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Article: APPL1 potentiates insulin secretion in pancreatic β cells by enhancing protein kinase Akt-dependent expression of SNARE proteins in mice

TitleAPPL1 potentiates insulin secretion in pancreatic β cells by enhancing protein kinase Akt-dependent expression of SNARE proteins in mice
Authors
Issue Date2012
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2012, v. 109 n. 23, p. 8919-8924 How to Cite?
AbstractInsulin resistance and defective insulin secretion are the two major features of type 2 diabetes. The adapter protein APPL1 is an obligatory molecule in regulating peripheral insulin sensitivity, but its role in insulin secretion remains elusive. Here, we show that APPL1 expression in pancreatic β cells is markedly decreased in several mouse models of obesity and diabetes. APPL1 knockout mice exhibit glucose intolerance and impaired glucose-stimulated insulin secretion (GSIS), whereas transgenic expression of APPL1 prevents high-fat diet (HFD)-induced glucose intolerance partly by enhancing GSIS. In both pancreatic islets and rat β cells, APPL1 deficiency causes a marked reduction in expression of the exocytotic machinery SNARE proteins (syntaxin-1, synaptosomal-associated protein 25, and vesicle-associated membrane protein 2) and an obvious decrease in the number of exocytotic events. Such changes are accompanied by diminished insulin-stimulated Akt activation. Furthermore, the defective GSIS and reduced expression of SNARE proteins in APPL1-deficient β cells can be rescued by adenovirus-mediated expression of APPL1 or constitutively active Akt. These findings demonstrate that APPL1 couples insulin-stimulated Akt activation to GSIS by promoting the expression of the core exocytotic machinery involved in exocytosis and also suggest that reduced APPL1 expression in pancreatic islets may serve as a pathological link that couples insulin resistance to β-cell dysfunction in type 2 diabetes.
Persistent Identifierhttp://hdl.handle.net/10722/152745
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Research Grants Council of Hong KongHKU 781309M
783010M
T12-705/11
HKU4/CRF/10
National Basic Research Program of China2011CB504004
University of Hong Kong
National Science Foundation of China30811120429
Funding Information:

This work was supported by General Research Fund Grants HKU 781309M and 783010M (to A. X.), Theme-Based Research Scheme Grant T12-705/11, and Collaborative Research Fund Grant HKU4/CRF/10 from the Research Grants Council of Hong Kong, the National Basic Research Program of China Grant 2011CB504004, and its matching fund from The University of Hong Kong, and the National Science Foundation of China Grant 30811120429.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorCheng, KKYen_HK
dc.contributor.authorLam, KSLen_HK
dc.contributor.authorWu, Den_HK
dc.contributor.authorWang, Yen_HK
dc.contributor.authorSweeney, Gen_HK
dc.contributor.authorHoo, RLCen_HK
dc.contributor.authorZhang, Jen_HK
dc.contributor.authorXu, Aen_HK
dc.date.accessioned2012-07-16T09:47:30Z-
dc.date.available2012-07-16T09:47:30Z-
dc.date.issued2012en_HK
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2012, v. 109 n. 23, p. 8919-8924en_HK
dc.identifier.issn0027-8424en_HK
dc.identifier.urihttp://hdl.handle.net/10722/152745-
dc.description.abstractInsulin resistance and defective insulin secretion are the two major features of type 2 diabetes. The adapter protein APPL1 is an obligatory molecule in regulating peripheral insulin sensitivity, but its role in insulin secretion remains elusive. Here, we show that APPL1 expression in pancreatic β cells is markedly decreased in several mouse models of obesity and diabetes. APPL1 knockout mice exhibit glucose intolerance and impaired glucose-stimulated insulin secretion (GSIS), whereas transgenic expression of APPL1 prevents high-fat diet (HFD)-induced glucose intolerance partly by enhancing GSIS. In both pancreatic islets and rat β cells, APPL1 deficiency causes a marked reduction in expression of the exocytotic machinery SNARE proteins (syntaxin-1, synaptosomal-associated protein 25, and vesicle-associated membrane protein 2) and an obvious decrease in the number of exocytotic events. Such changes are accompanied by diminished insulin-stimulated Akt activation. Furthermore, the defective GSIS and reduced expression of SNARE proteins in APPL1-deficient β cells can be rescued by adenovirus-mediated expression of APPL1 or constitutively active Akt. These findings demonstrate that APPL1 couples insulin-stimulated Akt activation to GSIS by promoting the expression of the core exocytotic machinery involved in exocytosis and also suggest that reduced APPL1 expression in pancreatic islets may serve as a pathological link that couples insulin resistance to β-cell dysfunction in type 2 diabetes.en_HK
dc.languageengen_US
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_HK
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_HK
dc.subject.meshAdaptor Proteins, Signal Transducing - genetics - metabolismen_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshDiabetes Mellitus, Type 2 - metabolismen_HK
dc.subject.meshDiet, High-Faten_HK
dc.subject.meshGene Expression Regulation - geneticsen_HK
dc.subject.meshImmunohistochemistryen_HK
dc.subject.meshImmunoprecipitationen_HK
dc.subject.meshInsulin - secretionen_HK
dc.subject.meshInsulin-Secreting Cells - secretion - ultrastructureen_HK
dc.subject.meshMiceen_HK
dc.subject.meshMice, Inbred C57BLen_HK
dc.subject.meshMice, Knockouten_HK
dc.subject.meshMice, Transgenicen_HK
dc.subject.meshMicroscopy, Electronen_HK
dc.subject.meshProto-Oncogene Proteins c-akt - metabolismen_HK
dc.subject.meshRatsen_HK
dc.subject.meshReal-Time Polymerase Chain Reactionen_HK
dc.subject.meshSNARE Proteins - metabolismen_HK
dc.titleAPPL1 potentiates insulin secretion in pancreatic β cells by enhancing protein kinase Akt-dependent expression of SNARE proteins in miceen_HK
dc.typeArticleen_HK
dc.identifier.emailCheng, KKY: dorncky@hkucc.hku.hken_HK
dc.identifier.emailXu, A: amxu@hkucc.hku.hken_HK
dc.identifier.authorityCheng, KKY=rp01672en_HK
dc.identifier.authorityXu, A=rp00485en_HK
dc.description.naturelink_to_OA_fulltext-
dc.identifier.doi10.1073/pnas.1202435109en_HK
dc.identifier.pmid22566644-
dc.identifier.pmcidPMC3384168-
dc.identifier.scopuseid_2-s2.0-84861853310en_HK
dc.identifier.hkuros201142en_US
dc.identifier.hkuros213322-
dc.identifier.hkuros226370-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84861853310&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume109en_HK
dc.identifier.issue23en_HK
dc.identifier.spage8919en_HK
dc.identifier.epage8924en_HK
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000304991100035-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectA Multi-disciplinary Approach to Investigate Vascular Dysfunction in Obesity and Diabetes: From Molecular Mechanism to Therapeutic Intervention-
dc.relation.projectPersonalized Medicine for Cardiovascular Diseases: From Genomic Testing and Biomarkers to Human Pluripotent Stem Cell Platform-
dc.relation.projectCharacterization of Novel Adaptor Proteins Involved in Regulating Insulin Sensitivity and Glucose Homeostasis: from Molecular Mechanism to Physiological Implication-
dc.identifier.scopusauthoridCheng, KKY=7402997599en_HK
dc.identifier.scopusauthoridLam, KSL=55192819200en_HK
dc.identifier.scopusauthoridWu, D=7404297751en_HK
dc.identifier.scopusauthoridWang, Y=37008681000en_HK
dc.identifier.scopusauthoridSweeney, G=7102852659en_HK
dc.identifier.scopusauthoridHoo, RLC=55241367700en_HK
dc.identifier.scopusauthoridZhang, J=35118483500en_HK
dc.identifier.scopusauthoridXu, A=7202655409en_HK

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