No abstract

Generation of long-chain fatty acids through hydrolysis of fat is a critical step for fat-induced stimulation of GLP-1 in humans; the signal is mediated via CCK release and CCK-1 receptors.

GLP-1 receptor antagonism slightly modulates appetite during ad libitum eating, but food and fluid intakes and meal duration remain unchanged, suggesting that endogenous GLP-1 is a weak satiation signal. However, concomitant substantial increases in plasma PYY and glucagon may counteract a desatiating effect of ex9-39. The effect of ex9-39 on PYY secretion supports an autoinhibitory feedback mechanism that controls L cell secretion; the effect on insulin and glucagon confirms the role of GLP-1 in glycemic control through its action on pancreatic α and β cells.

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.