Timp3 deficiency in insulin receptor-haploinsufficient mice promotes diabetes and vascular inflammation via increased TNF-alpha.
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
Massimo
M
Center for Atherosclerosis, Policlinico Tor Vergata University Hospital, Rome, Italy. federicm@uniroma2.it
Hribal
Marta L
ML
Menghini
Rossella
R
Kanno
Hiroko
H
Marchetti
Valentina
V
Porzio
Ottavia
O
Sunnarborg
Susan W
SW
Rizza
Stefano
S
Serino
Matteo
M
Cunsolo
Veronica
V
Lauro
Davide
D
Mauriello
Alessandro
A
Smookler
David S
DS
Sbraccia
Paolo
P
Sesti
Giorgio
G
Lee
David C
DC
Khokha
Rama
R
Accili
Domenico
D
Lauro
Renato
R
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
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