Abstract
Aims/HypothesisImpaired L-arginine transport has been reported in cardiovascular diseases, providing a possible mechanism for reduced nitric oxide (NO) production. Given that cardiovascular diseases are also associated with insulin resistance, and insulin is known to induce vasodilation via a NO-dependent pathway, we hypothesised that abnormal insulin modulation of L-arginine transport may contribute to vascular dysfunction in diabetes.MethodsForearm blood flow (FBF) responses to insulin and sodium nitroprusside (SNP) were measured in control and type 2 diabetic volunteers using venous occlusion plethysmography. Effects of intra-arterial insulin on the forearm veno-arterial flux of arginine and related amino acids were determined by HPLC. The effect of locally delivered insulin on arginine transport was assessed during an intra-arterial infusion of [4,5-3H] L-arginine.ResultsIn controls, intrabrachial infusion of 5 mUnits/min insulin lead to a progressive rise in FBF (p<0.001) while this was not evident in diabetics. In support of this observation, we observed a concomitant, significant increase in the flux of N-hydroxy-L-arginine (the NO precursor) in controls (baseline vs. 60 mins insulin: 16.2±12.2 vs. 33.0±13.1 nmol/100 ml tissue/min; p<0.01), whilst no increase was observed in diabetics. Moreover, insulin augmented the clearance of [3H]L-arginine from the forearm circulation in controls (baseline vs insulin: 123±22 vs. 150±28 ml/min; p<0.05) but not in diabetics.ConclusionThese findings suggest that insulin resistance may contribute substantially to the onset and development of cardiovascular disease in type 2 diabetics via abnormal insulin-mediated regulation of L-arginine transport.
Highlights
Endothelial dysfunction has been associated with several disorders affecting the cardiovascular system, including type 2 diabetes, essential hypertension, hypercholesterolemia, obesity, atherosclerosis, coronary artery disease, and congestive heart failure [1–7]
Forearm blood flow (FBF) tended to be slightly lower in diabetics as compared to controls, the difference was not statistically significant
The increase in forearm blood flow during insulin infusion was 57% less in diabetic subjects compared to controls after adjusting for covariates age, BMI, MAP and HDL-cholesterol (Figure 1B)
Summary
Endothelial dysfunction has been associated with several disorders affecting the cardiovascular system, including type 2 diabetes, essential hypertension, hypercholesterolemia, obesity, atherosclerosis, coronary artery disease, and congestive heart failure [1–7]. In this context, we and others have recently demonstrated that L-arginine transport is impaired in both heart failure and hypertensive subjects with established endothelial dysfunction [8–10]. Insulin has been previously reported to exert vasodilator actions that are significantly attenuated when co-infused with the Larginine analogue, L-N-mono-methyl-arginine (LNMMA), which competitively antagonises the synthesis of NO [11] This has been interpreted to suggest that insulin increases blood flow by stimulating endothelium-derived NO production, the precise underlying mechanisms remain unclear. We hypothesised that insulin facilitates L-arginine transport, thereby augmenting endothelial function and inducing a NO-dependent vasorelaxant effect
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