{"id":{"repo_id":"ucl","oai_identifier":"oai:eprints.ucl.ac.uk.OAI2:14467"},"canonical_url":"https://search.dev.ndltd.org/etd/ucl/oai:eprints.ucl.ac.uk.OAI2:14467","repository":{"repo_id":"ucl","name":"University College London","base_url":"https://discovery.ucl.ac.uk/cgi/oai2"},"display":{"title":"The use of a genetic strategy to study the role of modulation of oxidative stress by uncoupling proteins 2 and 3 in the pathogenesis of Type 2 Diabetes","abstract":"Mitochondrial dysfunction has been implicated in the early pathogenesis of Type 2 Diabetes. The uncoupling proteins 2 and 3 are mitochondrial proteins found in man that have been implicated in protecting mammals from the effects of over-nutrition. Examination of the effect of genetic variation in the UCP2-UCP3 genetic cluster has so far been inconclusive. The aim of this thesis was to examine, using a genetic strategy, the hypothesis that the role of the uncoupling proteins 2 and 3 in the pathogenesis of Type 2 Diabetes is via modification of oxidative stress. In a prospective study of nearly 3000 men the risk of type 2 diabetes at 10 years was increased for both the UCP2-866AA (1.94 [1.18-3.19]: p=0.009) and the UCP3-55TT (2.06 [1.06-3.99]: p=0.03) homozygotes. This increased risk was not explained by the association with any measured conventional risk factors. Paradoxically, in a Europe-wide cross-sectional study of 598 subjects the UCP2-866A variant was associated with lower waist-hip ratio (GX v AA,1.00 [0.06] v 0.98 [0.07]; p=0.003), although also associated with lower insulin secretion (42.6 [24.6] v 35.6 [18.6]; p=0.03). The UCP3 variant was not significantly associated with any metabolic trait. The significant heritability of plasma markers of oxidative stress (TAS 0.54, TOAS 0.49) suggests anti-oxidant function is a plausible mechanism to determine Type 2 Diabetes risk. The predictors of anti-oxidant stress in a family study were examined, as was the impact of UCP2-UCP3 gene cluster variation. Genetic variation in the UCP2-UCP3 was found to increase the risk of the Type 2 diabetes. While UCP2 may modify insulin secretion directly, the mechanism of action for UCP3 is likely to involve novel risk factors for Type 2 Diabetes such as modification of mitochondrial oxidative stress. Finally, the development of a human model is described to examine genetic influences on oxidative stress burden using a meal rich in used cooking oil.","abstract_html":"Mitochondrial dysfunction has been implicated in the early pathogenesis of Type 2 Diabetes. The uncoupling proteins 2 and 3 are mitochondrial proteins found in man that have been implicated in protecting mammals from the effects of over-nutrition. Examination of the effect of genetic variation in the UCP2-UCP3 genetic cluster has so far been inconclusive. The aim of this thesis was to examine, using a genetic strategy, the hypothesis that the role of the uncoupling proteins 2 and 3 in the pathogenesis of Type 2 Diabetes is via modification of oxidative stress. In a prospective study of nearly 3000 men the risk of type 2 diabetes at 10 years was increased for both the UCP2-866AA (1.94 [1.18-3.19]: p=0.009) and the UCP3-55TT (2.06 [1.06-3.99]: p=0.03) homozygotes. This increased risk was not explained by the association with any measured conventional risk factors. Paradoxically, in a Europe-wide cross-sectional study of 598 subjects the UCP2-866A variant was associated with lower waist-hip ratio (GX v AA,1.00 [0.06] v 0.98 [0.07]; p=0.003), although also associated with lower insulin secretion (42.6 [24.6] v 35.6 [18.6]; p=0.03). The UCP3 variant was not significantly associated with any metabolic trait. The significant heritability of plasma markers of oxidative stress (TAS 0.54, TOAS 0.49) suggests anti-oxidant function is a plausible mechanism to determine Type 2 Diabetes risk. The predictors of anti-oxidant stress in a family study were examined, as was the impact of UCP2-UCP3 gene cluster variation. Genetic variation in the UCP2-UCP3 was found to increase the risk of the Type 2 diabetes. While UCP2 may modify insulin secretion directly, the mechanism of action for UCP3 is likely to involve novel risk factors for Type 2 Diabetes such as modification of mitochondrial oxidative stress. Finally, the development of a human model is described to examine genetic influences on oxidative stress burden using a meal rich in used cooking oil.","abstract_has_math":false,"creators":["Gable, D.R."],"institution":"UCL (University College London)","degree_name":null,"degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2009,"date_issued":"2009-01","date_published":"2009-01","updated_at":"2026-07-24T05:10:21Z","subjects":["Centre for Cardiovascular Genetics"],"languages":["en","eng"],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":null,"outbound_label":null,"outbound_source":null},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:creator","label":"Author","values":["Gable, D.R."]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date","label":"Dc Date","values":["2009-01"]},{"key":"dc:date.issued","label":"Date","values":["2009-01"]},{"key":"dc:publisher.department","label":"Dc Publisher Department","values":["Centre for Cardiovascular Genetics"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["UCL (University College London)"]},{"key":"dc:relation.isreferencedby","label":"Dc Relation Isreferencedby","values":["https://discovery.ucl.ac.uk/id/eprint/14467/"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Centre for Cardiovascular Genetics"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en","eng"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://discovery.ucl.ac.uk/id/eprint/14467/1/14467.pdf"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Mitochondrial dysfunction has been implicated in the early pathogenesis of Type 2 Diabetes. The uncoupling proteins 2 and 3 are mitochondrial proteins found in man that have been implicated in protecting mammals from the effects of over-nutrition. Examination of the effect of genetic variation in the UCP2-UCP3 genetic cluster has so far been inconclusive. The aim of this thesis was to examine, using a genetic strategy, the hypothesis that the role of the uncoupling proteins 2 and 3 in the pathogenesis of Type 2 Diabetes is via modification of oxidative stress. In a prospective study of nearly 3000 men the risk of type 2 diabetes at 10 years was increased for both the UCP2-866AA (1.94 [1.18-3.19]: p=0.009) and the UCP3-55TT (2.06 [1.06-3.99]: p=0.03) homozygotes. This increased risk was not explained by the association with any measured conventional risk factors. Paradoxically, in a Europe-wide cross-sectional study of 598 subjects the UCP2-866A variant was associated with lower waist-hip ratio (GX v AA,1.00 [0.06] v 0.98 [0.07]; p=0.003), although also associated with lower insulin secretion (42.6 [24.6] v 35.6 [18.6]; p=0.03). The UCP3 variant was not significantly associated with any metabolic trait. The significant heritability of plasma markers of oxidative stress (TAS 0.54, TOAS 0.49) suggests anti-oxidant function is a plausible mechanism to determine Type 2 Diabetes risk. The predictors of anti-oxidant stress in a family study were examined, as was the impact of UCP2-UCP3 gene cluster variation. Genetic variation in the UCP2-UCP3 was found to increase the risk of the Type 2 diabetes. While UCP2 may modify insulin secretion directly, the mechanism of action for UCP3 is likely to involve novel risk factors for Type 2 Diabetes such as modification of mitochondrial oxidative stress. Finally, the development of a human model is described to examine genetic influences on oxidative stress burden using a meal rich in used cooking oil."]},{"key":"dc:format","label":"Dc Format","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["The use of a genetic strategy to study the role of modulation of oxidative stress by uncoupling proteins 2 and 3 in the pathogenesis of Type 2 Diabetes"]}]}],"canonical_facts":{"dc:creator":["Gable, D.R."],"dc:date":["2009-01"],"dc:date.issued":["2009-01"],"dc:description.abstract":["Mitochondrial dysfunction has been implicated in the early pathogenesis of Type 2 Diabetes. The uncoupling proteins 2 and 3 are mitochondrial proteins found in man that have been implicated in protecting mammals from the effects of over-nutrition. Examination of the effect of genetic variation in the UCP2-UCP3 genetic cluster has so far been inconclusive. The aim of this thesis was to examine, using a genetic strategy, the hypothesis that the role of the uncoupling proteins 2 and 3 in the pathogenesis of Type 2 Diabetes is via modification of oxidative stress. In a prospective study of nearly 3000 men the risk of type 2 diabetes at 10 years was increased for both the UCP2-866AA (1.94 [1.18-3.19]: p=0.009) and the UCP3-55TT (2.06 [1.06-3.99]: p=0.03) homozygotes. This increased risk was not explained by the association with any measured conventional risk factors. Paradoxically, in a Europe-wide cross-sectional study of 598 subjects the UCP2-866A variant was associated with lower waist-hip ratio (GX v AA,1.00 [0.06] v 0.98 [0.07]; p=0.003), although also associated with lower insulin secretion (42.6 [24.6] v 35.6 [18.6]; p=0.03). The UCP3 variant was not significantly associated with any metabolic trait. The significant heritability of plasma markers of oxidative stress (TAS 0.54, TOAS 0.49) suggests anti-oxidant function is a plausible mechanism to determine Type 2 Diabetes risk. The predictors of anti-oxidant stress in a family study were examined, as was the impact of UCP2-UCP3 gene cluster variation. Genetic variation in the UCP2-UCP3 was found to increase the risk of the Type 2 diabetes. While UCP2 may modify insulin secretion directly, the mechanism of action for UCP3 is likely to involve novel risk factors for Type 2 Diabetes such as modification of mitochondrial oxidative stress. Finally, the development of a human model is described to examine genetic influences on oxidative stress burden using a meal rich in used cooking oil."],"dc:format":["application/pdf"],"dc:identifier.uri":["https://discovery.ucl.ac.uk/id/eprint/14467/1/14467.pdf"],"dc:language":["en","eng"],"dc:publisher.department":["Centre for Cardiovascular Genetics"],"dc:publisher.institution":["UCL (University College London)"],"dc:relation.isreferencedby":["https://discovery.ucl.ac.uk/id/eprint/14467/"],"dc:subject":["Centre for Cardiovascular Genetics"],"dc:title":["The use of a genetic strategy to study the role of modulation of oxidative stress by uncoupling proteins 2 and 3 in the pathogenesis of Type 2 Diabetes"],"dc:type":["Thesis"],"dc:type.qualificationlevel":["Doctoral"]},"updated_at":"2026-07-24T05:10:21Z"}