Endothelial dysfunction in insulin resistance and type 2 diabetes.

Macrovascular disease is the number one killer in type 2 diabetes patients. The cluster of risk factors in the insulin resistance syndrome (IRS) partly explains this notion. Insulin action in muscle, liver or adipose tissue has been thoroughly described in the literature, whilst this has been less described for the endothelium. Insulin stimulates nitric oxide (NO) production in the endothelium and reduced bioavailability of NO is usually defined as endothelial dysfunction. This impairment might be related to defective insulin signalling in the endothelial cell. Therefore, insulin resistance mechanisms in the endothelial cell will be emphasized in this review. Imbalance between the vasodilating agent NO and the vasoconstrictor endothelin-1 (ET-1) contributes to endothelial dysfunction. Different methods and circulating markers to assess endothelial function will be outlined. Circulating markers of an activated endothelium appear long before type 2 diabetes develops suggesting a unique role of the endothelium in the pathophysiology of the disease. Hampered blood flow in nutritive capillaries due to endothelial dysfunction is coupled with decreased glucose uptake and hyperglycemia. The forearm model combined with muscle microdialysis enables us to measure interstitial glucose and an index for capillary recruitment, the permeability surface area (PS). Available data from this method suggest that capillary recruitment in response of insulin is impaired in insulin resistant human subjects.