Pathophysiological endothelial dysfunction results from the following: recurrent hyperglycemia; elevated free fatty acids; systemic insulin resistance caused by impairment of insulin signaling; decreased vascular bioavailability of NO caused by reduced production and/or increased inactivation of NO; and increased oxidative stress with the consequence of enhanced vasoconstriction, inflammation, and thrombosis (17). Here, INS is linked to endothelial dysfunction.