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Conference Paper: MDM2 inhibitor nutlin-3a impairs glucose homeostasis and insulin secretion in mice

TitleMDM2 inhibitor nutlin-3a impairs glucose homeostasis and insulin secretion in mice
Authors
KeywordsMedical sciences
Issue Date2013
PublisherHong Kong Academy of Medicine Press. The Journal's web site is located at http://www.hkmj.org.hk
Citation
The 18th Medical Research Conference (MRC 2013), Department of Medicine, The University of Hong Kong, 12 January 2013. In Hong Kong Medical Journal, 2013, v. 19 suppl. 1, p. 33, abstract no. 48 How to Cite?
AbstractIntroduction: Mdm2, an E3 ubiquitin ligase, regulates the tumour suppressor p53 by enhancing its proteasomemediated degradation through the protein-protein interaction. A small molecule Nutlin-3a has been shown to disrupt the interaction between p53 and MDM2, thereby up-regulating expression of p53 in cancer cells. Therefore, this small molecular represents a promising therapeutic agent for cancer. However, the effect of nutlin-3a on glucose homeostasis has never been explored so far. In this study, we aimed to investigate whether nutlin-3a affects glucose metabolism using both in-vivo and in-vitro approaches. Methods: Twelve-week male C57BL/6 mice were treated with nutlin-3 or DMSO (as a vehicle control) by oral gavage 2 hours before the experiment. Glucose tolerance and insulin sensitivity were assessed by intraperitoneal glucose tolerance test (GTT) or insulin tolerance test (ITT). Insulin secretion during GTT was examined. Effect of nutlin-3a on glucose or non-glucose secretagogues-stimulated insulin secretion was determined in mouse pancreatic islets and beta cell lines. Results: The mice treated with nutlin-3 exhibited glucose intolerance which is accompanied with blunted insulin secretion, but similar insulin sensitivity compared to the DMSO control group. Further analysis revealed that beta cells treated with nutlin-3a exhibited impairment of glucose-stimulated insulin secretion (GSIS), which was associated with diminished ATP production and calcium influx. Furthermore, nutlin-3a treatment also suppresses insulin secretion induced by non-glucose secretagogues, including the mitochondria activators, the potassium channel blockers and the cell membrane depolarisation agents. Conclusion: These findings demonstrated that disruption of the interaction between MDM2 and p53 by nutlin-3 leads to glucose intolerance, owing to defective insulin secretory capacity. Such inhibitory effects on insulin secretion may attribute to impaired glucose metabolism, mitochondria activation and/or calcium mobilisation.
DescriptionOral Presentation
Persistent Identifierhttp://hdl.handle.net/10722/191676
ISSN
2019 Impact Factor: 1.679
2015 SCImago Journal Rankings: 0.279

 

DC FieldValueLanguage
dc.contributor.authorLi, Xen_US
dc.contributor.authorCheng, KKYen_US
dc.contributor.authorChen, Cen_US
dc.contributor.authorWang, Ben_US
dc.contributor.authorLam, KSLen_US
dc.contributor.authorXu, Aen_US
dc.date.accessioned2013-10-15T07:16:54Z-
dc.date.available2013-10-15T07:16:54Z-
dc.date.issued2013en_US
dc.identifier.citationThe 18th Medical Research Conference (MRC 2013), Department of Medicine, The University of Hong Kong, 12 January 2013. In Hong Kong Medical Journal, 2013, v. 19 suppl. 1, p. 33, abstract no. 48en_US
dc.identifier.issn1024-2708en_US
dc.identifier.urihttp://hdl.handle.net/10722/191676-
dc.descriptionOral Presentationen_US
dc.description.abstractIntroduction: Mdm2, an E3 ubiquitin ligase, regulates the tumour suppressor p53 by enhancing its proteasomemediated degradation through the protein-protein interaction. A small molecule Nutlin-3a has been shown to disrupt the interaction between p53 and MDM2, thereby up-regulating expression of p53 in cancer cells. Therefore, this small molecular represents a promising therapeutic agent for cancer. However, the effect of nutlin-3a on glucose homeostasis has never been explored so far. In this study, we aimed to investigate whether nutlin-3a affects glucose metabolism using both in-vivo and in-vitro approaches. Methods: Twelve-week male C57BL/6 mice were treated with nutlin-3 or DMSO (as a vehicle control) by oral gavage 2 hours before the experiment. Glucose tolerance and insulin sensitivity were assessed by intraperitoneal glucose tolerance test (GTT) or insulin tolerance test (ITT). Insulin secretion during GTT was examined. Effect of nutlin-3a on glucose or non-glucose secretagogues-stimulated insulin secretion was determined in mouse pancreatic islets and beta cell lines. Results: The mice treated with nutlin-3 exhibited glucose intolerance which is accompanied with blunted insulin secretion, but similar insulin sensitivity compared to the DMSO control group. Further analysis revealed that beta cells treated with nutlin-3a exhibited impairment of glucose-stimulated insulin secretion (GSIS), which was associated with diminished ATP production and calcium influx. Furthermore, nutlin-3a treatment also suppresses insulin secretion induced by non-glucose secretagogues, including the mitochondria activators, the potassium channel blockers and the cell membrane depolarisation agents. Conclusion: These findings demonstrated that disruption of the interaction between MDM2 and p53 by nutlin-3 leads to glucose intolerance, owing to defective insulin secretory capacity. Such inhibitory effects on insulin secretion may attribute to impaired glucose metabolism, mitochondria activation and/or calcium mobilisation.en_US
dc.languageengen_US
dc.publisherHong Kong Academy of Medicine Press. The Journal's web site is located at http://www.hkmj.org.hken_US
dc.relation.ispartofHong Kong Medical Journalen_US
dc.subjectMedical sciencesen_US
dc.titleMDM2 inhibitor nutlin-3a impairs glucose homeostasis and insulin secretion in miceen_US
dc.typeConference_Paperen_US
dc.identifier.emailLi, X: lixiaomu@hku.hken_US
dc.identifier.emailCheng, KKY: dorncky@hkucc.hku.hken_US
dc.identifier.emailChen, C: endocc@hku.hken_US
dc.identifier.emailLam, KSL: ksllam@hku.hken_US
dc.identifier.emailXu, A: amxu@hkucc.hku.hken_US
dc.identifier.authorityCheng, KKY=rp01672en_US
dc.identifier.authorityLam, KSL=rp00343en_US
dc.identifier.authorityXu, A=rp00485en_US
dc.identifier.hkuros225767en_US
dc.identifier.volume19en_US
dc.identifier.issuesuppl. 1en_US
dc.identifier.spage33, abstract no. 48en_US
dc.identifier.epage33, abstract no. 48en_US
dc.publisher.placeHong Kongen_US
dc.customcontrol.immutablesml 131018-
dc.identifier.issnl1024-2708-

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