States of insulin resistance are characterized by hyperinsulinemia that often appears to be out of proportion to the minimal degree of hyperglycemia. One possible explanation for these findings is that mild hyperglycemia per se can cause an adaptive increase in islet sensitivity to glucose, leading to increased insulin output at a given glucose level. To test this hypothesis, we compared acute insulin responses (AIR) and acute glucagon responses (AGR) to 5-g arginine injections before and after 20-h glucose infusions (200 mg X m-2 X min-1) in 11 healthy men of varying age and degree of adiposity. The 20-h glucose infusion caused an increase in fasting plasma glucose (PG) in all subjects (95 +/- 2 vs. 130 +/- 3 mg/dl). PG was clamped at three levels (approximately 95, 165, and 235 mg/dl) before and after the 20-h glucose infusion. Despite matching of PG levels, consistent increases of AIR were observed after the 20-h glucose infusion: 86 +/- 10 vs. 57 +/- 8 at PG = 95 (P = 0.002); 241 +/- 20 vs. 192 +/- 22 at PG = 165 (P = 0.02); and 508 +/- 59 vs. 380 +/- 50 microU/ml at PG = 235 mg/dl (P = 0.009). In addition, the slope of the relationship between AIR and PG level (potentiation slope), a measure of B cell sensitivity to glucose, increased consistently from 2.28 +/- 0.35 (control) to 3.07 +/- 0.45 (P = 0.004) after the 20-h infusion.(ABSTRACT TRUNCATED AT 250 WORDS)