Specific Impairment of Endothelium-Dependent Vasodilation in Subjects with Type 2 Diabetes Independent of Obesity

Abstract

In subjects with type 2 diabetes in whom an impaired response to an endothelial-dependent vasodilator has been characterized, the populations have also been at least moderately obese. Obesity has been characterized as an independent predictor of endothelial dysfunction in nondiabetic subjects. We hypothesized that in normotensive subjects with type 2 diabetes compared with age-matched control subjects, 1) endothelium-dependent vasodilation, as demonstrated by the forearm blood flow (FABF) response to intraarterial acetylcholine, would be decreased; 2) endothelium-independent vasodilation, as demonstrated by the FABF response to intraarterial nitroprusside, would be similar; 3) the degree of insulin resistance, as measured by the insulin sensitivity index (SI), would predict greater impairment in the FABF response to acetylcholine; and 4) these relationships would be independent of obesity. We measured FABF by venous occlusion plethysmography during brachial arterial infusions of the endothelium-dependent vasodilator acetylcholine and the endothelium-independent vasodilator nitroprusside in 20 control and 17 subjects with type 2 diabetes. We measured SI using the frequently sampled i.v. glucose tolerance test. Among the diabetic relative to the control subjects we identified a decrease in the acetylcholine-mediated percent increase in FABF (P = 0.02). Using the absolute FABF response to acetylcholine and including adjustments for body mass index and other covariates, the overall group difference remained and was noted to be greatest in those subjects who had lower baseline FABFs. In contrast, no significant difference in the nitroprusside-mediated increase in the percent change FABF was identified between groups (P = 0.30). Finally, the degree of insulin resistance, as measured by SI, did not independently predict greater impairment of the FABF response to acetylcholine. This study is the first to identify specific endothelial cell dysfunction that remains significant after adjustment for obesity in a population of normotensive subjects with type 2 diabetes.

Diabetic dyslipidaemia: from basic research to clinical practice*

“…Recently convincing tenets seem to explain the atherogeneity of small dense LDL particles. Solid data shows that LDL size is a strong determinant of endothelial function in Type 2 diabetic subjects as well as in normal healthy men [122,123,124,125]. In our study the subjects with small dense LDL, but comparable LDL cholesterol concentration, had impaired response to endothelium-dependent vasodilator acetylcholine [124,125].…”

Diabetes, the Metabolic Syndrome, and Ischemic Stroke

“…OXIDE -Both diabetic patients and those with impaired glucose tolerance have decreased endothelium-dependent vasodilation (93)(94)(95), due to either decreased nitric oxide (NO) production or impaired NO metabolism (95). Normally, NO exerts a protective effect against platelet aggregation and plays an important role in the response to ischemic challenge (96,97).…”

Elevations of plasma methylarginines in obesity and ageing are related to insulin sensitivity and rates of protein turnover

“…Furthermore, in states of lesser insulin resistance ± insufficiency, alterations in protein turnover also occur [11][12][13]. Until recently, it has been considered that obesity does not regulate plasma methylarginine levels [14,15], but this was in subjects with type 2 diabetes. We hypothesised: (1) that MA would be elevated in obese and elderly persons with reduced insulin sensitivity; (2) that protein turnover is a major regulator of plasma MA levels; and (3) that these two points are correlated.…”