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.

Federici, M., Hribal, M., Menghini, R., Kanno, H., Marchetti, V., Porzio, O., et al. (2005). Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha. THE JOURNAL OF CLINICAL INVESTIGATION, 115(12), 3494-3505 [10.1172/JCI26052].

Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha

FEDERICI, MASSIMO;MENGHINI, ROSSELLA;PORZIO, OTTAVIA;RIZZA, STEFANO;LAURO, DAVIDE;MAURIELLO, ALESSANDRO;SBRACCIA, PAOLO;LAURO, RENATO;
2005

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.
Pubblicato
Rilevanza internazionale
Articolo
Sì, ma tipo non specificato
Settore MED/09 - Medicina Interna
Settore M-EDF/01 - Metodi e Didattiche delle Attivita' Motorie
eng
Con Impact Factor ISI
insulin receptor; tissue inhibitor of metalloproteinase 3; transforming growth factor alpha; animal experiment; animal model; animal tissue; article; controlled study; diabetes mellitus; enzyme activity; glucose intolerance; hyperglycemia; hyperinsulinemia; inflammation; mouse; mouse strain; nonhuman; nucleotide sequence; priority journal; vascular disease; wild type; Analysis of Variance; Animals; Deoxyglucose; Diabetes Mellitus; Electrophoresis, Polyacrylamide Gel; Gene Expression Profiling; Genetic Vectors; Glucose; Glucose Tolerance Test; Glycogen; Heterozygote; Homeostasis; Hyperglycemia; Hyperinsulinism; Inflammation; Insulin; Liver; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Skeletal; Muscles; Phosphorylation; Promoter Regions (Genetics); Protein Binding; Receptor, Insulin; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; RNA, Small Interfering; Signal Transduction; Time Factors; Tissue Inhibitor of Metalloproteinase-3; Tumor Necrosis Factor-alpha
Federici, M., Hribal, M., Menghini, R., Kanno, H., Marchetti, V., Porzio, O., et al. (2005). Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha. THE JOURNAL OF CLINICAL INVESTIGATION, 115(12), 3494-3505 [10.1172/JCI26052].
Federici, M; Hribal, Ml; Menghini, R; Kanno, H; Marchetti, V; Porzio, O; Sunnarborg, Sw; Rizza, S; Serino, M; Cunsolo, V; Lauro, D; Mauriello, A; Smookler, Ds; Sbraccia, P; Sesti, G; Lee, Dc; Khokha, R; Accili, ; Lauro, R
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/40280
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