Insulin treatment attenuates diabetes-increased atherosclerotic intimal lesions and matrix metalloproteinase 9 expression in apolipoprotein E-deficient mice

Abstract

Patients with diabetes mellitus have increased mortality and morbidity of cardiovascular diseases compared with nondiabetic patients. Although clinical studies have shown that effective glycemic control with insulin treatment in patients with type 1 diabetes is associated with reduced cardiovascular events, the underlying mechanisms have not been well understood. In this study, we treated diabetic apolipoprotein E-deficient (apoEK/K) mice with insulin for 20 weeks and studied the effect of insulin treatment on intimal lesion size and matrix metalloproteinase (MMP) 9 expression known to be involved in plaque destabilization. Results showed that insulin treatment, which effectively reduced plasma glucose level in diabetic mice, attenuated diabetes-increased intimal lesion size and significantly inhibited diabetes-increased MMP9 expression, but had no effect on tissue inhibitor of metalloproteinase 1 in atherosclerotic plaques. Furthermore, we observed that insulin treatment did not reduce diabetes-increased macrophage content but inhibited interleukin 6 expression, a stimulator for MMP expression. Taken together, this study has shown for the first time that insulin treatment in diabetic apoEK/K mice changes atherosclerotic lesions and gene expression to a state that favors plaque stability.

M1 and M2 macrophage proteolytic and angiogenic profile analysis in atherosclerotic patients reveals a distinctive profile in type 2 diabetes

“…Previous studies reported that the expression of MMP-9 is increased in atherosclerotic plaques from diabetic patients and that insulin treatment reduces MMP-9 tissue expression as well as its secretion by macrophages. 30 Moreover, we observed that M1 macrophages from diabetic patients also displayed a more important proangiogenic activity (increased VEGF/TFPI-2 and TF/TFPI-2 ratios) compared to non-diabetic patients. Our histological and in vitro results could explain the link between increased number of microvessels and plaque vulnerability observed in diabetic patients.…”

Molecular hydrogen stabilizes atherosclerotic plaque in low-density lipoprotein receptor-knockout mice

“…1C). In addition, the content of MMP-9, which was mainly secreted by macrophages and known to be involved in plaque destabilization [22,23], was lowered in H 2 -or simvastatin-treated mice (Fig. 1D and E).…”

Exendin-4 Inhibits Matrix Metalloproteinase-9 Activation and Reduces Infarct Growth After Focal Cerebral Ischemia in Hyperglycemic Mice

“…In this regard, insulin also has the potential to inhibit MMP-9 activity and protect endothelial cells in subacute arterial injury 36 or in atherosclerotic intimal lesions of diabetic apolipoprotein E-deficient (apoE −/− ) mice. 37 However, it is still controversial whether insulin-mediated reduction in blood glucose in acute hyperglycemia during ischemic stroke represents an effective intervention. 10 Moreover, caution must be used when attempting to achieve euglycemic control with insulin treatment because of the risk of hypoglycemia.…”