The objective of this study was to examine the effect of serum glucose concentration on interdigestive gastrointestinal motility and plasma motilin levels in humans. Motility studies were performed for a 3-h baseline period and a 3-h test period during which serum glucose levels were maintained with a glucose clamp at 250, 175, 140, or 120 mg/dl. During the basal recording, three phases of the interdigestive migrating motor complex (MMC) were easily recognizable, with a mean cycle duration of 97 +/- 12 min. Plasma motilin levels fluctuated in phase with the MMC. Gastric contractions were nearly absent at a serum glucose level of 250 mg/dl and markedly reduced at 175 and 140 mg/dl. Gastric phase III activity was inhibited during these infusions. Gastric contractions and phase III activity were not affected by glucose infusion at 120 mg/dl. In contrast, the frequency of duodenal phase III activity was unchanged at all levels of glucose infusion. Mean motilin levels were significantly reduced during glucose infusion at 250 and 175 mg/dl (p less than 0.05), but not at 140 and 120 mg/dl. We conclude that hyperglycemia inhibits the occurrence of the MMC in the stomach and suppresses plasma motilin levels. The differential sensitivity of motility and motilin concentration to different degrees of hyperglycemia suggests that hyperglycemia can inhibit antral motility independent of plasma motilin. In contrast, the duodenal MMC appears to be insensitive to hyperglycemia. This suggests that the antral and duodenal MMCs are mediated by different mechanisms. Our observations indicate the importance of serum glucose in regulating gastric motility.