{"id":{"repo_id":"unsw","oai_identifier":"oai:unsworks.library.unsw.edu.au:1959.4/54132"},"canonical_url":"https://search.dev.ndltd.org/etd/unsw/oai:unsworks.library.unsw.edu.au:1959.4/54132","repository":{"repo_id":"unsw","name":"University of New South Wales","base_url":"https://unsworks.unsw.edu.au/oai/provider"},"display":{"title":"The non-canonical NF-kappaB pathway as a novel player in beta cell dysfunction in diabetes","abstract":"Loss of pancreatic β cell mass and function is a feature of both type-1 and type-2 diabetes. The non-canonical NF-κB pathway has recently garnered attention at being involved in the development of peripheral insulin resistance (liver, muscle) in diabetes. Whether pancreatic β cell non-canonical NF-κB signalling contributes to glucose homeostasis and diabetes is unknown. We found that the non-canonical NF-κB pathway was activated in islets from diet-induced obese (DIO) mice compared to chow controls, as evidenced by accumulation of NF-κB-inducing kinase (NIK), IKKα phosphorylation, p100 to p52 processing and RelB accumulation. To examine the effect of NIK accumulation in β cells, we generated a genetic β cell-specific mouse model of constitutive NIK activation. The TRAF2/TRAF3/BIRC2/3 E3 ubiquitin ligase complex tightly controls activation of NIK. Deletion of either component (βTRAF or βBIRC) promotes β cell-intrinsic NIK activation. βTRAF2 mice showed exacerbated glucose intolerance and impaired first-phase insulin secretion in a DIO model. β cell mass was increased in βTRAF2 mice, indicating severely impaired insulin secretory capacity. βTRAF2 islets exhibited dysregulated TNFα-stimulated canonical NF-κB and MAPK signalling. To dissect out whether NIK activation was promoting β cell dysfunction, we next utilized a β cell-specific deletion of TRAF3. βTRAF3 mice phenocopied βTRAF2 mice showing defective first-phase insulin secretion and increased β cell mass. βTRAF3 islets exhibited hyper-activation of NIK but normal TNFα-stimulated canonical NF-κB and MAPK signalling. Next, we set out to determine whether increased β cell expansion in NIK ON mice per se might trigger β cell dysfunction or whether acute NIK activation would also alter β cell function. Using a drug-based approach, we examined function in islets treated with a BIRC-inhibitor (MV1; Smac-mimetic). Ex vivo, MV1-treated mouse islets showed impaired GSIS. In vivo, MV1 disrupted glucose homeostasis as MV1-treated islets failed to provide normal metabolic control in syngeneic transplant recipients, and MV1-injected zebrafish larvae exhibited hyper-glycosuria. In summary, we have discovered that the diabetic milieu triggers β cell-intrinsic NIK activation. Constitutive as well as acute activation of NIK precipitates β cell secretory defects in mice and fish. Thus, NIK is a critical signalling node regulating glucose homeostasis in diabetes.","abstract_html":"Loss of pancreatic β cell mass and function is a feature of both type-1 and type-2 diabetes. The non-canonical NF-κB pathway has recently garnered attention at being involved in the development of peripheral insulin resistance (liver, muscle) in diabetes. Whether pancreatic β cell non-canonical NF-κB signalling contributes to glucose homeostasis and diabetes is unknown. We found that the non-canonical NF-κB pathway was activated in islets from diet-induced obese (DIO) mice compared to chow controls, as evidenced by accumulation of NF-κB-inducing kinase (NIK), IKKα phosphorylation, p100 to p52 processing and RelB accumulation. To examine the effect of NIK accumulation in β cells, we generated a genetic β cell-specific mouse model of constitutive NIK activation. The TRAF2/TRAF3/BIRC2/3 E3 ubiquitin ligase complex tightly controls activation of NIK. Deletion of either component (βTRAF or βBIRC) promotes β cell-intrinsic NIK activation. βTRAF2 mice showed exacerbated glucose intolerance and impaired first-phase insulin secretion in a DIO model. β cell mass was increased in βTRAF2 mice, indicating severely impaired insulin secretory capacity. βTRAF2 islets exhibited dysregulated TNFα-stimulated canonical NF-κB and MAPK signalling. To dissect out whether NIK activation was promoting β cell dysfunction, we next utilized a β cell-specific deletion of TRAF3. βTRAF3 mice phenocopied βTRAF2 mice showing defective first-phase insulin secretion and increased β cell mass. βTRAF3 islets exhibited hyper-activation of NIK but normal TNFα-stimulated canonical NF-κB and MAPK signalling. Next, we set out to determine whether increased β cell expansion in NIK ON mice per se might trigger β cell dysfunction or whether acute NIK activation would also alter β cell function. Using a drug-based approach, we examined function in islets treated with a BIRC-inhibitor (MV1; Smac-mimetic). Ex vivo, MV1-treated mouse islets showed impaired GSIS. In vivo, MV1 disrupted glucose homeostasis as MV1-treated islets failed to provide normal metabolic control in syngeneic transplant recipients, and MV1-injected zebrafish larvae exhibited hyper-glycosuria. In summary, we have discovered that the diabetic milieu triggers β cell-intrinsic NIK activation. Constitutive as well as acute activation of NIK precipitates β cell secretory defects in mice and fish. Thus, NIK is a critical signalling node regulating glucose homeostasis in diabetes.","abstract_has_math":false,"creators":["Malle, Elisabeth Karin"],"institution":"UNSW, Sydney","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2014,"date_issued":"2014","date_published":"2014","updated_at":"2026-07-24T05:32:53Z","subjects":["Islet","Beta cell dysfunction","NF-kappaB","Inflammation","Diabetes"],"languages":["EN"],"rights":["open access","CC BY-NC-ND 3.0","free_to_read"],"rights_urls":["https://purl.org/coar/access_right/c_abf2","https://creativecommons.org/licenses/by-nc-nd/3.0/au/"],"identifier_entries":[{"key":"dc:identifier","label":"Identifier","values":["https://doi.org/10.26190/unsworks/2684"],"render_values":[{"text":"https://doi.org/10.26190/unsworks/2684","href":"https://doi.org/10.26190/unsworks/2684","code":true}]}]},"links":{"outbound_url":"http://hdl.handle.net/1959.4/54132","outbound_label":"Handle","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Malle, Elisabeth Karin"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2014"]},{"key":"dc:publisher","label":"Institution","values":["UNSW, Sydney"]},{"key":"dc:type","label":"Dc Type","values":["doctoral thesis","http://purl.org/coar/resource_type/c_db06"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Islet","Beta cell dysfunction","NF-kappaB","Inflammation","Diabetes"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["EN"]},{"key":"dc:rights","label":"Dc Rights","values":["open access","https://purl.org/coar/access_right/c_abf2","CC BY-NC-ND 3.0","https://creativecommons.org/licenses/by-nc-nd/3.0/au/","free_to_read"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["http://hdl.handle.net/1959.4/54132","https://unsworks.unsw.edu.au/bitstreams/035384ec-fc23-4eb9-9d43-f96a2becb293/download","https://doi.org/10.26190/unsworks/2684"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Loss of pancreatic β cell mass and function is a feature of both type-1 and type-2 diabetes. The non-canonical NF-κB pathway has recently garnered attention at being involved in the development of peripheral insulin resistance (liver, muscle) in diabetes. Whether pancreatic β cell non-canonical NF-κB signalling contributes to glucose homeostasis and diabetes is unknown. We found that the non-canonical NF-κB pathway was activated in islets from diet-induced obese (DIO) mice compared to chow controls, as evidenced by accumulation of NF-κB-inducing kinase (NIK), IKKα phosphorylation, p100 to p52 processing and RelB accumulation. To examine the effect of NIK accumulation in β cells, we generated a genetic β cell-specific mouse model of constitutive NIK activation. The TRAF2/TRAF3/BIRC2/3 E3 ubiquitin ligase complex tightly controls activation of NIK. Deletion of either component (βTRAF or βBIRC) promotes β cell-intrinsic NIK activation. βTRAF2 mice showed exacerbated glucose intolerance and impaired first-phase insulin secretion in a DIO model. β cell mass was increased in βTRAF2 mice, indicating severely impaired insulin secretory capacity. βTRAF2 islets exhibited dysregulated TNFα-stimulated canonical NF-κB and MAPK signalling. To dissect out whether NIK activation was promoting β cell dysfunction, we next utilized a β cell-specific deletion of TRAF3. βTRAF3 mice phenocopied βTRAF2 mice showing defective first-phase insulin secretion and increased β cell mass. βTRAF3 islets exhibited hyper-activation of NIK but normal TNFα-stimulated canonical NF-κB and MAPK signalling. Next, we set out to determine whether increased β cell expansion in NIK ON mice per se might trigger β cell dysfunction or whether acute NIK activation would also alter β cell function. Using a drug-based approach, we examined function in islets treated with a BIRC-inhibitor (MV1; Smac-mimetic). Ex vivo, MV1-treated mouse islets showed impaired GSIS. In vivo, MV1 disrupted glucose homeostasis as MV1-treated islets failed to provide normal metabolic control in syngeneic transplant recipients, and MV1-injected zebrafish larvae exhibited hyper-glycosuria. In summary, we have discovered that the diabetic milieu triggers β cell-intrinsic NIK activation. Constitutive as well as acute activation of NIK precipitates β cell secretory defects in mice and fish. Thus, NIK is a critical signalling node regulating glucose homeostasis in diabetes."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["The non-canonical NF-kappaB pathway as a novel player in beta cell dysfunction in diabetes"]}]}],"canonical_facts":{"dc:creator":["Malle, Elisabeth Karin"],"dc:date":["2014"],"dc:description":["Loss of pancreatic β cell mass and function is a feature of both type-1 and type-2 diabetes. The non-canonical NF-κB pathway has recently garnered attention at being involved in the development of peripheral insulin resistance (liver, muscle) in diabetes. Whether pancreatic β cell non-canonical NF-κB signalling contributes to glucose homeostasis and diabetes is unknown. We found that the non-canonical NF-κB pathway was activated in islets from diet-induced obese (DIO) mice compared to chow controls, as evidenced by accumulation of NF-κB-inducing kinase (NIK), IKKα phosphorylation, p100 to p52 processing and RelB accumulation. To examine the effect of NIK accumulation in β cells, we generated a genetic β cell-specific mouse model of constitutive NIK activation. The TRAF2/TRAF3/BIRC2/3 E3 ubiquitin ligase complex tightly controls activation of NIK. Deletion of either component (βTRAF or βBIRC) promotes β cell-intrinsic NIK activation. βTRAF2 mice showed exacerbated glucose intolerance and impaired first-phase insulin secretion in a DIO model. β cell mass was increased in βTRAF2 mice, indicating severely impaired insulin secretory capacity. βTRAF2 islets exhibited dysregulated TNFα-stimulated canonical NF-κB and MAPK signalling. To dissect out whether NIK activation was promoting β cell dysfunction, we next utilized a β cell-specific deletion of TRAF3. βTRAF3 mice phenocopied βTRAF2 mice showing defective first-phase insulin secretion and increased β cell mass. βTRAF3 islets exhibited hyper-activation of NIK but normal TNFα-stimulated canonical NF-κB and MAPK signalling. Next, we set out to determine whether increased β cell expansion in NIK ON mice per se might trigger β cell dysfunction or whether acute NIK activation would also alter β cell function. Using a drug-based approach, we examined function in islets treated with a BIRC-inhibitor (MV1; Smac-mimetic). Ex vivo, MV1-treated mouse islets showed impaired GSIS. In vivo, MV1 disrupted glucose homeostasis as MV1-treated islets failed to provide normal metabolic control in syngeneic transplant recipients, and MV1-injected zebrafish larvae exhibited hyper-glycosuria. In summary, we have discovered that the diabetic milieu triggers β cell-intrinsic NIK activation. Constitutive as well as acute activation of NIK precipitates β cell secretory defects in mice and fish. Thus, NIK is a critical signalling node regulating glucose homeostasis in diabetes."],"dc:format":["application/pdf"],"dc:identifier":["http://hdl.handle.net/1959.4/54132","https://unsworks.unsw.edu.au/bitstreams/035384ec-fc23-4eb9-9d43-f96a2becb293/download","https://doi.org/10.26190/unsworks/2684"],"dc:language":["EN"],"dc:publisher":["UNSW, Sydney"],"dc:rights":["open access","https://purl.org/coar/access_right/c_abf2","CC BY-NC-ND 3.0","https://creativecommons.org/licenses/by-nc-nd/3.0/au/","free_to_read"],"dc:subject":["Islet","Beta cell dysfunction","NF-kappaB","Inflammation","Diabetes"],"dc:title":["The non-canonical NF-kappaB pathway as a novel player in beta cell dysfunction in diabetes"],"dc:type":["doctoral thesis","http://purl.org/coar/resource_type/c_db06"]},"updated_at":"2026-07-24T05:32:53Z"}