References
Query Results -- Details
MGI Accession ID: MGI:3612650
J Number: J:104707
Other Accession IDs:
Title: Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha.
Authors: 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 D; Lauro R
Journal: J Clin Invest
Volume: 115
Issue: 12
Date: 2005 Dec
Year: 2005
Pages: 3494-505
Review Status: Peer Reviewed
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.
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