To ascertain whether the ability of glucose to influence the pancreatic islets response to a nonglucose stimulus is normal in type II diabetics, we have evaluated the modulating effect (Md) of the plasma glucose level (PG) on the acute insulin response (IRI) and glucagon response (IRG) to intravenous arginine in noninsulin-dependent diabetics (NIDDM) and nondiabetics (ND). MdIRI or MdIRG is the change in the hormonal response to arginine resulting from changes in plasma glucose level divided by the change in plasma glucose. Md has been determined over two ranges of PG: between normal fasting PG (level I) and mild hyperglycemia (∼160 mg/dl, level II) and between mild hyperglycemia and marked hyperglycemia (∼350 mg/dl, level III). Increases in PG augmented the IRI response in both groups, but the degree of augmentation was impaired in the NIDOM group. MDIRI, for ND and NIDDM between levels I and II were 20 ± 3 and 1.9 ± 0.6, respectively, and between levels II and III were 23 ± 5 and 2.3 ± 0.5, respectively (P < 0.01). MdIRI correlated with fasting PG in ND and NIDDM. Changes in PG resulted in equivalent changes in the IRG response to arginine in both groups. MdIRG for level I to II was −6.1 ±1.0 and −6.0 ± 1.2, and for level II and III was −0.9 ± 0.4 and −1.2 ± 0.5 in ND and NIDDM, respectively. The impairment of MDIRI and its relationship to fasting PG in NIDDM support the hypothesis that fasting hyperglycemia may be, in part, a compensatory mechanism for maintaining beta-cell response to nonglucose stimuli, thereby maintaining basal insulin levels. MdIRG was normal in NIDDM when evaluated at comparable glucose levels in the ND and NIDDM groups.