In this paper we present an evaluation of portal versus peripheral routes for insulin delivery in diabetes with three representative closed-loop glucose control algorithms. A novel noninvasive approach is used which is based on a model of the blood glucose regulation system which simulates a Type I diabetic subject. The two routes and three algorithms are compared in controlling the simulated patient for 24 h, challenged with two dynamic glucose perturbations. The evaluation is performed by comparing both plasma accessible variables (e.g., glucose and insulin) and metabolic fluxes (e.g., glucose production and uptake, peripheral glucose utilization). Similar performances are achieved by the three algorithms both with peripheral and with portal infusions, especially in the postabsorptive steady state. An almost complete metabolic normalization is obtained with the portal route. With the peripheral route, normality is not restored; in particular, hyperinsulinemia and enhanced insulin-dependent glucose utilization are produced. From these simulation results, it is the site of insulin infusion, which appears to play an essential role in terms of the ability to normalize the metabolic state of a diabetic subject.