Mechanisms by which the amylin analog pramlintide reduces postprandial glucose (PPG) excursions in humans: Important role for splanchnic glucose sequestration

Pramlintide helps reduce PPG excursions by slowing gastric emptying (GE). PPG increases occur due to increases in the rate of glucose appearance. The latter is the sum of endogenous glucose production and the appearance of ingested glucose not been sequestered by the liver. Thus PPG reduction could result from greater suppression of endogenous glucose production or greater meal splanchnic sequestration.

Methods: Nine healthy subjects were studied (4M, 5F, 41 3 y, BW 84 3kg, BMI 27.8 1.1kg/m2). After 3-h primed continuous 13-C glucose infusion, 30µg pramlintide or placebo (PBO) were injected sc and subjects ate a mixed solid meal (450 kcal: 50g glucose, 25g fat and 20g protein), enriched with 3g 6,6-dideuteroglucose. Also, the meal was labelled to measure GE scintigraphically. Endogenous glucose production and splanchnic glucose sequestration were measured by double-isotope glucose enrichment technique.

Results: Starting with comparable glucose conc. (4.5 0.1 vs. 4.4 0.1mM, ns, PBO vs. verum), PPG excursions were greater over the initial 120min with PBO (5.2 0.1 vs. 4.8 0.1mM, p<0.001 PBO vs. verum). Insulin concentrations followed a similar pattern and were greater in PBO (48.0 4.3 vs. 23.9 4.2µU/ml, p<0.001). No differences in glucagon were found (53.7 4.7 vs. 52.8 5.2 pg/ml, ns). Despite lower PP insulin, PPG excursions were lower in the verum, corresponding to significant reduction in total plasma glucose appearance (24.6 1.3 vs. 18.5 1.4µmol/kg/min, p=0.007). Endogenous glucose production trended lower with PBO (6.2 0.6 vs. 8.7 0.9µmol/kg/min, p=0.05). Slowed GE in the verum arm (67.6 3.1 vs. 78.2 2.7 retention at 120min p<0.05) led to a reduction in the rate of appearance of the oral glucose (18.4 1.2 vs. 9.9 1.5µmol/kg/min, p<0.05) consistent with greater splanchnic sequestration of the meal despite lower insulin concentrations. Pramlintide was well tolerated.

Conclusion: Pramlintide reduced PPG excursions by slowing GE which led to greater splanchnic sequestration of the meal and reduced plasma glucose. We suggest the gastric emptying rate as major determinant of post-prandial splanchnic glucose sequestration.