The endothelium in diabetes: its role in insulin access and diabetic complications

Abstract

The vascular endothelium has been identified as an important component in diabetes-associated complications, which include many cardiovascular disorders such as atherosclerosis, hypertension and peripheral neuropathy. Additionally, insulin's actions on the endothelium are now seen as a major factor in the metabolic effects of the hormone by increasing access to insulin sensitive tissues. Endothelial function is impaired in diabetes, obesity, and the metabolic syndrome, which could reduce insulin access to the tissue, and thus reduce insulin sensitivity independently of direct effects at the muscle cell. As such, the endothelium is a valid target for treatment of both the impaired glucose metabolism in diabetes, as well as the vascular based complications of diabetes. Here we review the basics of the endothelium in insulin action, with a focus on the skeletal muscle as insulin's major metabolic organ, and how this is affected by diabetes. We will focus on the most recent developments in the field, including current treatment possibilities.

Figure 1

Insulin receptors in endothelial cells co-localize with cavaolae, and insulin signaling in endothelial cells leads to two downstream signaling pathways. Activation of the ERK pathway leads to ET-1 release, causing vasoconstriction in vascular smooth muscle cells, and the PI3K pathway leads to NO release and vasodilation. Studies have also shown that insulin binding to the insulin receptor is required for transcytosis of cavaeloe, possibly for translocation of insulin from the plasma to the interstitial space. (Image created in powerpoint)

Figure 2

Blood is distributed throughout the tissue in capillaries. The number of perfused capillaries can be increased by exercise and insulin, leading to a situation depicted on the left. However, in cases of insulin resistance, insulin is no longer able to recruit capillaries, and more of the tissue is left unperfused, as shown on the right. This reduced flow will reduce insulin delivery to tissues, but can also cause ischemia in the retina, kidney and peripheral nerves and muscle, leading to complications associated with diabetes. (Image created in paint)