Timp3 deficiency in insulin receptor–haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-α
Massimo Federici, Marta L. Hribal, Rossella Menghini, Hiroko Kanno, Valentina Marchetti, Ottavia Porzio, Susan W. Sunnarborg, Stefano Rizza, Matteo Serino, Veronica Cunsolo, Davide Lauro, Alessandro Mauriello, David S. Smookler, Paolo Sbraccia, Giorgio Sesti, David C. Lee, Rama Khokha, Domenico Accili, Renato Lauro
Massimo Federici, Marta L. Hribal, Rossella Menghini, Hiroko Kanno, Valentina Marchetti, Ottavia Porzio, Susan W. Sunnarborg, Stefano Rizza, Matteo Serino, Veronica Cunsolo, Davide Lauro, Alessandro Mauriello, David S. Smookler, Paolo Sbraccia, Giorgio Sesti, David C. Lee, Rama Khokha, Domenico Accili, Renato Lauro
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Research Article Metabolism

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

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-α–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-α, 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

Massimo Federici, Marta L. Hribal, Rossella Menghini, Hiroko Kanno, Valentina Marchetti, Ottavia Porzio, Susan W. Sunnarborg, Stefano Rizza, Matteo Serino, Veronica Cunsolo, Davide Lauro, Alessandro Mauriello, David S. Smookler, Paolo Sbraccia, Giorgio Sesti, David C. Lee, Rama Khokha, Domenico Accili, Renato Lauro

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Effect of Timp3 KD on insulin signaling in WT and Insr+/– mice. (A) TNF-...
Effect of Timp3 KD on insulin signaling in WT and Insr+/– mice. (A) TNF-α signaling in skeletal muscle measured by phosphorylation state of JNK-1/2 and of Ser307 in IRS1. After an overnight fast, 6-month-old WT, WT/Timp3KD, Insr+/– and Insr+/–/Timp3KD mice were injected with either saline (–) or 25 mU/kg of insulin (Ins). Skeletal muscle (B–E), livers (F–H), and WAT (I) were collected 5–10 minutes later. Protein extracts were prepared, immunoprecipitated with antibodies against Insr (B) and IRS-1 (C), and after gel separation were immunoblotted with antibodies specific for phosphotyrosine (pyTyr) (PY20) and normalized by reblotting with specific antibodies. PI3K activity (D, F, and I) was measured in phosphotyrosine immunoprecipitates by ELISA assay. The levels of total AKT1/2 and activated AKT (p-Ser473) (E and G), total glycogen synthase kinase 3β (GSK3β) and inactivated GSK3β (p-Ser9) (H) were determined by immunoblotting of the original lysates. Band intensities were quantified by densitometry and expressed as mean ± SD (n = 3 mice per group). *P < 0.05, **P < 0.01, †P < 0.001 by 1-way ANOVA for Insr+/–N/Timp3KD compared with other groups.