Vasodilator response to local hyperinsulinemia.

Vasodilator Response to Local Hyperinsulinemia To the Editor: Cardillo et al recently reported that systemic but not local hyperinsulinemia causes nitric oxide (NO)-dependent vasodilatation.1 They suggest that mechanisms stimulated only by systemic but not local hyperinsulinemia contribute to insulinmediated vasodilatation. We believe that this conclusion is mistaken. The changes in forearm blood flow during systemic and local hyperinsulinemia in their study were not directly comparable. Thus, although similar concentrations of insulin were achieved in both protocols, there was an artificial dissociation of insulin and glucose levels in the experiment with local hyperinsulinemia: in other words, no glucose supplement was administered in the local experiment, whereas euglycemia was maintained in the systemic study (using the clamp technique). It is likely, therefore, that glucose levels fell in the infused arm in the local experiment and that a discrepancy in forearm glucose uptake between the two conditions may have accounted for the different vasodilator responses to insulin observed. In support of this alternative explanation, we have consistently shown that intra-arterial infusion of insulin at 5 mU/min (resulting in insulin concentrations of 100 mU/mL in deep venous effluent sampled from the infused forearm), using a strict experimental protocol with a double-blind crossover design and measurement of forearm blood flow ratio (infused: control arm), causes detectable but weak vasodilatation (approximately 20%). In contrast, insulin at the same dose and supplemented by D-glucose at 75 mmol/min (maintaining local venous euglycemia) causes early and significant (50% to 60%) vasodilatation in the human forearm.2 This response is not replicated when the stereoisomer L-glucose (which is not recognized by glucose transporters) is substituted. Our results strongly suggest that insulin causes direct, locally-mediated vasodilatation that is dependent on local glucose uptake. Furthermore, glucosedependent insulin-mediated vasodilatation has been welldocumented in in vitro experiments3,4 There have been conflicting reports on the direct vascular actions of insulin. While several investigators have shown insulin-mediated vasodilatation during systemic hyperinsulinemia in euglycemic clamp studies, local administration of insulin has been reported to produce either no change in blood flow or only a small response. Our study clearly suggests that the discrepancy between systemic and local insulin administration may result from artificially low rates of local glucose availability and uptake in the latter.2 As under physiological circumstances, insulin is secreted by the B-cell in response to elevated glucose concentrations; however, concomitant hyperinsulinemia and hypoglycemia as used in the study by Castillo et al does not occur except when exogenous insulin is infused. We believe, therefore, that the local hyperinsulinemia model without concomitant D-glucose infusion is of questionable relevance in the investigation of the physiology of insulin’s vascular effects.