{"id":{"repo_id":"uiuc","oai_identifier":"oai:www.ideals.illinois.edu:2142/83531"},"canonical_url":"https://search.dev.ndltd.org/etd/uiuc/oai:www.ideals.illinois.edu:2142/83531","repository":{"repo_id":"uiuc","name":"University of Illinois - Urbana-Champaign","base_url":"https://www.ideals.illinois.edu/oai-pmh"},"display":{"title":"Cellular Mechanisms Involved in Reactive Carbonyl and Hyperinsulinemia Enhancement of Diabetic Complications","abstract":"The findings in this thesis demonstrate that (1) hyperinsulinemia negatively impacts B-cell survival (2) and impairs the anti-inflammatory actions of IL-4 in macrophages and finally (3) the reactive carbonyl methylglyoxal enhances chemotherapeutic drug-dependent cytotoxicity. We report that hyperinsulinemia decreases survival of serum deprived B-cells through a PI 3-kinase and JNK pathway. We describe a mechanism where rapamycin sensitive serine/threonine-proline phosphorylation of IRS-2 reduces IL-4/IRS-2/PI 3-kinase dependent reduction of TNF-alpha receptor (TNF-R1). Finally, we show that the circulating glucose metabolite, methylglyoxal (MGO), enhances cisplatin-induced apoptosis by activating protein kinase Cdelta (PKCdelta). Taken together, these data indicate that exposure to chronic insulin disrupts cell survival and impairs IRS-dependent cytokine signaling which may alter the immune response and contribute to the accelerated proinflammatory conditions of diabetes mellitus. Furthermore, these findings suggest that elevated blood MGO levels may increase the cytotoxic effects of anti-neoplastic agents in the patient with DM.","abstract_html":"The findings in this thesis demonstrate that (1) hyperinsulinemia negatively impacts B-cell survival (2) and impairs the anti-inflammatory actions of IL-4 in macrophages and finally (3) the reactive carbonyl methylglyoxal enhances chemotherapeutic drug-dependent cytotoxicity. We report that hyperinsulinemia decreases survival of serum deprived B-cells through a PI 3-kinase and JNK pathway. We describe a mechanism where rapamycin sensitive serine/threonine-proline phosphorylation of IRS-2 reduces IL-4/IRS-2/PI 3-kinase dependent reduction of TNF-alpha receptor (TNF-R1). Finally, we show that the circulating glucose metabolite, methylglyoxal (MGO), enhances cisplatin-induced apoptosis by activating protein kinase Cdelta (PKCdelta). Taken together, these data indicate that exposure to chronic insulin disrupts cell survival and impairs IRS-dependent cytokine signaling which may alter the immune response and contribute to the accelerated proinflammatory conditions of diabetes mellitus. Furthermore, these findings suggest that elevated blood MGO levels may increase the cytotoxic effects of anti-neoplastic agents in the patient with DM.","abstract_has_math":false,"creators":["Godbout, Jonathan Philip"],"institution":"University of Illinois at Urbana-Champaign","degree_name":"Ph.D.","degree_level":"Dissertation","degree_discipline":"Animal Sciences","degree_department":null,"school":null,"contributors":["Freund, Gregory G."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2015,"date_issued":"2015-09-25T21:07:59Z","date_published":"2015-09-25T21:07:59Z","updated_at":"2026-07-22T22:26:21Z","subjects":["Chemistry, Biochemistry"],"languages":["eng"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["(MiAaPQ)AAI3017082"],"render_values":[{"text":"(MiAaPQ)AAI3017082","href":null,"code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/2142/83531","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Freund, Gregory G."]},{"key":"dc:creator","label":"Author","values":["Godbout, Jonathan Philip"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2015-09-25T21:07:59Z","10000-01-01","2001"]},{"key":"dc:type","label":"Dc Type","values":["text"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Animal Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D."]},{"key":"thesis:institution_name","label":"Thesis Institution Name","values":["University of Illinois at Urbana-Champaign"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Chemistry, Biochemistry"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/2142/83531","(MiAaPQ)AAI3017082"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["The findings in this thesis demonstrate that (1) hyperinsulinemia negatively impacts B-cell survival (2) and impairs the anti-inflammatory actions of IL-4 in macrophages and finally (3) the reactive carbonyl methylglyoxal enhances chemotherapeutic drug-dependent cytotoxicity. We report that hyperinsulinemia decreases survival of serum deprived B-cells through a PI 3-kinase and JNK pathway. We describe a mechanism where rapamycin sensitive serine/threonine-proline phosphorylation of IRS-2 reduces IL-4/IRS-2/PI 3-kinase dependent reduction of TNF-alpha receptor (TNF-R1). Finally, we show that the circulating glucose metabolite, methylglyoxal (MGO), enhances cisplatin-induced apoptosis by activating protein kinase Cdelta (PKCdelta). Taken together, these data indicate that exposure to chronic insulin disrupts cell survival and impairs IRS-dependent cytokine signaling which may alter the immune response and contribute to the accelerated proinflammatory conditions of diabetes mellitus. Furthermore, these findings suggest that elevated blood MGO levels may increase the cytotoxic effects of anti-neoplastic agents in the patient with DM.","Made available in DSpace on 2015-09-25T21:07:59Z (GMT). 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We report that hyperinsulinemia decreases survival of serum deprived B-cells through a PI 3-kinase and JNK pathway. We describe a mechanism where rapamycin sensitive serine/threonine-proline phosphorylation of IRS-2 reduces IL-4/IRS-2/PI 3-kinase dependent reduction of TNF-alpha receptor (TNF-R1). Finally, we show that the circulating glucose metabolite, methylglyoxal (MGO), enhances cisplatin-induced apoptosis by activating protein kinase Cdelta (PKCdelta). Taken together, these data indicate that exposure to chronic insulin disrupts cell survival and impairs IRS-dependent cytokine signaling which may alter the immune response and contribute to the accelerated proinflammatory conditions of diabetes mellitus. Furthermore, these findings suggest that elevated blood MGO levels may increase the cytotoxic effects of anti-neoplastic agents in the patient with DM.","Made available in DSpace on 2015-09-25T21:07:59Z (GMT). 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