Matrix metalloproteinases: keys to healthier blood vessels in diabetes?

The fact that type 2 diabetes has become pandemic is difficult to escape. Increased morbidity and mortality in cardiovascular events, which frequently accompany the disease, are the most severe consequences of the diabetes pandemic. This problem is caused by an acceleration of atherosclerosis in patients with diabetes. In fact, it has become apparent that glucose intolerance or frank diabetes occurs in up to three of four patients with acute myocardial infarction, even if these patients have not previously been diagnosed with diabetes (Anselmino et al. 2010). This notwithstanding the cause of accelerated atherosclerosis in diabetes is not fully understood. Although inflammation now has been implicated in impairment of insulin sensitivity (Shoelson et al. 2007) and perturbation of insulin secretion (Dinarello et al. 2010) in type 2 diabetes, it is not clear whether inflammatory processes, known to play an important role in atherosclerosis, are exaggerated in the vessel wall of patients with diabetes. Toxic effects of elevated plasma glucose as well as circulating lipids, known as glucotoxicity and lipotoxicity, respectively, may be precipitating or potentiating factors. Epigenetic changes in the vascular wall have also been implicated in the advent of the vascular complications of diabetes (El-Osta et al. 2008). All these notions agree with the fact that improved glycemic control significantly reduces the late complications of any type of diabetes, and this includes cardiovascular disease.

In this issue of Journal of Endocrinology, Schuyler et al. (2011) provide new insights into the pathogenesis of atherosclerosis in diabetes. They hypothesized that enhanced plaque stability could account for the beneficial effects of improved glycemic control on cardiovascular complications in diabetes. The authors were particularly interested in matrix metalloproteinases (MMP), which are a family of zinc-dependent endopeptidases. These enzymes degrade extracellular matrix components and may hence remodel vascular tissue and affect plaque stability (Galis & Khatri 2002). For their studies, they used apoE^−/− mice that are a well-established murine model for atherosclerosis. The mice were made diabetic by streptozotocin, a cytotoxic agent that selectively kills the insulin-producing β-cells. Then, the hyperglycemic apoE^−/− mice were treated with insulin and compared with untreated as well as non-diabetic apoE^−/− mice and with an unrelated mouse line, C57BL/6. As expected, insulin treatment lowered plasma glucose levels. Interestingly, plasma cholesterol levels were higher in diabetic apoE^−/− mice, and this elevation was hindered by the insulin treatment. When analyzing aortic plaques, the intimal size directly reflected glycemic control: plaques were greatest in the untreated diabetic apoE^−/− mice. This was further paralleled by increased MMP9 expression, as assessed both by immunocytochemistry and by quantitative real-time PCR. However, the expression of MMP2 and MMP13 remained unchanged in the untreated diabetic apoE^−/− mice, implying that insulin treatment selectively affected MMP9. Finally, interleukin 6 (IL6) is a known regulator of MMP9 and has previously been implicated in inflammatory changes in type 2 diabetes (Pedersen 2009). The authors found that expression of IL6 was increased in the untreated diabetic apoE^−/− mice, an increase that was attenuated by insulin secretion. This provided a possible mechanism for the protection against plaque growth by insulin and MMP9. Of note, insulin treatment did not reduce macrophage content in the plaques of insulin-treated apoE^−/− mice.

The interesting findings by Schuyler et al. raise some important questions. In the studies, plasma glucose levels differed among the groups of mice. Therefore, it is difficult to know, based on the present data, whether the beneficial effects in the treated mice can be attributed to insulin itself or to the amelioration of the metabolic perturbation, i.e. plasma glucose and cholesterol, both of which were reduced by insulin. This is a clinically relevant question because in type 2 diabetes, hyperglycemia can be treated in several ways. One way of testing this possibility is treatment of diabetic apoE^−/− mice with phlorizin, a drug that increases renal excretion of glucose. Also, in the model studied by the authors, insulinopenia was induced by a destruction of β-cells. In many patients with type 2 diabetes, there is hyperinsulinemia. Thus, testing the concept of MMP9 and plaque stability could be of interest in an animal model for type 2 diabetes. This could also resolve whether it is the actual lack of insulin that allows increased expression of MMP9. Moreover, in vitro studies in endothelial and smooth muscle cells of the regulation of MMP9 expression would be helpful. Nevertheless, the study by Schuyler et al. should inspire further investigation of this interesting and clinically important phenomenon.