Insulin resistance has been demonstrated both in insulin deficiency and insulin excess in man and in animals. This study was carried out in normal man to evaluate the role of insulinopenia in the pathogenesis of insulin resistance. Insulin suppression was obtained by 4 h somatostatin (SRIF) infusion. Insulin receptors on circulating monocytes were evaluated before and after SRIF infusion; an insulin tolerance test (ITT) was performed after SRIF, saline or SRIF and replacing basal insulin secretion. Insulin binding to circulating monocytes did not change after 4 h insulinopenia (2.19 ± 0.30 vs. 2.35 ± 0.80%), while insulin sensitivity appeared decreased after SRIF (K<sub>ITT</sub> = 0.97 ± 0.13) as compared with saline (K<sub>ITT</sub> = 3.30 ± 0.42), and this effect was prevented by insulin (K<sub>ITT</sub> = 2.46 ± 0.38). A relationship was detected between K<sub>ITT</sub> and plasma insulin concentration before ITT (r = 0.85, p < 0.01), suggesting that insulin deficiency is the main cause of the phenomenon observed. The present data suggest that basal insulin concentration plays an essential role in the control of insulin sensitivity. If insulin binding on monocytes mimics the behavior of major insulin target tissues, it is possible that the impaired insulin action after 4 h of insulin deficiency is related to a post binding effect.