Epidemiological studies suggested that a tight control of risk factors may reduce chronic inflammation, so as to help the prevention of cardiovascular events in patients affected by type 2 diabetes and lower the risk for type 2 diabetes in patients affected by cardiovascular disease (28
). Although clinical trials with angiotensin-converting enzyme inhibitors and salicylates suggest that the reduction of inflammation can help to maintain glucose homeostasis (29
), the molecular mechanisms explaining how control of inflammation influences both type 2 diabetes and atherosclerosis are only partially known.
Here, we describe a novel concept in diabetes/atherosclerosis pathogenesis: interaction between defective insulin action and loss of control of TACE, a protease that regulates soluble TNF-α levels, may synergize to induce concurrently hyperglycemia and vascular inflammation. Increased activation of TACE is a consequence of the reduced expression of its inhibitor Timp3. We demonstrated through in vivo assays that genetic interaction between systemic Insr
haploinsufficiency and Timp3 deficiency in the skeletal muscle impairs glucose uptake, a sign of insulin resistance. The phenotype of mice carrying a reduced Timp3 expression in muscle and vasculature combined with systemic Insr
haploinsufficiency resembles that of muscle-specific, insulin-resistant knockout–50% (MIRKO-50%) mice, in which only the combination of a specific muscle Insr
deletion along with another mild defect (a systemic Insr
haploinsufficiency) causes hyperglycemia and hyperinsulinemia in aged animals (31
). It was also suggested that a defect in adipose tissue and liver is necessary to cause overt diabetes (32
). Remarkably, glucose uptake is impaired in liver and WAT of Insr+/–
N/Timp3KD mice. Therefore, it is possible that as a consequence of the interaction between the Insr
haploinsufficiency and Timp3 deficiency, glucose shunted from muscle is not adequately metabolized in fat and liver. A similar mechanism has been suggested for muscle-specific GLUT4-null mice (32
). Therefore, our model supports the hypothesis that to determine diabetes, a strong defect in one of the peripheral target tissues, as the one induced by interaction of Insr+/–
and Timp3 in the muscle, should be flanked by mild defects in the other organs, such as those caused by Insr
haploinsufficiency alone. Studies with mice with a systemic chronic haploinsufficiency of both Insr
reveal that young animals manifest mild defects in insulin sensitivity and glucose tolerance, while adult heterozygous mice develop marked hyperglycemia and hyperinsulinemia. A similar phenotype was observed in double heterozygous Insr+/–Irs1+/–
Using Insr+/– diabetic mice, in which there is evidence of unchecked TACE activation, we tested the hypothesis that recovery of Timp3 activity could be a valid approach to concurrently reducing diabetes and vascular inflammation. In fact, the blockage of TACE as well as MMP-2 and MMP-9 by a synthetic inhibitor markedly improves hyperglycemia, hyperinsulinemia, and markers of inflammation such as VCAM-1, LOX-1, MCP-1, and cox-2.
Since type 2 diabetes and atherosclerosis are multifactorial diseases and many patients develop macrovascular disease before frank hyperglycemia occurs, it is plausible that common pathways play a role in the development of both the diseases (3
). We suggest that Timp3, which is a powerful regulator of inflammation (14
), can also curtail failure in glucose metabolism sustained by genetic or secondary insulin resistance. Since Timp3 is also an inhibitor of VEGF activity (34
mice could be a useful model for studying the connection between insulin sensitivity, inflammation, and vascular complications of diabetes.
Anti–TNF-α treatment in human diseases such as diabetes/obesity and heart failure is biologically relevant, but the few attempts using monoclonal antibodies for chronic TNF-α neutralization have been ineffective (35
). Our study suggests that TNF-α neutralization might also be obtained through use of appropriate TACE inhibitors.
In conclusion, we provide a direct mechanistic relationship among insulin action, control of inflammation, and the pathophysiology of atherosclerosis and diabetes. In the Insr+/–D mice, through recovery of Timp3 activity, it is possible to inhibit TACE and to break the synergistic effect of TNF-α and Insr haploinsufficiency on insulin sensitivity. Based on our findings, we propose that the TIMP3/TACE system is involved in the pathogenesis of atherosclerosis and type 2 diabetes in human subjects and as such may be exploited for therapeutic purposes.