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dc.contributor.authorJourdan, Tony
dc.contributor.authorGodlewski, Grzegorz
dc.contributor.authorCinar, Resat
dc.contributor.authorBertola, Adeline
dc.contributor.authorSzanda, Gergo
dc.contributor.authorLiu, Jie
dc.contributor.authorTam, Joseph
dc.contributor.authorHan, Tiffany
dc.contributor.authorMukhopadhyay, Bani
dc.contributor.authorSkarulis, Monica C.
dc.contributor.authorJu, Cynthia
dc.contributor.authorAouadi, Myriam
dc.contributor.authorCzech, Michael P.
dc.contributor.authorKunos, George
dc.date2022-08-11T08:08:31.000
dc.date.accessioned2022-08-23T15:57:55Z
dc.date.available2022-08-23T15:57:55Z
dc.date.issued2013-09-01
dc.date.submitted2015-03-24
dc.identifier.citationNat Med. 2013 Sep;19(9):1132-40. doi: 10.1038/nm.3265. Epub 2013 Aug 18. <a href="http://dx.doi.org/10.1038/nm.3265">Link to article on publisher's site</a>
dc.identifier.issn1078-8956 (Linking)
dc.identifier.doi10.1038/nm.3265
dc.identifier.pmid23955712
dc.identifier.urihttp://hdl.handle.net/20.500.14038/30314
dc.description.abstractType 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB1 receptors (CB(1)Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB(1)R signaling in beta cells, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB(1)R-deficient (Cnr1(-/-)) or Nlrp3(-/-) mice, with the endocannabinoid anandamide. Peripheral CB(1)R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB(1)R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB(1)R as a therapeutic target in T2DM.
dc.language.isoen_US
dc.relation<a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=23955712&dopt=Abstract">Link to Article in PubMed</a>
dc.relation.urlhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050982/
dc.subjectAnimals
dc.subjectApoptosis
dc.subjectArachidonic Acids
dc.subjectCannabinoid Receptor Agonists
dc.subjectCarrier Proteins
dc.subjectCell Line
dc.subjectCell Survival
dc.subjectDiabetes Mellitus, Type 2
dc.subjectEndocannabinoids
dc.subjectHumans
dc.subjectHyperglycemia
dc.subjectInflammasomes
dc.subjectInsulin Resistance
dc.subjectInsulin-Secreting Cells
dc.subjectIslets of Langerhans
dc.subjectMacrophages
dc.subjectMale
dc.subjectMice
dc.subjectMice, Inbred C57BL
dc.subjectMice, Knockout
dc.subjectObesity
dc.subjectPolyunsaturated Alkamides
dc.subjectRNA Interference
dc.subjectRNA, Small Interfering
dc.subjectRats
dc.subjectCellular and Molecular Physiology
dc.subjectEndocrine System Diseases
dc.subjectEndocrinology
dc.subjectEndocrinology, Diabetes, and Metabolism
dc.subjectNutritional and Metabolic Diseases
dc.titleActivation of the Nlrp3 inflammasome in infiltrating macrophages by endocannabinoids mediates beta cell loss in type 2 diabetes
dc.typeJournal Article
dc.source.journaltitleNature medicine
dc.source.volume19
dc.source.issue9
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/faculty_pubs/577
dc.identifier.contextkey6889242
html.description.abstract<p>Type 2 diabetes mellitus (T2DM) progresses from compensated insulin resistance to beta cell failure resulting in uncompensated hyperglycemia, a process replicated in the Zucker diabetic fatty (ZDF) rat. The Nlrp3 inflammasome has been implicated in obesity-induced insulin resistance and beta cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB1 receptors (CB(1)Rs) and also promote beta cell failure. Here we show that beta cell failure in adult ZDF rats is not associated with CB(1)R signaling in beta cells, but rather in M1 macrophages infiltrating into pancreatic islets, and that this leads to activation of the Nlrp3-ASC inflammasome in the macrophages. These effects are replicated in vitro by incubating wild-type human or rodent macrophages, but not macrophages from CB(1)R-deficient (Cnr1(-/-)) or Nlrp3(-/-) mice, with the endocannabinoid anandamide. Peripheral CB(1)R blockade, in vivo depletion of macrophages or macrophage-specific knockdown of CB(1)R reverses or prevents these changes and restores normoglycemia and glucose-induced insulin secretion. These findings implicate endocannabinoids and inflammasome activation in beta cell failure and identify macrophage-expressed CB(1)R as a therapeutic target in T2DM.</p>
dc.identifier.submissionpathfaculty_pubs/577
dc.contributor.departmentProgram in Molecular Medicine
dc.source.pages1132-40


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