Objective: Regulation of postprandial (pp) plasma glucose excursions is complex. Insulin and glucagon are thought to play the predominant role. Nevertheless, only 50% of the variation in pp plasma glucose excursions is explained by variations by the latter. Theoretically, gastric emptying (GE) should be another important factor. However, its impact on pp glucose homeostasis is unknown. Research Design and Methods: We examined the consequences of pramlintide-induced delay in GE on pp glycemia and glucose fluxes, determined isotopically. GE was recorded by scintigraphy. Fourteen healthy subjects (8 men, 6 women; age 40 ± 3 yr, body mass index 27.8 ± 1.1 kg/m2) ate a mixed meal, and 30 μg of pramlintide (PRAM) or placebo (PBO) were injected subcutaneously. Results: At 60 min, greater proportions of the initial gastric contents remained in the stomach (PBO vs. PRAM). Thereafter, GE slopes paralleled until 240 min. Fifty percent retention times were lower when PBO was given ( P < 0.001). GE was greater from 240 min to the end of the PRAM experiments, so that only slightly greater proportions of the meal remained in the stomach at 330 min. Reductions of GE lowered pp glucose (7.5 ± 0.3 vs. 6.0 ± 0.2 mmol/l, P < 0.001), even though plasma insulin was lower with PRAM (164 ± 13 vs. 138 ± 13 pmol/ml, both P < 0.01). Reduction in total glucose appearance ( P < 0.001) was due to reduced meal-derived glucose appearance (10.2 ± 0.5 vs. 7.0 ± 0.4 μmol·kg−1·min−1, P < 0.001). Endogenous glucose appearance was greater with PRAM ( P < 0.001). Splanchnic glucose uptake was greater with PRAM (26.5 ± 1.6 vs. 32.5 ± 2.1%, P = 0.014). Conclusions: These data support the concept that GE is an important physiological regulator of pp glucose homeostasis in humans.

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.

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