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- Title
Tace/Adam17 Is Activated in Vascular System of Prediabetic and Diabetic Subjects.
- Authors
Federici, Massimo; Cardellini, Marina; Menghini, Rossella; Rizza, Stefano; Savo, Alessia; Folli, Franco; Lauro, Renato
- Abstract
A chronic low grade activation of the immune system may play a role in the pathogenesis of insulin resistance and atherosclerosis. ADAM17 is a membrane-bound metalloproteinase that regulates the shedding of several cell surface-anchored molecules such as cytokines, growth factors and receptors and is activated in chronic inflammation. To investigate if a deregulation of the proteolytic membrane-bound system is related to diabetes and its vascular complications we studied: 1) healthy first degree relatives (FDRs) of type 2 diabetic patients; and 2) atherosclerotic patients (diabetics, DM2, or nondiabetics, ATS) who underwent to carotid endoarteriectomy. In FDRs (n=35) we evaluated insulin sensitivity by euglycemic-hyperinsulinemic clamp study, the carotid artery intima-media thickness, as an early manifestation of atherosclerosis, and the endothelial dysfunction by flow mediated vasodilation (FMD). Monocytes were isolated in order to assess expression of ADAM17 (Taqman assay). Soluble molecules, such as sICAM-1, sVCAM-1, sTNF RI, sIL-6R and IL-6, were measured to evaluated the membrane proteolytic cleavage through elisa assays. In FDRs, both insulin sensitivity (r=-0,381 p=0,04) and intima-media thickness (r=0,545 p=0,003) were significantly correlated with plasmatic levels of soluble receptor of interleukin 6 (sR-IL6), a specific substrate for ADAM17. Next, we dichotomized FDRs in insulin sensitive and insulin resistant using the glucose disposal rate. We observed that ADAM17 expression was significantly increased in insulin resistant (n= 17) compared with insulin sensitive (n=18) subjects (p=0,03). In the second cohort (n=70, DM2=21, ATS=49) we analyzed expression of ADAM17 in the atherosclerotic plaques obtained from carotid endoarteriectomy. We found that the expression of ADAM 17 is higher in plaques from diabetic patients than in non-diabetic patients (p=0,05) and it correlates with HOMA-IR (r=0.42, p<0.04) and fasting plasma glucose (r=0.315, p<0.02). Our data suggest that ADAM17 expression and activity is increased in prediabetic subjects showing early atherosclerosis and in patients affected by atherosclerosis and diabetes compared with normoglucose tolerant atherosclerotic patients.
- Subjects
ENZYME activation; METALLOPROTEINASES; BLOOD vessels; PEOPLE with diabetes; INSULIN resistance; ATHEROSCLEROSIS; TYPE 2 diabetes
- Publication
Diabetes, 2007, Vol 56, pA175
- ISSN
0012-1797
- Publication type
Article