title: Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha.
abstract: Activation of inflammatory pathways may contribute to the beginning and the progression of both atherosclerosis and type 2 diabetes. Here we report a novel interaction between insulin action and control of inflammation, resulting in glucose intolerance and vascular inflammation and amenable to therapeutic modulation. In insulin receptor heterozygous (Insr+/-) mice, we identified the deficiency of tissue inhibitor of metalloproteinase 3 (Timp3, an inhibitor of both TNF-alpha-converting enzyme [TACE] and MMPs) as a common bond between glucose intolerance and vascular inflammation. Among Insr+/- mice, those that develop diabetes have reduced Timp3 and increased TACE activity. Unchecked TACE activity causes an increase in levels of soluble TNF-alpha, which subsequently promotes diabetes and vascular inflammation. Double heterozygous Insr+/-Timp3+/- mice develop mild hyperglycemia and hyperinsulinemia at 3 months and overt glucose intolerance and hyperinsulinemia at 6 months. A therapeutic role for Timp3/TACE modulation is supported by the observation that pharmacological inhibition of TACE led to marked reduction of hyperglycemia and vascular inflammation in Insr+/- diabetic mice, as well as by the observation of increased insulin sensitivity in Tace+/- mice compared with WT mice. Our results suggest that an interplay between reduced insulin action and unchecked TACE activity promotes diabetes and vascular inflammation.
authors.affiliation: Center for Atherosclerosis, Policlinico Tor Vergata University Hospital, Rome, Italy. federicm@uniroma2.it
authors.forename: Massimo
authors.initials: M
authors.lastname: Federici
authors.forename: Marta L
authors.initials: ML
authors.lastname: Hribal
authors.forename: Rossella
authors.initials: R
authors.lastname: Menghini
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kanno
authors.forename: Valentina
authors.initials: V
authors.lastname: Marchetti
authors.forename: Ottavia
authors.initials: O
authors.lastname: Porzio
authors.forename: Susan W
authors.initials: SW
authors.lastname: Sunnarborg
authors.forename: Stefano
authors.initials: S
authors.lastname: Rizza
authors.forename: Matteo
authors.initials: M
authors.lastname: Serino
authors.forename: Veronica
authors.initials: V
authors.lastname: Cunsolo
authors.forename: Davide
authors.initials: D
authors.lastname: Lauro
authors.forename: Alessandro
authors.initials: A
authors.lastname: Mauriello
authors.forename: David S
authors.initials: DS
authors.lastname: Smookler
authors.forename: Paolo
authors.initials: P
authors.lastname: Sbraccia
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sesti
authors.forename: David C
authors.initials: DC
authors.lastname: Lee
authors.forename: Rama
authors.initials: R
authors.lastname: Khokha
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
authors.forename: Renato
authors.initials: R
authors.lastname: Lauro
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003847:Deoxyglucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000473:pathology; D004591:Electrophoresis, Polyacrylamide Gel; D020869:Gene Expression Profiling; D005822:Genetic Vectors; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006003:Glycogen / Q000737:chemistry; D006579:Heterozygote; D006706:Homeostasis; D006943:Hyperglycemia / Q000473:pathology; D006946:Hyperinsulinism / Q000473:pathology; D007249:Inflammation / Q000235:genetics*; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000473:pathology; D009132:Muscles / Q000473:pathology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012313:RNA / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: D007328:Insulin; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha; D012313:RNA; D006003:Glycogen; D003847:Deoxyglucose; D011972:Receptor, Insulin; D005947:Glucose