This review focused on one key feature of type 2 diabetes, insulin resistance; one type of lesional cell, the macrophage; and one overall context of atherosclerosis, advanced plaque progression. Even within this focused area of research, more work is needed to further define mechanisms whereby insulin resistance affects specific signaling pathways involved in the panoply of atherosclerosis-relevant macrophage activities, including, interaction with lipoproteins and intracellular metabolism of lipoprotein-derived lipids; inflammation and the resolution thereof; stress responses, including oxidative, heat shock, and ER stress; secretion of proteases, pro-coagulant molecules, and other factors involved in plaque progression; phagocytosis, efferocytosis, and antigen presentation; apoptosis-cell survival balance; and interaction with other cells and extracellular matrix. Moreover, it is likely that insulin resistance affects these processes differently in different subsets of macrophages and in other types of myeloid cells, notably dendritic cells, mast cells, and neutrophils. A limitation of our in vivo
studies has been the lack of a mouse model that fully recapitulates features of human plaque disruption and athero-thrombosis,92
and so further developments to improve mouse models of diabetic atherothrombotic vascular disease is an important goal. Nonetheless, it is becoming clear that key morphologic features of such plaques are worsened by ER stress33
and insulin resistance in macrophages.69
Beyond the specific areas of plaque macrophages, insulin resistance, and advanced plaque progression, other areas of focus may offer additional clues as to why heart disease is enhanced in type 2 diabetes.61
For example, decreased insulin signaling in endothelial cells, through impaired Akt signaling, is also likely to have important pro-atherogenic consequences through decreased eNOS activity and increased expression of inflammatory genes and VCAM-1.73
In the liver, hyperinsulinemia and insulin signaling may increase VLDL secretion while having the opposite effects on LDL receptor expression.93
The other major feature of type 2 diabetes, hyperglycemia, may promote plaque instability by enhancing the inflammatory response in macrophages through effects on plasma triglyceride-rich lipoproteins and free fatty acids.94
Hyperglycemia may also cause endothelial cell abnormalities, including oxidative stress and RAGE-induced inflammation, that promote the earlier stages of atherogenesis.95, 96
Interestingly, there are recent data suggesting that hyperglycemia may exert some of its pro-atherogenic effects in endothelial cells through FoxO1 and also through the induction of ER stress.97, 98
These hyperglycemia-endothelial cell studies, together with the insulin resistance-macrophage studies described in this review, raise the interesting possibility that hyperglycemia may affect mostly the earlier stages of atherogenesis, while insulin resistance has its greatest effect on promoting advanced plaque progression. In this context, a recent analysis of the Veterans Affairs Diabetes Trial found that intensive glucose lowering reduced cardiovascular events in diabetics with a coronary artery calcium store < 100 (multivariable hazard ratio [HR] = 0.08, p=0.03), but not in those with a calcium score >100 (HR = 0.74, p=0.21).99
Smooth muscle cells, a key cell type in the generation of the “protective” fibrous cap in advanced lesions, and platelets, the final effector of acute vascular occlusion, may be affected by insulin resistance, hyperglycemia, or fatty acid abnormalities, which provide additional opportunities for investigation.61
Continued progress in these areas will provide a more complete understanding of how multiple features of diabetes promotes heart disease.
The ultimate goal of these studies is to complement our current efforts at identifying and treating systemic risk factors that promote cardiovascular disease in diabetics. Despite the relative success of this strategy, risk is still very high,100
, and the tremendous scale of this epidemic is such that overall risk will still be high even if compliance is improved and the experimental modalities prove useful. Further understanding of the specific mechanisms of increased vascular disease in diabetics, particularly at the molecular level in arterial wall cells, may be a promising approach for further eradication in the future—and one that should be additive or even synergistic with reduction of lipid and other systemic risk factors. One approach is to increase insulin sensitivity in diabetic macrophages, such has been demonstrated recently using a PPARγ activator in vivo68
vitamin D in vitro
Another approach is to develop agents to prevent ER stress or downstream pro-apoptotic processes in macrophages by pharmacologic means, e.g.
, through the use of chemical chaperones102
or inhibitors of the calcium-mediated pro-apoptotic pathway.103, 104
Moreover, in view of the importance of defective efferocytosis in the generation of plaque necrosis and the ob/ob
efferocytosis study described above, experimental therapeutic modalities designed to enhance efferocytosis58, 105
may be particularly useful in diabetics. Delivery of such drugs to plaques might be facilitated by specific vehicles targeted to plaques,106
while clinical assessment in phase 2 and phase 3 studies could be assisted by imaging techniques such as carotid MRI, that have the capacity to measure important plaque features such as necrotic core area and cap thickness.107
Studies in these areas occurring in parallel with ongoing efforts at systemic risk reduction offer the best chance to curb the growing epidemic of diabetes-associated atherothrombotic vascular disease.