Abstract
CD226 is a co-stimulatory adhesion molecule found on immune and endothelial cells. Here, we evaluated a possible role for CD226 in inhibiting glucose uptake in isolated human umbilical vein endothelial cells (HUVECs) and in wild-type (WT) and CD226 knockout (KO) mice with high-fat diet (HFD)-induced type 2 diabetes (T2DM). CD226 expression increased under hyperglycemic conditions in the presence of TNF-α. Furthermore, CD226 knockdown improved glucose uptake in endothelial cells, and CD226 KO mice exhibited increased glucose tolerance. Levels of soluble CD226 in plasma were higher in T2DM patients following an oral glucose tolerance test (OGTT) than under fasting conditions. Our results indicate that low-grade inflammation coupled with elevated blood glucose increases CD226 expression, resulting in decreased endothelial cell glucose uptake in T2DM.
Highlights
Type 2 diabetes mellitus (T2DM), which affects more than 150 million people worldwide, increases the risk of cardiovascular mortality [1, 2]
We previously showed that CD226 is expressed very weakly in resting human umbilical vein endothelial cells (HUVECs), but CD226 levels increased when these cells were stimulated [12]
CD226 expression in liver sinusoidal endothelial cells marked by CD31 was higher in ob/ob mice than in WT mice (Figure 1C)
Summary
Type 2 diabetes mellitus (T2DM), which affects more than 150 million people worldwide, increases the risk of cardiovascular mortality [1, 2]. Chronic low-grade inflammation in T2DM patients orchestrates obesityinduced insulin resistance [3]. Diabetic hyperglycemia causes a variety of pathological changes in blood vessels. Blood vessel endothelial dysfunction is characterized by impaired vasodilation, altered vascular remodeling, and loss of barrier function, which leads to increased permeability [4]. Some studies show that insulin delivery to the skeletal muscle interstitium through endothelial cells is the rate-limiting step in insulin-stimulated glucose uptake [5]. The molecular mechanisms by which hyperglycemia leads to vascular diseases in diabetics remain unknown
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