{"id":{"repo_id":"toronto-retro","oai_identifier":"oai:utoronto.scholaris.ca:1807/26331"},"canonical_url":"https://search.dev.ndltd.org/etd/toronto-retro/oai:utoronto.scholaris.ca:1807/26331","repository":{"repo_id":"toronto-retro","name":"University of Toronto","base_url":"https://utoronto.scholaris.ca/server/oai/request"},"display":{"title":"Mechanisms of High Glucose-induced Decrease in β-cell Function","abstract":"Chronic hyperglycemia, a hallmark of type 2 diabetes, can decrease β-cell function and mass (β-cell glucotoxicity); however, the mechanisms are incompletely understood. The objective was to examine the mechanisms of β-cell glucotoxicity using in vivo and ex vivo models. The hypothesis is that oxidative stress plays a causal role in high glucose-induced β-cell dysfunction in vivo via pathways that involve endoplasmic reticulum (ER) stress and JNK. The model of β-cell glucotoxicity was achieved by prolonged i.v. glucose infusion (to achieve hyperglycemia). In Study 1, 48h glucose infusion increased total and mitochondrial superoxide levels in islets, and impaired β-cell function in vivo and ex vivo. Co-infusion of the superoxide dismutase mimetic Tempol decreased total and mitochondrial superoxide, and prevented high glucose-induced β-cell dysfunction in vivo and ex vivo. These results suggest that increased superoxide generation plays a role in β-cell glucotoxicity. In Study 2, 48h glucose infusion increased activation of the unfolded protein response (XBP-1 mRNA splicing and phospho-eIF2α levels). This was partially prevented by Tempol. Co-infusion of the chemical chaperone 4-phenylbutyrate with glucose decreased spliced XBP-1 levels, and prevented high glucose-induced β-cell dysfunction in vivo and ex vivo. Co-infusion of 4-phenylbutyrate also decreased total and mitochondrial superoxide induced by high glucose. These results suggest that 1) ER stress plays a causal role in high glucose-induced β-cell dysfunction, and 2) there is a link between oxidative stress and ER stress in high glucose-induced β-cell dysfunction in vivo. In Study 3, JNK inhibition using the inhibitor SP600125 in rats or JNK-1 null mice prevented high glucose-induced β-cell dysfunction ex vivo and in vivo. SP600125 prevented high-glucose-induced β-cell dysfunction without decreasing total and mitochondrial superoxide levels. Both Tempol and 4-phenylbutyrate prevented JNK activation induced by high glucose. These results suggest a role of JNK activation in high glucose-induced β-cell dysfunction downstream of increased superoxide generation and ER stress in vivo. Together, the results suggest that 1) oxidative stress, ER stress and JNK activation are causally involved in β-cell glucotoxicity, and 2) High glucose-induced oxidative stress and ER stress are linked, and both impair β-cell dysfunction via JNK activation in vivo.","abstract_html":"Chronic hyperglycemia, a hallmark of type 2 diabetes, can decrease β-cell function and mass (β-cell glucotoxicity); however, the mechanisms are incompletely understood. The objective was to examine the mechanisms of β-cell glucotoxicity using in vivo and ex vivo models. The hypothesis is that oxidative stress plays a causal role in high glucose-induced β-cell dysfunction in vivo via pathways that involve endoplasmic reticulum (ER) stress and JNK. The model of β-cell glucotoxicity was achieved by prolonged i.v. glucose infusion (to achieve hyperglycemia). In Study 1, 48h glucose infusion increased total and mitochondrial superoxide levels in islets, and impaired β-cell function in vivo and ex vivo. Co-infusion of the superoxide dismutase mimetic Tempol decreased total and mitochondrial superoxide, and prevented high glucose-induced β-cell dysfunction in vivo and ex vivo. These results suggest that increased superoxide generation plays a role in β-cell glucotoxicity. In Study 2, 48h glucose infusion increased activation of the unfolded protein response (XBP-1 mRNA splicing and phospho-eIF2α levels). This was partially prevented by Tempol. Co-infusion of the chemical chaperone 4-phenylbutyrate with glucose decreased spliced XBP-1 levels, and prevented high glucose-induced β-cell dysfunction in vivo and ex vivo. Co-infusion of 4-phenylbutyrate also decreased total and mitochondrial superoxide induced by high glucose. These results suggest that 1) ER stress plays a causal role in high glucose-induced β-cell dysfunction, and 2) there is a link between oxidative stress and ER stress in high glucose-induced β-cell dysfunction in vivo. In Study 3, JNK inhibition using the inhibitor SP600125 in rats or JNK-1 null mice prevented high glucose-induced β-cell dysfunction ex vivo and in vivo. SP600125 prevented high-glucose-induced β-cell dysfunction without decreasing total and mitochondrial superoxide levels. Both Tempol and 4-phenylbutyrate prevented JNK activation induced by high glucose. These results suggest a role of JNK activation in high glucose-induced β-cell dysfunction downstream of increased superoxide generation and ER stress in vivo. Together, the results suggest that 1) oxidative stress, ER stress and JNK activation are causally involved in β-cell glucotoxicity, and 2) High glucose-induced oxidative stress and ER stress are linked, and both impair β-cell dysfunction via JNK activation in vivo.","abstract_has_math":false,"creators":["Tang, Christine"],"institution":null,"degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":"Physiology","school":null,"contributors":[],"advisors":["Giacca, Adria"],"committee_chairs":[],"committee_members":[],"year":2011,"date_issued":"2011-02-23T15:28:33Z","date_published":"2011-02-23T15:28:33Z","updated_at":"2026-07-27T21:28:20Z","subjects":["Glucotoxicity","Oxidative Stress","Type 2 Diabetes","Endoplasmic Reticulum Stress","c-jun N-terminal kinase"],"languages":["en_ca"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/1807/26331","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Giacca, Adria"]},{"key":"dc:contributor.department","label":"Department","values":["Physiology"]},{"key":"dc:creator","label":"Author","values":["Tang, Christine"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2010-11"]},{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2011-02-23T15:28:33Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["NO_RESTRICTION","2011-02-23T15:28:33Z"]},{"key":"dc:date.issued","label":"Date","values":["2011-02-23T15:28:33Z"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Glucotoxicity","Oxidative Stress","Type 2 Diabetes","Endoplasmic Reticulum Stress","c-jun N-terminal kinase"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en_ca"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/1807/26331"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Chronic hyperglycemia, a hallmark of type 2 diabetes, can decrease β-cell function and mass (β-cell glucotoxicity); however, the mechanisms are incompletely understood. The objective was to examine the mechanisms of β-cell glucotoxicity using in vivo and ex vivo models. The hypothesis is that oxidative stress plays a causal role in high glucose-induced β-cell dysfunction in vivo via pathways that involve endoplasmic reticulum (ER) stress and JNK. The model of β-cell glucotoxicity was achieved by prolonged i.v. glucose infusion (to achieve hyperglycemia). In Study 1, 48h glucose infusion increased total and mitochondrial superoxide levels in islets, and impaired β-cell function in vivo and ex vivo. Co-infusion of the superoxide dismutase mimetic Tempol decreased total and mitochondrial superoxide, and prevented high glucose-induced β-cell dysfunction in vivo and ex vivo. These results suggest that increased superoxide generation plays a role in β-cell glucotoxicity. In Study 2, 48h glucose infusion increased activation of the unfolded protein response (XBP-1 mRNA splicing and phospho-eIF2α levels). This was partially prevented by Tempol. Co-infusion of the chemical chaperone 4-phenylbutyrate with glucose decreased spliced XBP-1 levels, and prevented high glucose-induced β-cell dysfunction in vivo and ex vivo. Co-infusion of 4-phenylbutyrate also decreased total and mitochondrial superoxide induced by high glucose. These results suggest that 1) ER stress plays a causal role in high glucose-induced β-cell dysfunction, and 2) there is a link between oxidative stress and ER stress in high glucose-induced β-cell dysfunction in vivo. In Study 3, JNK inhibition using the inhibitor SP600125 in rats or JNK-1 null mice prevented high glucose-induced β-cell dysfunction ex vivo and in vivo. SP600125 prevented high-glucose-induced β-cell dysfunction without decreasing total and mitochondrial superoxide levels. Both Tempol and 4-phenylbutyrate prevented JNK activation induced by high glucose. These results suggest a role of JNK activation in high glucose-induced β-cell dysfunction downstream of increased superoxide generation and ER stress in vivo. Together, the results suggest that 1) oxidative stress, ER stress and JNK activation are causally involved in β-cell glucotoxicity, and 2) High glucose-induced oxidative stress and ER stress are linked, and both impair β-cell dysfunction via JNK activation in vivo."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["PhD"]},{"key":"dc:title","label":"Title","values":["Mechanisms of High Glucose-induced Decrease in β-cell Function"]}]}],"canonical_facts":{"dc:contributor.advisor":["Giacca, Adria"],"dc:contributor.department":["Physiology"],"dc:creator":["Tang, Christine"],"dc:date":["2010-11"],"dc:date.accessioned":["2011-02-23T15:28:33Z"],"dc:date.available":["NO_RESTRICTION","2011-02-23T15:28:33Z"],"dc:date.issued":["2011-02-23T15:28:33Z"],"dc:description.abstract":["Chronic hyperglycemia, a hallmark of type 2 diabetes, can decrease β-cell function and mass (β-cell glucotoxicity); however, the mechanisms are incompletely understood. The objective was to examine the mechanisms of β-cell glucotoxicity using in vivo and ex vivo models. The hypothesis is that oxidative stress plays a causal role in high glucose-induced β-cell dysfunction in vivo via pathways that involve endoplasmic reticulum (ER) stress and JNK. The model of β-cell glucotoxicity was achieved by prolonged i.v. glucose infusion (to achieve hyperglycemia). In Study 1, 48h glucose infusion increased total and mitochondrial superoxide levels in islets, and impaired β-cell function in vivo and ex vivo. Co-infusion of the superoxide dismutase mimetic Tempol decreased total and mitochondrial superoxide, and prevented high glucose-induced β-cell dysfunction in vivo and ex vivo. These results suggest that increased superoxide generation plays a role in β-cell glucotoxicity. In Study 2, 48h glucose infusion increased activation of the unfolded protein response (XBP-1 mRNA splicing and phospho-eIF2α levels). This was partially prevented by Tempol. Co-infusion of the chemical chaperone 4-phenylbutyrate with glucose decreased spliced XBP-1 levels, and prevented high glucose-induced β-cell dysfunction in vivo and ex vivo. Co-infusion of 4-phenylbutyrate also decreased total and mitochondrial superoxide induced by high glucose. These results suggest that 1) ER stress plays a causal role in high glucose-induced β-cell dysfunction, and 2) there is a link between oxidative stress and ER stress in high glucose-induced β-cell dysfunction in vivo. In Study 3, JNK inhibition using the inhibitor SP600125 in rats or JNK-1 null mice prevented high glucose-induced β-cell dysfunction ex vivo and in vivo. SP600125 prevented high-glucose-induced β-cell dysfunction without decreasing total and mitochondrial superoxide levels. Both Tempol and 4-phenylbutyrate prevented JNK activation induced by high glucose. These results suggest a role of JNK activation in high glucose-induced β-cell dysfunction downstream of increased superoxide generation and ER stress in vivo. Together, the results suggest that 1) oxidative stress, ER stress and JNK activation are causally involved in β-cell glucotoxicity, and 2) High glucose-induced oxidative stress and ER stress are linked, and both impair β-cell dysfunction via JNK activation in vivo."],"dc:description.degree":["PhD"],"dc:identifier.uri":["http://hdl.handle.net/1807/26331"],"dc:language.iso":["en_ca"],"dc:subject":["Glucotoxicity","Oxidative Stress","Type 2 Diabetes","Endoplasmic Reticulum Stress","c-jun N-terminal kinase"],"dc:title":["Mechanisms of High Glucose-induced Decrease in β-cell Function"],"dc:type":["Thesis"]},"updated_at":"2026-07-27T21:28:20Z"}