OBJECTIVE -Slowing of gastric emptying by hyperglycemia, a physiological response to minimize postprandial hyperglycemia, may be impaired in patients with type 1 diabetes. The causes and consequences on glucose homeostasis are unknown.RESEARCH DESIGN AND METHODS -Consequences of euglycemia-and hyperglycemia-induced changes in gastric emptying on postprandial glucose fluxes and excursions were studied in 10 healthy subjects and 15 type 1 diabetic subjects after ingestion of a mixed meal using the double isotope approach ([6,6-2 H 2 ] and [1-13 C]glucose) and scintigraphic measurements of gastric emptying.RESULTS -Gastric emptying was greater in type 1 diabetic subjects (90 -120 min, P Ͻ 0.03), and 50% retention times were comparable in healthy subjects and type 1 diabetic subjects (167 Ϯ 8 vs. 152 Ϯ 10, P ϭ 0.32). Hyperglycemia markedly delayed gastric emptying in healthy subjects but did not alter it in type 1 diabetic subjects (50% retention time 222 Ϯ 18 vs. 167 Ϯ 8 min, P ϭ 0.003 and 148 Ϯ 9 vs. 152 Ϯ 10 min, P ϭ 0.51). Plasma islet amyloid polypeptide (IAPP) increased approximately fourfold in healthy subjects (P Ͻ 0.001), whereas it was undetectable in type 1 diabetic subjects. IAPP replacement, using the analog pramlintide, in type 1 diabetic subjects slowed gastric emptying to a comparable extent, as did hyperglycemia in healthy subjects (P Ͻ 0.14), and greatly reduced postprandial hyperglycemia (P Ͻ 00.1). Mealderived glucose appearance in plasma (10.7 Ϯ 0.5 vs. 6.8 Ϯ 0.7 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.001) was reduced, and splanchnic glucose sequestration increased (14.0 Ϯ 3.0 vs. 25.0 Ϯ 6.0%, P ϭ 0.04).CONCLUSIONS -In patients with type 1 diabetes the ability to delay gastric emptying in response to hyperglycemia is impaired. This impairment contributes to exaggerated rates of meal-derived glucose appearance and, ultimately, postprandial glucose excursions.