-cells decrease fasting blood glucose and dramatically improve glucose tolerance in normal mice and in mouse models of diabetes. We further show that transplantation of PC1/3-expressing alpha-cells prevents streptozotocin (STZ)- induced hyperglycemia. We also found that PC1/3-expressing alpha-cells also improve cold-induced thermogenesis in db/db mice, demonstrating a previously unappreciated effect of one or more of the PC1/3-derived proglucagon products. Studies in isolated mouse islets demonstrate that adenoviral delivery of PC1/3 to isolated islets increases islet GLP-1 secretion and improves glucose-stimulated insulin secretion and islet survival. Experiments with diabetic mice show that these GLP-1-producing islets are better able to restore normoglycemia in recipient mice following islet transplantation. Taken together, these studies demonstrate that the alpha-cell can be induced to process proglucagon into PC1/3-derived products, and that this shift redirects the alpha-cell from a hyperglycemia-promoting fate to a blood glucose-lowering one. This research opens up avenues for further investigating the therapeutic potential of inducing islet GLP-1 production in isolated human islets and in vivo in diabetes patients, and may represent a novel way to intervene in the progressive loss of beta-cells that characterizes diabetes."],"dc:format":["25388517","application/pdf"],"dc:identifier":["http://hdl.handle.net/2429/222","http://circle.library.ubc.ca/bitstream/2429/222/1/ubc_2008_spring_wideman_rhonda.pdf"],"dc:language":["eng"],"dc:publisher":["University of British Columbia"],"dc:rights":["http://creativecommons.org/licenses/by-nc-nd/4.0/","Attribution-NonCommercial-NoDerivatives 4.0 International"],"dc:title":["Manipulating proglucagon processing in the pancreatic alpha-cell for the treatment of diabetes"],"dc:type":["Text"],"thesis:degree_discipline":["Physiology"],"thesis:degree_level":["doctoral"],"thesis:degree_name":["Doctor of Philosophy - PhD"],"thesis:institution_name":["University of British Columbia"]},"updated_at":"2026-07-24T05:07:06Z"}