We have examined the effect of an acute stable hyperglycemia on gastric acid secretion during the gastric phase of digestion. Gastric acid output was measured with a recovery marker (phenol red) under basal conditions and after repeated intragastric instillation of a liquid meal in seven healthy subjects on two separate occasions: during normoglycemia (serum glucose, 15 mM). Premeal gastric acid output was significantly (P < 0.05) reduced during hyperglycemia compared with during normoglycemia (2.6 +/- 1.0 vs. 5.8 +/- 1.8 mmol/h). Intragastric meal-stimulated incremental acid output during hyperglycemia was significantly (P < 0.05) reduced compared with during normoglycemia (19 +/- 4 vs. 38 +/- 9 mmol/120 min). Meal-stimulated gastrin release during hyperglycemia was significantly (P < 0.05) reduced compared with that during normoglycemia (4.9 +/- 1.3 vs. 6.6 +/- 1.6 micrograms.1(-1).120 min-1). The intragastric meal induced significant (P < 0.05) increases in pancreatic polypeptide concentrations only during normoglycemia. During hyperglycemia, recovery rates of gastric contents were significantly (P < 0.05) increased compared with during normoglycemia, both before (81 +/- 4 vs. 71 +/- 6%) and after (72 +/- 4 vs. 57 +/- 4%) meal ingestion, pointing to delayed gastric emptying of liquids during hyperglycemia. In conclusion, 1) gastric acid secretion under unstimulated conditions and during the gastric phase of digestion is reduced during hyperglycemia; 2) meal-stimulated gastrin release is significantly reduced during hyperglycemia; 3) the reduction in meal-stimulated acid output is correlated with the reduction in gastrin releases; and 4) pancreatic polypeptide secretion is significantly reduced during hyperglycemia, pointing to impaired vagal cholinergic tone.