Does Elevated Glucose Promote Atherosclerosis? Pros and Cons
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Dripping water hollows out stone, not through force but through persistence.
The quote above, by the Roman poet Publius Ovidius Naso (43 BC to 17 AD), has been an inspiration to me since childhood. It reminds me that accumulating pieces of evidence to tackle difficult questions will in time make an impact. Of course, some discoveries happen suddenly and unexpectedly, whereas others take lifetimes. A question my laboratory has long examined is whether elevated glucose promotes atherosclerosis by acting directly on vascular cells in lesions of atherosclerosis in the setting of diabetes mellitus.1 This problem seems to belong to the category Ovid might have had in mind when he coined the quote above. The reason we keep tackling this question from different angles and by different methods is of course the increased risk of cardiovascular complications associated with type 1 diabetes mellitus and type 2 diabetes mellitus (T2DM). There is still no consensus on how diabetes mellitus promotes atherosclerosis and resulting cardiovascular events and whether glucose has a direct proatherosclerotic effect. Considerable time and resources have been devoted to studies of effects of glucose in isolated cultured vascular cells. In my opinion, for reasons described below, we now need to tackle the role of elevated glucose, hyperglycemia, and glucose fluctuations by using animal models and studies in humans.
Studies in isolated vascular cells and animal models have begun to reveal that inhibition of glucose uptake and utilization in cells involved in atherosclerosis can prevent proatherosclerotic events in the absence of diabetes mellitus. This is not surprising because cellular activation often is associated with metabolic reprogramming. Thus, reducing expression of the glucose transporter GLUT1 in macrophages or hematopoietic cells limits inflammatory activation of macrophages, expansion of hematopoietic cells, and atherosclerosis in mice.2,3 Other studies demonstrate that …