Insulin clamp studies have shown that insulin’s suppressive actions on endogenous glucose production (EGP) are markedly more sensitive than that for stimulating glucose disposal. However, clamp conditions do not adequately mimic postprandial physiological responses. Here, in healthy subjects, using the variable infusion dual-tracer approach, we used a 3-fold range of ingested glucose doses (25, 50 and 75 g) to investigate how physiologic changes in plasma insulin influence EGP. Remarkably, the glucose responses were similar for all doses tested, yet there was a dose-dependent increase in insulin secretion and plasma insulin levels. Nonetheless, EGP was suppressed with the same rapidity and magnitude (~55%) across all doses. The progressive hyperinsulinemia, however, caused a dose-dependent increase in the estimated rates of glucose disposal which likely accounts for the lack of a dose-effect on plasma glucose excursions. This suggests that following glucose ingestion, the body preferentially permits a transient and optimal degree of postprandial hyperglycemia so as to efficiently enhance insulin-induced changes in glucose fluxes, thereby minimizing the demand for insulin secretion. This may represent an evolutionarily conserved mechanism that not only reduces the secretory burden on β-cells but also avoids the potential negative consequences of excessive insulin release into the systemic arterial circulation.