{"id":{"repo_id":"dundee","oai_identifier":"oai:discovery.dundee.ac.uk:studenttheses/bff6b386-2095-4265-aa97-159378d29019"},"canonical_url":"https://search.dev.ndltd.org/etd/dundee/oai:discovery.dundee.ac.uk:studenttheses/bff6b386-2095-4265-aa97-159378d29019","repository":{"repo_id":"dundee","name":"University of Dundee","base_url":"https://discovery.dundee.ac.uk/ws/oai"},"display":{"title":"The Role of Interleukin-6 in the Regulation of Glucose Sensing in Hypothalamic GT1-7 Neurons","abstract":"Hypoglycaemia is the major complication associated with insulin therapy in type 1 diabetes. Repeated exposure to hypoglycaemia leads to suppression of normal counter regulatory responses (CRR) to subsequent hypoglycaemia, which increases the risk of severe episodes of hypoglycaemia. Studies have demonstrated the important role the brain plays in the regulation of whole body glucose homeostasis, including a vital role in mounting the CRR. Detection of hypoglycaemia by specialised glucose-sensing neurons of the hypothalamus is critical for initiating the associated CRR. It is believed that defective CRRs are mediated by brain adaptations leading to impaired central glucose sensing, although the mechanisms by which these occur remain unknown. Hypoglycaemia evokes a significant systemic and central stress response with an increase in inflammatory mediators including interleukin-6 (IL-6). The aim of the current study was to investigate whether IL-6 played a role in the regulation of central glucose sensing. This was addressed by examining the effects of IL-6 exposure on electrophysiological and biochemical responses in hypothalamic glucose-excited GT1-7 neurons. Antecedent exposure to IL-6 induced defective glucose sensing of subsequent hypoglycaemia, with a role for the exchange protein activated by cAMP (EPAC) implicated in this observation. The results obtained suggest that EPAC may mediate this effect by enhancing the sensitivity of ATP-sensitive potassium (KATP) channels to ATP-mediated inhibition following IL-6 exposure. The current results identify IL-6 and EPAC2 as novel mediators of defective hypothalamic glucose sensing, suggesting they may contribute to the development of blunted CRR observed with recurrent hypoglycaemia exposure.","abstract_html":"Hypoglycaemia is the major complication associated with insulin therapy in type 1 diabetes. Repeated exposure to hypoglycaemia leads to suppression of normal counter regulatory responses (CRR) to subsequent hypoglycaemia, which increases the risk of severe episodes of hypoglycaemia. Studies have demonstrated the important role the brain plays in the regulation of whole body glucose homeostasis, including a vital role in mounting the CRR. Detection of hypoglycaemia by specialised glucose-sensing neurons of the hypothalamus is critical for initiating the associated CRR. It is believed that defective CRRs are mediated by brain adaptations leading to impaired central glucose sensing, although the mechanisms by which these occur remain unknown. Hypoglycaemia evokes a significant systemic and central stress response with an increase in inflammatory mediators including interleukin-6 (IL-6). The aim of the current study was to investigate whether IL-6 played a role in the regulation of central glucose sensing. This was addressed by examining the effects of IL-6 exposure on electrophysiological and biochemical responses in hypothalamic glucose-excited GT1-7 neurons. Antecedent exposure to IL-6 induced defective glucose sensing of subsequent hypoglycaemia, with a role for the exchange protein activated by cAMP (EPAC) implicated in this observation. The results obtained suggest that EPAC may mediate this effect by enhancing the sensitivity of ATP-sensitive potassium (KATP) channels to ATP-mediated inhibition following IL-6 exposure. The current results identify IL-6 and EPAC2 as novel mediators of defective hypothalamic glucose sensing, suggesting they may contribute to the development of blunted CRR observed with recurrent hypoglycaemia exposure.","abstract_has_math":false,"creators":["Denwood, Geoffrey T."],"institution":"University of Dundee","degree_name":"Doctor of Philosophy","degree_level":"Doctoral Thesis","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["McCrimmon, Rory","Ashford, Michael"],"committee_chairs":[],"committee_members":[],"year":2015,"date_issued":"2015","date_published":"2015","updated_at":"2026-07-24T02:08:12Z","subjects":[],"languages":["eng"],"rights":[],"rights_urls":[],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["oai:discovery.dundee.ac.uk:studenttheses/bff6b386-2095-4265-aa97-159378d29019"],"render_values":[{"text":"oai:discovery.dundee.ac.uk:studenttheses/bff6b386-2095-4265-aa97-159378d29019","href":null,"code":true}]}]},"links":{"outbound_url":"https://discovery.dundee.ac.uk/en/studentTheses/bff6b386-2095-4265-aa97-159378d29019","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["McCrimmon, Rory","Ashford, Michael"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["Juvenile Diabetes Research Foundation"]},{"key":"dc:creator","label":"Author","values":["Denwood, Geoffrey T."]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2015"]},{"key":"dc:date.issued","label":"Date","values":["2015"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["Cardiovascular and Diabetes Medicine"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Dundee"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://discovery.dundee.ac.uk/en/studentTheses/bff6b386-2095-4265-aa97-159378d29019"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral Thesis"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["eng"]},{"key":"dc:rights.embargodate","label":"Dc Rights Embargodate","values":["2017-04-01"]},{"key":"dc:rights.embargoreason","label":"Dc Rights Embargoreason","values":["/dk/atira/pure/core/document/studentthesisembargoreason/commercialexploitation"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["oai:discovery.dundee.ac.uk:studenttheses/bff6b386-2095-4265-aa97-159378d29019","https://discovery.dundee.ac.uk/en/studentTheses/bff6b386-2095-4265-aa97-159378d29019"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://discovery.dundee.ac.uk/files/8263270/Geoffrey_Denwood_Thesis.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Hypoglycaemia is the major complication associated with insulin therapy in type 1 diabetes. Repeated exposure to hypoglycaemia leads to suppression of normal counter regulatory responses (CRR) to subsequent hypoglycaemia, which increases the risk of severe episodes of hypoglycaemia. Studies have demonstrated the important role the brain plays in the regulation of whole body glucose homeostasis, including a vital role in mounting the CRR. Detection of hypoglycaemia by specialised glucose-sensing neurons of the hypothalamus is critical for initiating the associated CRR. It is believed that defective CRRs are mediated by brain adaptations leading to impaired central glucose sensing, although the mechanisms by which these occur remain unknown. Hypoglycaemia evokes a significant systemic and central stress response with an increase in inflammatory mediators including interleukin-6 (IL-6). The aim of the current study was to investigate whether IL-6 played a role in the regulation of central glucose sensing. This was addressed by examining the effects of IL-6 exposure on electrophysiological and biochemical responses in hypothalamic glucose-excited GT1-7 neurons. Antecedent exposure to IL-6 induced defective glucose sensing of subsequent hypoglycaemia, with a role for the exchange protein activated by cAMP (EPAC) implicated in this observation. The results obtained suggest that EPAC may mediate this effect by enhancing the sensitivity of ATP-sensitive potassium (KATP) channels to ATP-mediated inhibition following IL-6 exposure. The current results identify IL-6 and EPAC2 as novel mediators of defective hypothalamic glucose sensing, suggesting they may contribute to the development of blunted CRR observed with recurrent hypoglycaemia exposure."]},{"key":"dc:title","label":"Title","values":["The Role of Interleukin-6 in the Regulation of Glucose Sensing in Hypothalamic GT1-7 Neurons"]}]}],"canonical_facts":{"dc:contributor.advisor":["McCrimmon, Rory","Ashford, Michael"],"dc:contributor.sponsor":["Juvenile Diabetes Research Foundation"],"dc:creator":["Denwood, Geoffrey T."],"dc:date":["2015"],"dc:date.issued":["2015"],"dc:description.abstract":["Hypoglycaemia is the major complication associated with insulin therapy in type 1 diabetes. Repeated exposure to hypoglycaemia leads to suppression of normal counter regulatory responses (CRR) to subsequent hypoglycaemia, which increases the risk of severe episodes of hypoglycaemia. Studies have demonstrated the important role the brain plays in the regulation of whole body glucose homeostasis, including a vital role in mounting the CRR. Detection of hypoglycaemia by specialised glucose-sensing neurons of the hypothalamus is critical for initiating the associated CRR. It is believed that defective CRRs are mediated by brain adaptations leading to impaired central glucose sensing, although the mechanisms by which these occur remain unknown. Hypoglycaemia evokes a significant systemic and central stress response with an increase in inflammatory mediators including interleukin-6 (IL-6). The aim of the current study was to investigate whether IL-6 played a role in the regulation of central glucose sensing. This was addressed by examining the effects of IL-6 exposure on electrophysiological and biochemical responses in hypothalamic glucose-excited GT1-7 neurons. Antecedent exposure to IL-6 induced defective glucose sensing of subsequent hypoglycaemia, with a role for the exchange protein activated by cAMP (EPAC) implicated in this observation. The results obtained suggest that EPAC may mediate this effect by enhancing the sensitivity of ATP-sensitive potassium (KATP) channels to ATP-mediated inhibition following IL-6 exposure. 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